WO2004026905A2

WO2004026905A2 - Transporter/channel proteins

Info

Publication number: WO2004026905A2
Application number: PCT/GB2003/004014
Authority: WO
Inventors: Anna Elizabeth Lobley; David Michalovich; Valerie Nathalie Pierron; Kirsty Louisa-Jane Leake
Original assignee: Inpharmatica Limited
Priority date: 2002-09-17
Filing date: 2003-09-17
Publication date: 2004-04-01
Also published as: AU2003271848A1; AU2003271848A8; WO2004026905A3

Abstract

This invention relates to novel proteins (termed INPIONCH07, INPIONCH08, INPIONCH09 and INPIONCH10), herein identified as transporter/channel proteins and to the use of these proteins and nucleic acid sequences from the encoding genes in the diagnosis, prevention and treatment of disease.

Description

TRANSPORTER/CHANNEL PROTEINS

This invention relates to novel proteins (termed LNPIONCH07, INPIONCH08, INPIONCH09 and INPIONCHIO), herein identified as transporter/channel proteins and to the use of these proteins and nucleic acid sequences from the encoding genes in the diagnosis, prevention and treatment of disease.

All publications, patents and patent applications cited herein are incorporated in full by reference.

BACKGROUND

The process of drug discovery is presently undergoing a fundamental revolution as the era of functional genomics comes of age. The term "functional genomics" applies to an approach utilising bioinformatics tools to ascribe function to protein sequences of interest. Such tools are becoming increasingly necessary as the speed of generation of sequence data is rapidly outpacing the ability of research laboratories to assign functions to these protein sequences.

As bioinformatics tools increase in potency and in accuracy, these tools are rapidly replacing the conventional techniques of biochemical characterisation. Indeed, the advanced bioinformatics tools used in identifying the present invention are now capable of outputting results in which a high degree of confidence can be placed.

Various institutions and commercial organisations are examining sequence data as they become available and significant discoveries are being made on an on-going basis. However, there remains a continuing need to identify and characterise further genes and the polypeptides that they encode, as targets for research and for drug discovery.

Background to transporters

Sodium/Hydrogen exchangers or 'antiporters' are diverse multi-domain proteins possessing an N-tenninal transmembrane domain and a large and variable intracellular C-terminal domain. Na⁺/H⁺ antiporters are usually expressed in a wide range of tissues and cell types and their functional roles involve maintenance of cytosolic pH levels and cellular volume. The transmembrane domain is thought to contain between 10-12 transmembrane helices and of these M6 and M7 are the most conserved. Reviews of the Na⁺ H⁺ antiporter family suggest that these proteins may act as ho odimers (Orlowski, J and Grinstein, S. (1997) Na+ H+ Exchangers of Mammalian Cells, JBC 272;36:22373-22376). Na⁺/H⁺ antiporters respond to a threshold level of intracellular pH. Once this level is reached, acid is rapidly extruded from the cell. Deletion mutagenesis studies have indicated that the N- terminal transmembrane domain contains site(s) responsible for pH sensing and that a mechanism present in the C-terminal domain determines the threshold pH level at which the antiporter will operate (Wakabayas i, S et al. The Na+/H+ antiporter cytoplasmic domain mediates growth factor signals and controls "H(+)-sensing", PNAS 89:2424-2428). ATP is required for optimal exchange between Na⁺ and H⁺ ions, although ion flux is driven by the combined gradients of Na⁺ and H ions.

Background to ion channel ion transport domains The ionic transport domain is present in a wide range of mainly voltage-gated and a few ligand-gated cation transporting ion channel families. The domain contains 6 transmembrane helices designated S1-S6. The S4 transmembrane region acts as a voltage sensor and features regular repeating positively charged amino acids throughout a hydrophobic transmembrane helix. The region between S5-S6 is termed the P loop and contributes to the pore region through the membrane.

Four copies of the ionic transport domain associate to form functional ion channels. The domain is found in four repeating copies within voltage-gated Calcium and Sodium channel subunits. Voltage-gated potassium channels on the other hand are composed of four pore forming subunits each containing a single copy of the ionic transport domain. The cyclic nucleotide gated ion channels (see below) are also tetrameric ion channels, with four copies of the domain in each subunit. These channels cannot be activated in the absence of cyclic nucleotide, however, it has been shown that the HCN pacemaker channel is sensitive to both voltage and cyclic nucleotide gating effects (Yellen et al. Voltage Gated K channels and their Relatives, (2002) Nature Review Vol. 419 Sept 5th 35-42). Background to cyclic nucleotide binding domains

The cyclic nucleotide binding domain is found in a variety of protein families including the cyclic nucleotide-gated ion channels, cAMP dependent and cGMP dependent protein kinases and the prokaryotic catabolite activator proteins. The prokaryotic catabolite gene activator cyclic nucleotide binding site is dimeric and is the most well studied of the cyclic nucleotide binding domain containing proteins. Each monomer is composed of three alpha-helices and a distinctive eight-stranded, antiparallel beta-barrel structure. There are three invariant glycine residues thought to be essential for maintaining the scaffold of the beta barrel structure. Cyclic nucleotide-gated ion channel subunits contain a cyclic nucleotide binding domain at their C-terminal and an ion transport domain N-terminal to this. The cyclic nucleotide-gated channels are tetrameric and the binding domain is active as a monomer. Binding of 3-4 molecules of intracellular cAMP or cGMP is enough to cause channel activation and opening (He, Y. et al. (2001) Probing the Interactions between cAMP and cGMP in Cyclic Nucleotide-Gated Channels Using Covalently Tethered Ligands, Biochemistry, 40, 286-295).

Disease relevance

Members of the Na /H⁺ antiporter transmembrane domain family are drug targets for inhibition by the diuretic amiloride (Orlowski, J. and Grinstein, S. (1997) Na+/H+ Exchangers of Mammalian Cells, JBC, 272, 36:22373-22376), by amiloride analogues and by benzoyl guanidinium compounds. Na⁺/H⁺ antiporter blockade inhibits enterocyte inflammatory response and protects against colitis (Nemeth, Z.H. et al. (2002) Jun;18(6):667- 672) and also prevents hypertrophy, fibrosis, and heart failure in beta(l)-adrenergic receptor transgenic mice (Engelhardt et al 2002 April 19; 90(7):814-9). The effects of SMP-300, a potent and selective Na⁺/H⁺ exchange inhibitor, were recently investigated in three experimental angina models and on myocardial infarction in rats. The results show reduced myocardial infarct size after 40 min of coronary artery occlusion and provide support for the potential use of Na^"1"/!!^1" exchangers as targets of anti-anginal drugs with a novel mode of action. (Yamamoto, S. et al. J. Cardiovasc. Pharmacol., (2002) Feb;39(2):234-41).

Na⁺/H⁺ exchanger activity is also suggested as a linking component between obesity, hyperinsulinemia and vascular disease (Kaloyianni, M. et al. Cell Physiol. Biochem., (2001) l l(5):253-8). Radiation hybrid mapping of the NHE exchanger genes has indicated that NHE5 may contribute to genetic susceptibility in end-stage renal disease (Yu H, Freedman BI, Rich SS, Bowden DW. Human Na+/H+ exchanger genes: identification of polymorphisms by radiation hybrid mapping and analysis of linkage in end-stage renal disease. Hypertension. 2000 Jan;35(l Pt l):135-43).

The acrosome reaction is characterised by various signal transduction events including Ca²⁺,

Na , H⁺ and K transportation, cyclic nucleotide changes and protein kinase C activation, the precise sources of which remain unknown (Hughes et al, Hum. Mol. Genet., 1999, 8(3):543-

9). Modulation of the acrosome reaction in humans would be of great importance in reproductive health, since it would allow new forms of infertility remedies or contraceptive methods to be devised.

The identification of proteins containing transporter domains, ionic transport domains and cyclic nucleotide binding domains is therefore of extreme importance in increasing the understanding of the underlying pathways that lead to certain disease states and associated conditions, particularly those mentioned above, and in developing more effective gene and/or drug therapies to treat these disorders, and also in increasing the understanding of the pathways involved in mammalian reproductive biology.

THE INVENTION

The invention is based on the discovery that the LNPIONCH07, INPIONCH08, LNPIONCH09 and INPIONCHIO proteins function as transporter/channel proteins.

LNPIONCH07 and LNPIONCH08 are orthologous sequences. LNPIONCH07 is found on human chromosomelq25.1 and LNPIONCH08 is found in the syntenic region on mouse chromosome 1. These sequences share 70% identity over their full lengths and are both orthologues of two overlapping testis specific macaque cDNA clones (Genbank Accessions: AB070051.1 and AB072793.1). The sequence identity of the human INPIONCH07 sequence and both macaque cDNA clones is >94% at the nucleotide level. The sequences given in Genbank Accession Nos. AB070051.1 and AB072793.1 and translation products thereof are specifically excluded from the scope of the present invention.

LNPIONCH09 and INPIONCHIO are paralogues of INPIONCH07 and INPIONCH08 respectively. They share a common domain structure and their sequence identity is ~40% over their full lengths at the amino acid level. INPIONCH09 is located on human chromosome 3 at cytogenetic locus ql3.2 and INPIONCHIO is found within a syntenic region on mouse chromosome 16. INPIONCH09 and INPIONCHIO share 60% sequence identity their over full length. A macaque cDNA (Genbank accession: AB070087.1) from a testis library has also been identified covering part of INPIONCHIO and LNPIONCH09. The sequence given in Genbank Accession No. AB070087.1 and translation products thereof are specifically excluded from the scope of the present invention. That macaque testis specific cDNA sequences have been identified provides further evidence towards the existence of this novel family of transporter/channel proteins. Two overlapping cDNA sequences cover the full length of LNPIONCH07 and part of LNPIONCH08 high quality sequences, and a third cDNA clone partially covers the LNPIONCH09 and fully the INPIONCHIO high quality cDNA sequences (SEQ ID NOs: 175-182). The fact that the macaque cDNAs were cloned from a testis library suggests a role for these transporter/channel proteins in fertilisation, sperm maturation and or development and possibly sperm motility. For example, many events leading up to or during fertilisation are as yet uncharacterized; the acrosome reaction is characterised by various signal transduction events including Ca2⁺, Na⁺, FT^1" and K⁺ transportation, cyclic nucleotide changes and protein kinase C activation, the precise sources of which remain unknown (Hughes et al., Hum. Mol. Genet, 1999, 8(3):543-9).

LNPIONCH07, INPIONCH08, LNPIONCH09 and INPIONCHIO together represent a novel gene family of multipass membrane proteins, herein described as 'transporter/channel protein(s)'. Each sequence contains an N-terminal partial transporter (Na⁺/H⁺ exchanger)-like domain, a partial ionic transport domain of the type usually associated with voltage-gated cation channels, and a C-terminal cyclic nucleotide monophosphate binding domain.

The Na⁺/H⁺ antiporter domain is functionally ill-defined. The Na⁺ binding site remains unassigned and the mechanism of pH sensing is undocumented. Transporter/channel proteins LNPIONCH07, INPIONCH08, INPIONCH09 and INPIONCHIO contain the latter half of this domain, which is reportedly important in sensing internal pH and binding Na⁺; there are reports of a truncated rat variant NHE2 cDNA sequence lacking the N terminal 116 residues of the Na⁺/H⁺ antiporter transmembrane domain (Collins, J.F. et al, (1993) May 1;90(9):3938- 42). The existence of this functional rat cDNA clone provides evidence that the truncated domain reported for the novel transporter/channel protein family has retained the capacity to sense pH and to transport protons across the membrane. LNPIONCH07, LNPIONCH08, INPIONCH09 and INPIONCHl 0 also possess transmembrane regions S1-S4 of the ionic transport domain found in multiple cation transporting ion channel families. Recent reviews of the K channel superfamily suggest that S1-S4 together make up the voltage sensor domain and that positively charged residues in S4 are critical for this function (Yellen et al. Voltage Gated K channels and their Relatives, (2002) Nature Vol. 419 pp 35-42). Sensing domains, whether ligand binding sites or voltage recognition sites, are usually multimeric. The cyclic nucleotide monophosphate binding domain is present at the C-terminal of each of the transporter/channel protein polypeptide sequences analogous to those present in the cyclic nucleotide gated ion channels.

Thus, LNPIONCH07, INPIONCH08, INPIONCH09 and INPIONCHIO are novel multidomain containing proteins. Sequence analysis and domain structure strongly suggest a role for these proteins in transportation of protons across the membrane in response to either cyclic nucleotide binding events and/or sensing of internal pH or voltage. It may be that, like the HCN pacemaker channel, ion transport can be regulated by voltage or by ligand, or like the CNG channels (Yellen et al. Voltage Gated K channels and their Relatives, (2002) Nature Vol. 419 pp 35-42), they may be insensitive to voltage. The physical exchange of Na li ^" ions is likely to be carried out by the Na⁺/H⁺ partial antiporter domain. These sequences may act as monomers or as multimeric protein complexes to perform their cellular roles.

In a first embodiment of the first aspect of the invention, there is provided a polypeptide which: (i) comprises or consists of the amino acid sequence as recited in SEQ ID NO: 2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:42 and/or SEQ ID NO:176;

(ii) is a fragment thereof having the activity of a polypeptide according to (i), or having an antigenic determinant in common with a polypeptide according to (i); or

(iii) is a functional equivalent of (i) or (ii).

By "the activity of a polypeptide according to (i)", we refer to activity characteristic of a transporter/channel protein. Thus, a transporter/channel protein may have one or more functions that are characteristic of domains selected from the group consisting of i) a Na⁺/H⁺ exchanger, ii) an ionic transport domain, preferably a voltage-gated cation channel and iii) a cyclic nucleotide monophospate binding domain. Preferably, a transporter/channel protein of the present invention has functions characteristic of two or more of these domains. More preferably, a transporter/channel protein of the present invention has functions characteristic of all three of these domains. The polypeptide having the sequence recited in SEQ ID NO:2 is referred to hereafter as "the LNPIONCH07 exon 1 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:4 is referred to hereafter as "the LNPIONCH07 exon 2 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:6 is referred to hereafter as "the LNPIONCH07 exon 3 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:8 is referred to hereafter as "the INPIONCH07 exon 4 polypeptide". The polypeptide having the sequence recited in SEQ ID NO: 10 is referred to hereafter as "the INPIONCH07 exon 5 polypeptide". The polypeptide having the sequence recited in SEQ ID NO: 12 is referred to hereafter as "the INPIONCH07 exon 6 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:14 is referred to hereafter as "the LNPIONCH07 exon 7 polypeptide". The polypeptide having the sequence recited in SEQ ID NO: 16 is referred to hereafter as "the LNPIONCH07 exon 8 polypeptide". The polypeptide having the sequence recited in SEQ ID NO: 18 is referred to hereafter as "the INPIONCH07 exon 9 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:20 is referred to hereafter as "the INPIONCH07 exon 10 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:22 is referred to hereafter as "LNPIONCH07 exon 11 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:24 is referred to hereafter as "INPIONCH07 exon 12 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:26 is referred to hereafter as "INPIONCH07 exon 13 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:28 is referred to hereafter as "INPIONCH07 exon 14 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:30 is referred to hereafter as "INPIONCH07 exon 15 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:32 is referred to hereafter as "LNPIONCH07 exon 16 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:34 is referred to hereafter as "INPIONCH07 exon 17 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:36 is referred to hereafter as "LNPIONCH07 exon 18 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:38 is referred to hereafter as "LNPIONCH07 exon 19 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:40 is referred to hereafter as "INPIONCH07 exon 20 polypeptide". Combining SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ LD NO:32, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38 and SEQ ID NO:40 produces the sequence recited in SEQ ID NO:42. The polypeptide having the sequence recited in SEQ ID NO:42 is referred to hereafter as the "LNPIONCH07 polypeptide".

The polypeptide having the sequence recited in SEQ ID NO: 176 is referred to hereafter as the "INPIONCH07 high quality polypeptide". However, as there are only 20 exons in INPIONCH07, it is possible that there may be one, two, three or more further exons that will provide amino acids that are N-terminal to the beginning of the sequence given in SEQ ID NO:42. Thus, a polypeptide of the present invention preferably comprises the amino acid sequence given in SEQ ID NO. -42 but may also include additional N-terminal amino acid residues. Furthermore, it is possible that the LNPIONCH07 exon 1 polypeptide in fact represents only part of an exon within a larger exon. Thus, it is possible that the sequence of the INPIONCH07 exon 1 polypeptide contains 1, 2, 3 or more amino acids N-terminal to those given in SEQ ID NO:2.

Splice variants of the INPIONCH07 exon 1 polypeptide, the LNPIONCH07 exon 2 polypeptide, the LNPIONCH07 exon 3 polypeptide, the LNPIONCH07 exon 4 polypeptide, the LNPIONCH07 exon 5 polypeptide, the INPIONCH07 exon 6 polypeptide, the INPIONCH07 exon 7 polypeptide, the INPIONCH07 exon 8 polypeptide, the LNPIONCH07 exon 9 polypeptide, the LNPIONCH07 exon 10 polypeptide, the INPIONCH07 exon 11 polypeptide, the INPIONCH07 exon 12 polypeptide, the LNPIONCH07 exon 13 polypeptide, the INPIONCH07 exon 14 polypeptide, the LNPIONCH07 exon 15 polypeptide, the INPIONCH07 exon 16 polypeptide, the INPIONCH07 exon 17 polypeptide, the LNPIONCH07 exon 18 polypeptide, the LNPIONCH07 exon 19 polypeptide, the LNPIONCH07 exon 20 polypeptide and the INPIONCH07 polypeptide are also encompassed by the first embodiment of the first aspect of the present invention.

The term "LNPIONCH07 exon polypeptides" as used herein includes polypeptides comprising or consisting of the LNPIONCH07 exon 1 polypeptide, the LNPIONCH07 exon 2 polypeptide, the LNPIONCH07 exon 3 polypeptide, the INPIONCH07 exon 4 polypeptide, the LNPIONCH07 exon 5 polypeptide, the INPIONCH07 exon 6 polypeptide, the LNPIONCH07 exon 7 polypeptide, the LNPIONCH07 exon 8 polypeptide, the LNPIONCH07 exon 9 polypeptide, the LNPIONCH07 exon 10 polypeptide, the LNPIONCH07 exon 11 polypeptide, the LNPIONCH07 exon 12 polypeptide, the LNPIONCH07 exon 13 polypeptide, the LNPIONCH07 exon 14 polypeptide, the LNPIONCH07 exon 15 polypeptide, the INPIONCH07 exon 16 polypeptide, the LNPIONCH07 exon 17 polypeptide, the LNPIONCH07 exon 18 polypeptide, the INPIONCH07 exon 19 polypeptide, the LNPIONCH07 exon 20 polypeptide or the INPIONCH07 polypeptide.

In a second embodiment of the first aspect of the invention, there is provided a polypeptide which: (i) comprises or consists of the amino acid sequence as recited in SEQ ID NO:44, SEQ ID NO:46, SEQ ID NO:48, SEQ ID NO:50, SEQ ID NO:52, SEQ ID NO:54, SEQ ID NO:56, SEQ ID NO:58, SEQ LD NO:60, SEQ ID NO:62, SEQ ID NO:64, SEQ ID NO:66, SEQ ID NO:68, SEQ ID NO:70, SEQ ID NO:72, SEQ ID NO:74, SEQ ID NO:76, SEQ ID NO:78, SEQ ID NO:80, SEQ ID NO:82, SEQ ID NO:84, SEQ ID NO:86 and/or SEQ ID NO: 178;

(iii) is a functional equivalent of (i) or (ii).

By "the activity of a polypeptide according to (i)", we refer to activity characteristic of a transporter/channel protein, as discussed above.

The polypeptide having the sequence recited in SEQ ID NO:44 is referred to hereafter as "the LNPIONCH08 exon 1 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:46 is referred to hereafter as "the LNPIONCH08 exon 2 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:48 is referred to hereafter as "the INPIONCH08 exon 3 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:50 is referred to hereafter as "the LNPIONCH08 exon 4 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:52 is referred to hereafter as "the LNPIONCH08 exon 5 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:54 is referred to hereafter as "the INPIONCH08 exon 6 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:56 is referred to hereafter as "the LNPIONCH08 exon 7 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:58 is referred to hereafter as "the LNPIONCH08 exon 8 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:60 is referred to hereafter as "the LNPIONCH08 exon 9 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:62 is referred to hereafter as "the LNPIONCH08 exon 10 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:64 is referred to hereafter as "the LNPIONCH08 exon 11 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:66 is referred to hereafter as "INPIONCH08 exon 12 polypeptide". The polypeptide having the sequence recited in SEQ ID NO: 68 is referred to hereafter as "INPIONCH08 exon 13 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:70 is referred to hereafter as "INPIONCH08 exon 14 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:72 is referred to hereafter as "LNPΪONCH08 exon 15 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:74 is referred to hereafter as "LNPIONCH08 exon 16 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:76 is referred to hereafter as "LNPIONCH08 exon 17 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:78 is referred to hereafter as "INPIONCH08 exon 18 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:80 is referred to hereafter as "INPIONCH08 exon 19 polypeptide". The polypeptide having the sequence recited in SEQ ID NO: 82 is referred to hereafter as "LNPIONCH08 exon 20 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:84 is referred to hereafter as "LNPIONCH08 exon 21 polypeptide". Combining SEQ ID NO:44, SEQ ID NO:46, SEQ ID NO:48, SEQ ID NO:50, SEQ ID NO:52, SEQ ID NO:54, SEQ ID NO:56, SEQ ID NO:58, SEQ ID NO:60, SEQ ID NO:62, SEQ ID NO:64, SEQ ID NO:66, SEQ ID NO:68, SEQ ID NO:70, SEQ ID NO:72, SEQ ID NO:74, SEQ ID NO:76, SEQ ID NO:78, SEQ ID NO:80, SEQ ID NO:82 and SEQ ID NO:84, produces the sequence recited in SEQ ID NO:86. The polypeptide having the sequence recited in SEQ ID NO:86 is referred to hereafter as the "INPIONCH08 polypeptide".

The polypeptide having the sequence recited in SEQ ID NO: 178 is referred to hereafter as the "LNPIONCH08 high quality polypeptide sequence".

It is possible that there may be one, two, three or more further exons that will provide amino acids that are N-terminal to the beginning of the sequence given in SEQ ID NO:86. Thus, a polypeptide of the present invention preferably comprises the amino acid sequence given in SEQ ID NO: 86 but may also include additional N-terminal amino acid residues. Furthermore, it is possible that the INPIONCH08 exon 1 polypeptide in fact represents only part of an exon within a larger exon. Thus, it is possible that the sequence of the LNPIONCH08 exon 1 polypeptide contains 1, 2, 3 or more amino acids N-terminal to those given in SEQ ID NO:44. Splice variants of the INPIONCH08 exon 1 polypeptide, the INPIONCH08 exon 2 polypeptide, the INPIONCH08 exon 3 polypeptide, the LNPIONCH08 exon 4 polypeptide, the LNPIONCH08 exon 5 polypeptide, the LNPIONCH08 exon 6 polypeptide, the INPIONCH08 exon 7 polypeptide, the LNPIONCH08 exon 8 polypeptide, the INPIONCH08 exon 9 polypeptide, the LNPIONCH08 exon 10 polypeptide, the LNPIONCH08 exon 11 polypeptide, the INPIONCH08 exon 12 polypeptide, the LNPIONCH08 exon 13 polypeptide, the LNPIONCH08 exon 14 polypeptide, the LNPIONCH08 exon 15 polypeptide, the LNPIONCH08 exon 16 polypeptide, the LNPIONCH08 exon 17 polypeptide, the INPIONCH08 exon 18 polypeptide, the LNPIONCH08 exon 19 polypeptide, the INPIONCH08 exon 20 polypeptide and the LNPIONCH08 exon 21 polypeptide are also encompassed by the second embodiment of the first aspect of the present invention.

The term "LNPIONCH08 exon polypeptides" as used herein includes polypeptides comprising or consisting of the LNPIONCH08 exon 1 polypeptide, the LNPIONCH08 exon 2 polypeptide, the LNPIONCH08 exon 3 polypeptide, the LNPIONCH08 exon 4 polypeptide, the

LNPIONCH08 exon 5 polypeptide, the LNPIONCH08 exon 6 polypeptide, the LNPIONCH08 exon 7 polypeptide, the INPIONCH08 exon 8 polypeptide, the INPIONCH08 exon 9 polypeptide, the LNPIONCH08 exon 10 polypeptide, the LNPIONCH08 exon 11 polypeptide, the LNPIONCH08 exon 12 polypeptide, the LNPIONCH08 exon 13 polypeptide, the

LNPIONCH08 exon 14 polypeptide, the LNPIONCH08 exon 15 polypeptide, the

LNPIONCH08 exon 16 polypeptide, the LNPIONCH08 exon 17 polypeptide, the

LNPIONCH08 exon 18 polypeptide, the LNPIONCH08 exon 19 polypeptide, the

LNPIONCH08 exon 20 polypeptide, the INPIONCH08 exon 21 polypeptide or the LNPIONCH08 polypeptide.

In a third embodiment of the first aspect of the invention, there is provided a polypeptide which:

(i) comprises or consists of the amino acid sequence as recited in SEQ ID NO:88, SEQ ID

NO 90, SEQ ID NO ):92, SEQ ID NO:94, SEQ ID NO 96, SEQ ID NO 98, SEQ ID NO 100, SEQ ID NO ):102, SEQ ID NO: 104, SEQ ID NO 106, SEQ ID NO 108, SEQ ID

NO 110, SEQ ID NO ): 112, SEQ ID NO: 114, SEQ LD NO 116, SEQ ID NO 118, SEQ ID NO 120, SEQ ID NO ):122, SEQ ID NO:124, SEQ ID NO 126, SEQ LD NO 128, SEQ ID NO: 130, or SEQ ID NO: 180;

(ϋ) is a fragment thereof having the activity of a polypeptide according to (i), or having an antigenic determinant in common with a polypeptide according to (i); or

(iϋ) is a functional equivalent of (i) or (ii). By "the activity of a polypeptide according to (i)", we refer to activity characteristic of a transporter/channel protein.

The polypeptide having the sequence recited in SEQ ID NO: 88 is referred to hereafter as "the INPIONCH09 exon 1 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:90 is referred to hereafter as "the LNPIONCH09 exon 2 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:92 is referred to hereafter as "the LNPIONCH09 exon 3 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:94 is referred to hereafter as "the LNPIONCH09 exon 4 polypeptide". The polypeptide having the sequence recited in SEQ ID NO: 96 is referred to hereafter as "the LNPIONCH09 exon 5 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:98 is referred to hereafter as "the LNPIONCH09 exon 6 polypeptide". The polypeptide having the sequence recited in SEQ ID NO: 100 is referred to hereafter as "the INPIONCH09 exon 7 polypeptide". The polypeptide having the sequence recited in SEQ ID NO: 102 is referred to hereafter as "the LNPIONCH09 exon 8 polypeptide". The polypeptide having the sequence recited in SEQ ID NO: 104 is referred to hereafter as "the INPIONCH09 exon 9 polypeptide". The polypeptide having the sequence recited in SEQ ID NO: 106 is referred to hereafter as "the LNPIONCH09 exon 10 polypeptide". The polypeptide having the sequence recited in SEQ ID NO: 108 is referred to hereafter as "the LNPIONCH09 exon 11 polypeptide". The polypeptide having the sequence recited in SEQ ID NO: 110 is referred to hereafter as "INPIONCH09 exon 12 polypeptide". The polypeptide having the sequence recited in SEQ ID NO.T 12 is referred to hereafter as "LNPIONCH09 exon 13 polypeptide". The polypeptide having the sequence recited in SEQ ID NO: 114 is referred to hereafter as "INPIONCH09 exon 14 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:116 is referred to hereafter as 'TNPIONCH09 exon 15 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:118 is referred to hereafter as "INPIONCH09 exon 16 polypeptide". The polypeptide having the sequence recited in SEQ ID NO: 120 is referred to hereafter as "LNPIONCH09 exon 17 polypeptide". The polypeptide having the sequence recited in SEQ ID NO: 122 is referred to hereafter as "LNPIONCH09 exon 18 polypeptide". The polypeptide having the sequence recited in SEQ ID NO: 124 is referred to hereafter as "INPIONCH09 exon 19 polypeptide". The polypeptide having the sequence recited in SEQ ID NO: 126 is referred to hereafter as "INPIONCH09 exon 20 polypeptide". The polypeptide having the sequence recited in SEQ ID NO: 128 is referred to hereafter as "INPIONCH09 exon 21 polypeptide". Combining SEQ ID NO:88, SEQ ID NO:90, SEQ ID NO:92, SEQ ID NO:94, SEQ ID NO:96, SEQ ID NO:98, SEQ ID NO:100, SEQ ID NO:102₅ SEQ ID NO:104, SEQ ID NO:106, SEQ ID NO:108, SEQ ID NO:110, SEQ ID N0:112, SEQ ID NO:114, SEQ ID NO:116, SEQ ID NO:118, SEQ ID NO:120, SEQ ID NO:122, SEQ ID NO:124, SEQ ID NO:126 and SEQ LD NO:128, produces the sequence recited in SEQ ID NO:130. The polypeptide having the sequence recited in SEQ ID NO: 130 is referred to hereafter as the "LNPIONCH09 polypeptide".

The polypeptide having the sequence recited in SEQ ID NO: 180 is referred to hereafter as the "LNPIONCH09 high quality polypeptide sequence". Splice variants of the LNPIONCH09 exon 1 polypeptide, the LNPIONCH09 exon 2 polypeptide, the LNPIONCH09 exon 3 polypeptide, the LNPIONCH09 exon 4 polypeptide, the INPIONCH09 exon 5 polypeptide, the INPIONCH09 exon 6 polypeptide, the INPIONCH09 exon 7 polypeptide, the INPIONCH09 exon 8 polypeptide, the INPIONCH09 exon 9 polypeptide, the INPIONCH09 exon 10 polypeptide, the INPIONCH09 exon 11 polypeptide, the LNPIONCH09 exon 12 polypeptide, the INPIONCH09 exon 13 polypeptide, the INPIONCH09 exon 14 polypeptide, the LNPIONCH09 exon 15 polypeptide, the INPIONCH09 exon 16 polypeptide, the LNPIONCH09 exon 17 polypeptide, the INPIONCH09 exon 18 polypeptide, the LNPIONCH09 exon 19 polypeptide, the LNPIONCH09 exon 20 polypeptide and the LNPIONCH09 exon 21 polypeptide are also encompassed by the third embodiment of the first aspect of the present invention.

The term "LNPIONCH09 exon polypeptides" as used herein includes polypeptides comprising or consisting of the INPIONCH09 exon 1 polypeptide, the LNPIONCH09 exon 2 polypeptide, the INPIONCH09 exon 3 polypeptide, the LNPIONCH09 exon 4 polypeptide, the LNPIONCH09 exon 5 polypeptide, the INPIONCH09 exon 6 polypeptide, the LNPIONCH09 exon 7 polypeptide, the INPIONCH09 exon 8 polypeptide, the LNPIONCH09 exon 9 polypeptide, the INPIONCH09 exon 10 polypeptide, the INPIONCH09 exon 11 polypeptide, the LNPIONCH09 exon 12 polypeptide, the INPIONCH09 exon 13 polypeptide, the LNPIONCH09 exon 14 polypeptide, the INPIONCH09 exon 15 polypeptide, the LNPIONCH09 exon 16 polypeptide, the LNPIONCH09 exon 17 polypeptide, the LNPIONCH09 exon 18 polypeptide, the LNPIONCH09 exon 19 polypeptide, the INPIONCH09 exon 20 polypeptide, the INPIONCH09 exon 21 polypeptide or the LNPIONCH09 polypeptide. In a fourth embodiment of the first aspect of the invention, there is provided a polypeptide which:

(i) comprises or consists of the amino acid sequence as recited in SEQ ID NO: 132, SEQ ID NO:134, SEQ ID NO:136, SEQ ID NO:138, SEQ ID NO:140, SEQ ID NO:142, SEQ ID NO:144, SEQ LD NO:146, SEQ ID NO:148, SEQ ID NO:150, SEQ ID NO:152, SEQ

ID O:154, SEQ ID NO:156, SEQ ID NO:158, SEQ ID NO:160, SEQ ID O:162, SEQ ID NO:164, SEQ ID NO:166, SEQ ID NO:168, SEQ ID NO:170, SEQ ID NO:172, SEQ ID NO:174, or SEQ LD NO: 182;

(iii) is a functional equivalent of (i) or (ii).

By "the activity of a polypeptide according to (i)", we refer to activity characteristic of a transporter/channel protein.

The polypeptide having the sequence recited in SEQ ID NO: 132 is referred to hereafter as "the INPIONCHIO exon 1 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:134 is referred to hereafter as "the INPIONCHIO exon 2 polypeptide". The polypeptide having the sequence recited in SEQ ID NO.T36 is referred to hereafter as "the INPIONCHIO exon 3 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:138 is referred to hereafter as "the INPIONCHIO exon 4 polypeptide". The polypeptide having the sequence recited in SEQ ID NO: 140 is referred to hereafter as "the INPIONCHIO exon 5 polypeptide". The polypeptide having the sequence recited in SEQ ID NO: 142 is referred to hereafter as "the INPIONCHIO exon 6 polypeptide". The polypeptide having the sequence recited in SEQ ID NO: 144 is referred to hereafter as "the INPIONCHIO exon 7 polypeptide". The polypeptide having the sequence recited in SEQ ID NO: 146 is referred to hereafter as "the INPIONCHIO exon 8 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:148 is referred to hereafter as "the INPIONCHIO exon 9 polypeptide". The polypeptide having the sequence recited in SEQ ID NO.T50 is referred to hereafter as "the INPIONCHIO exon 10 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:152 is referred to hereafter as "the INPIONCHIO exon 11 polypeptide". The polypeptide having the sequence recited in SEQ ID NO: 154 is referred to hereafter as "INPIONCHIO exon 12 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:156 is referred to hereafter as "INPIONCHIO exon 13 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:158 is referred to hereafter as "INPIONCHIO exon 14 polypeptide". The polypeptide having the sequence recited in SEQ ID NO: 160 is referred to hereafter as "INPIONCHIO exon 15 polypeptide". The polypeptide having the sequence recited in SEQ ID NO.T62 is referred to hereafter as "INPIONCHIO exon 16 polypeptide". The polypeptide having the sequence recited in SEQ ID NO: 164 is referred to hereafter as "INPIONCHIO exon 17 polypeptide". The polypeptide having the sequence recited in SEQ ID NO:166 is referred to hereafter as "INPIONCHIO exon 18 polypeptide". The polypeptide having the sequence recited in SEQ ID NO: 168 is referred to hereafter as "INPIONCHIO exon 19 polypeptide". The polypeptide having the sequence recited in SEQ ID NO: 170 is referred to hereafter as "INPIONCHl 0 exon 20 polypeptide". The polypeptide having the sequence recited in SEQ ID NO: 172 is referred to hereafter as "INPIONCHIO exon 21 polypeptide".

Combining SEQ ID NO:132, SEQ ID NO:134, SEQ ID NO:136, SEQ ID NO:138, SEQ ID NO:140, SEQ ID NO:142, SEQ ID NO:144, SEQ ID NO:146, SEQ ID NO:148, SEQ ID NO: 150, SEQ LD NO: 152, SEQ ID NO: 154, SEQ ID NO: 156, SEQ ID NO: 158, SEQ ID NO:160, SEQ ID NO:162, SEQ ID NO:164, SEQ ID NO:166, SEQ LD NO:168, SEQ ID NO:170 and SEQ ID NO:172, produces the sequence recited in SEQ ID NO:174. The polypeptide having the sequence recited in SEQ ID NO: 174 is referred to hereafter as the "INPIONCHIO polypeptide". The polypeptide having the sequence recited in SEQ ID NO: 182 is referred to hereafter as the "INPIONCHIO high quality polypeptide sequence".

Splice variants of the INPIONCHIO exon 1 polypeptide, the INPIONCHIO exon 2 polypeptide, the INPIONCHIO exon 3 polypeptide, the INPIONCHIO exon 4 polypeptide, the INPIONCHIO exon 5 polypeptide, the INPIONCHIO exon 6 polypeptide, the INPIONCHIO exon 7 polypeptide, the INPIONCHIO exon 8 polypeptide, the INPIONCHIO exon 9 polypeptide, the INPIONCHIO exon 10 polypeptide, the INPIONCHIO exon 11 polypeptide, the INPIONCHIO exon 12 polypeptide, the INPIONCHIO exon 13 polypeptide, the INPIONCHIO exon 14 polypeptide, the INPIONCHIO exon 15 polypeptide, the INPIONCHIO exon 16 polypeptide, the INPIONCHIO exon 17 polypeptide, the INPIONCHIO exon 18 polypeptide, the INPIONCHIO exon 19 polypeptide, the INPIONCHIO exon 20 polypeptide and the INPIONCHIO exon 21 polypeptide are also encompassed by the fourth embodiment of the first aspect of the present invention. The term "INPIONCHIO exon polypeptides" as used herein includes polypeptides comprising or consisting of the INPIONCHIO exon 1 polypeptide, the INPIONCHIO exon 2 polypeptide, the INPIONCHIO exon 3 polypeptide, the INPIONCHIO exon 4 polypeptide, the INPIONCHIO exon 5 polypeptide, the INPIONCHIO exon 6 polypeptide, the INPIONCHIO exon 7 polypeptide, the INPIONCHIO exon 8 polypeptide, the INPIONCHIO exon 9 polypeptide, the INPIONCHIO exon 10 polypeptide, the INPIONCHIO exon 11 polypeptide, the INPIONCHIO exon 12 polypeptide, the INPIONCHIO exon 13 polypeptide, the INPIONCHIO exon 14 polypeptide, the INPIONCHIO exon 15 polypeptide, the INPIONCHIO exon 16 polypeptide, the INPIONCHIO exon 17 polypeptide, the INPIONCHIO exon 18 polypeptide, the INPIONCHIO exon 19 polypeptide, the INPIONCHIO exon 20 polypeptide, the INPIONCHIO exon 21 polypeptide or the INPIONCHIO polypeptide.

In a second aspect, the invention provides a purified nucleic acid molecule which encodes a polypeptide of the first aspect of the invention. In one embodiment of the second aspect of the invention, the purified nucleic acid molecule preferably comprises or consists of the nucleic acid sequence as recited in SEQ ID NO:l (encoding the INPIONCH07 exon 1 polypeptide), SEQ ID NO:3 (encoding the INPIONCH07 exon 2 polypeptide), SEQ ID NO:5 (encoding the LNPIONCH07 exon 3 polypeptide), SEQ ID NO:7 (encoding the INPIONCH07 exon 4 polypeptide), SEQ ID NO:9 (encoding the INPIONCH07 exon 5 polypeptide), SEQ ID NO: 11 (encoding the INPIONCH07 exon 6 polypeptide), SEQ ID NO: 13 (encoding the INPIONCH07 exon 7 polypeptide), SEQ ID NO: 15 (encoding the LNPIONCH07 exon 8 polypeptide), SEQ ID NO: 17 (encoding the LNPIONCH07 exon 9 polypeptide), SEQ ID NO:19 (encoding the LNPIONCH07 exon 10 polypeptide), SEQ ID NO:21 (encoding the LNPIONCH07 exon 11 polypeptide), SEQ ID NO:23 (encoding the INPIONCH07 exon 12 polypeptide), SEQ ID NO:25 (encoding the LNPIONCH07 exon 13 polypeptide), SEQ ID NO:27 (encoding the INPIONCH07 exon 14 polypeptide), SEQ ID NO:29 (encoding the LNPIONCH07 exon 15 polypeptide), SEQ ID NO:31 (encoding the LNPIONCH07 exon 16 polypeptide), SEQ ID NO:33 (encoding the LNPIONCH07 exon 17 polypeptide), SEQ ID NO:35 (encoding the LNPIONCH07 exon 18 polypeptide), SEQ ID NO:37 (encoding the LNPIONCH07 exon 19 polypeptide), SEQ ID NO:39 (encoding the LNPIONCH07 exon 20 polypeptide), SEQ ID NO:41 (encoding the LNPIONCH07 polypeptide) or SEQ ID NO: 175 (encoding the INPIONCH07 high quality polypeptide sequence) or is a redundant equivalent or fragment of any one of these sequences. Combining the sequences recited in SEQ ID NO:l, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:ll, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17 and SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:23, SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:31, SEQ ID NO:33, SEQ ID NO:35, SEQ ID NO:37 and SEQ ID NO:39 produces the sequence recited in SEQ ID NO:41.

In a second embodiment of the second aspect of the invention, the purified nucleic acid molecule preferably comprises or consists of the nucleic acid sequence as recited in SEQ ID NO:43 (encoding the LNPIONCH08 exon 1 polypeptide), SEQ ID NO:45 (encoding the INPIONCH08 exon 2 polypeptide), SEQ ID NO:47 (encoding the INPIONCH08 exon 3 polypeptide), SEQ ID NO:49 (encoding the INPIONCH08 exon 4 polypeptide), SEQ ID NO:51 (encoding the LNPIONCH08 exon 5 polypeptide), SEQ ID NO:53 (encoding the INPIONCH08 exon 6 polypeptide), SEQ ID NO:55 (encoding the INPIONCH08 exon 7 polypeptide), SEQ ID NO:57 (encoding the LNPIONCH08 exon 8 polypeptide), SEQ ID NO:59 (encoding the LNPIONCH08 exon 9 polypeptide), SEQ ID NO:61 (encoding the INPIONCH08 exon 10 polypeptide), SEQ ID NO:63 (encoding the INPIONCH08 exon 11 polypeptide), SEQ ID NO:65 (encoding the LNPIONCH08 exon 12 polypeptide), SEQ ID NO:67 (encoding the LNPIONCH08 exon 13 polypeptide), SEQ ID NO:69 (encoding the LNPIONCH08 exon 14 polypeptide), SEQ ID NO:71 (encoding the LNPIONCH08 exon 15 polypeptide), SEQ ID NO:73 (encoding the LNPIONCH08 exon 16 polypeptide), SEQ ID NO:75 (encoding the LNPIONCH08 exon 17 polypeptide), SEQ ID NO:77 (encoding the INPIONCH08 exon 18 polypeptide), SEQ ID NO:79 (encoding the INPIONCH08 exon 19 polypeptide) , SEQ ID NO:81 (encoding the LNPIONCH08 exon 20 polypeptide) , SEQ ID NO:83 (encoding the LNPIONCH08 exon 21 polypeptide), SEQ ID NO:85 (encoding the INPIONCH08 polypeptide) or SEQ ID NO:177 (encoding the LNPIONCH08 high quality polypeptide sequence) or is a redundant equivalent or fragment of any one of these sequences.

Combining the sequences recited in SEQ ID NO:43, SEQ ID NO:45, SEQ ID NO:47 SEQ ID NO:49, SEQ ID NO:51, SEQ ID NO:53, SEQ ID NO:55, SEQ ID NO:57, SEQ ID NO:59, SEQ ID NO:61, SEQ ID NO:63, SEQ ID NO:65, SEQ H⁾ NO:67, SEQ ID NO:69, SEQ ID NO:71, SEQ ID NO:73, SEQ ID NO:75, SEQ ID NO:77, SEQ ID NO:79, SEQ ID NO:81 and SEQ ID NO:83 produces the sequence recited in SEQ ID NO:85.

In a third embodiment of the second aspect of the invention, the purified nucleic acid molecule preferably comprises or consists of the nucleic acid sequence as recited in SEQ ID NO:87 (encoding the LNPIONCH09 exon 1 polypeptide), SEQ ID NO:89 (encoding the LNPIONCH09 exon 2 polypeptide), SEQ ID NO:91 (encoding the INPIONCH09 exon 3 polypeptide), SEQ ID NO:93 (encoding the LNPIONCH09 exon 4 polypeptide), SEQ ID NO:95 (encoding the INPIONCH09 exon 5 polypeptide), SEQ ID NO:97 (encoding the LNPIONCH09 exon 6 polypeptide), SEQ ID NO:99 (encoding the LNPIONCH09 exon 7 polypeptide), SEQ ID NO: 101 (encoding the INPIONCH09 exon 8 polypeptide), SEQ ID NO:103 (encoding the LNPIONCH09 exon 9 polypeptide), SEQ ID NO:105 (encoding the INPIONCH09 exon 10 polypeptide), SEQ ID NO:107 (encoding the INPIONCH09 exon 11 polypeptide), SEQ ID NO: 109 (encoding the LNPIONCH09 exon 12 polypeptide), SEQ ID NO.111 (encoding the LNPIONCH09 exon 13 polypeptide), SEQ ID NO:113 (encoding the LNPIONCH09 exon 14 polypeptide), SEQ ID NO:115 (encoding the INPIONCH09 exon 15 polypeptide), SEQ ID NO: 117 (encodmg the LNPIONCH09 exon 16 polypeptide), SEQ ID NO:119 (encoding the LNPIONCH09 exon 17 polypeptide), SEQ ID NO:121 (encoding the LNPIONCH09 exon 18 polypeptide), SEQ ID NO: 123 (encoding the INPIONCH09 exon 19 polypeptide) , SEQ ID NO: 125 (encoding the LNPIONCH09 exon 20 polypeptide) , SEQ ID NO: 127 (encoding the LNPIONCH09 exon 21 polypeptide), SEQ ID NO: 129 (encoding the LNPIONCH09 polypeptide) or SEQ ID NO: 179 (encoding the LNPIONCH09 high quality polypeptide sequence) or is a redundant equivalent or fragment of any one of these sequences.

Combining the sequences recited in SEQ ID NO:87, SEQ ID NO:89, SEQ ID NO:91, SEQ ID NO:93, SEQ ID NO:95, SEQ ID NO:97, SEQ ID NO:99, SEQ ID NO:101, SEQ ID NO:103, SEQ ID NO.T05, SEQ ID NO: 107, SEQ ID NO:109, SEQ ID NO.T 11, SEQ ID NO:113, SEQ ID NO: 115, SEQ ID NO:117, SEQ ID NO: 119, SEQ ID NO:121, SEQ ID NO:123, SEQ LD NO: 125 and SEQ ID NO: 127 produces the sequence recited in SEQ ID NO: 129.

In a fourth embodiment of the second aspect of the invention, the purified nucleic acid molecule preferably comprises or consists of the nucleic acid sequence as recited in SEQ ID NO: 131 (encoding the INPIONCHIO exon 1 polypeptide), SEQ ID NO: 133 (encoding the INPIONCHIO exon 2 polypeptide), SEQ ID NO: 135 (encoding the INPIONCHIO exon 3 polypeptide), SEQ ID NO: 137 (encoding the INPIONCHIO exon 4 polypeptide), SEQ ID NO:139 (encoding the INPIONCHIO exon 5 polypeptide), SEQ ID NO:141 (encoding the INPIONCHIO exon 6 polypeptide), SEQ ID NO:143 (encoding the INPIONCHIO exon 7 polypeptide), SEQ ID NO: 145 (encoding the INPIONCHIO exon 8 polypeptide), SEQ ID NO:147 (encodmg the INPIONCHIO exon 9 polypeptide), SEQ ID NO:149 (encoding the INPIONCHIO exon 10 polypeptide), SEQ ID NO:151 (encoding the INPIONCHIO exon 11 polypeptide), SEQ ID NO:153 (encoding the INPIONCHIO exon 12 polypeptide), SEQ ID NO:155 (encoding the INPIONCHIO exon 13 polypeptide), SEQ ID NO:157 (encoding the INPIONCHIO exon 14 polypeptide), SEQ ID NO:159 (encoding the INPIONCHIO exon 15 polypeptide), SEQ ID NO:161 (encoding the INPIONCHIO exon 16 polypeptide), SEQ ID NO: 163 (encoding the INPIONCHIO exon 17 polypeptide), SEQ ID NO: 165 (encoding the INPIONCHIO exon 18 polypeptide), SEQ ID NO:167 (encoding the INPIONCHIO exon 19 polypeptide) , SEQ ID NO: 169 (encoding the INPIONCHIO exon 20 polypeptide) , SEQ ID NO:171 (encoding the INPIONCHIO exon 21 polypeptide), SEQ ID NO:173 (encoding the INPIONCHIO polypeptide) or SEQ ID NO:181 (encoding the INPIONCHIO high quality polypeptide sequence) or is a redundant equivalent or fragment of any one of these sequences.

Combining the sequences recited in SEQ ID NO.T31, SEQ ID NO:133, SEQ ID NO:135, SEQ ID NO.T37, SEQ ID NO.T39, SEQ ID NO:141, SEQ ID NO:143, SEQ ID NO:145, SEQ ID NO:147, SEQ ID NO:149, SEQ ID NO:151, SEQ ID NO:153, SEQ ID NO:155, SEQ ID NO:157, SEQ ID NO:159, SEQ ID NO:161, SEQ ID NO:163, SEQ ID NO:165, SEQ ID NO:167, SEQ ID NO:169 and SEQ ID NO:171 produces the sequence recited in SEQ ID NO:173.

In a third aspect, the invention provides a purified nucleic acid molecule which hybridises under high stringency conditions with a nucleic acid molecule of the second aspect of the invention. In a fourth aspect, the invention provides a vector, such as an expression vector, that contains a nucleic acid molecule of the second or third aspect of the invention.

In a fifth aspect, the invention provides a host cell transformed with a vector of the fourth aspect of the invention.

In a sixth aspect, the invention provides a ligand which binds specifically to members of the transporter/channel proteins of the first aspect of the invention or to multimeric complexes of these transporter/channel proteins. Preferably, the ligand inhibits the function of a polypeptide of the first aspect of the invention. Ligands to a polypeptide according to the invention may come in various forms, including natural or modified substrates, enzymes, receptors, small organic molecules such as small natural or synthetic organic molecules of up to 2000Da, preferably 800Da or less, peptidomimetics, inorganic molecules, peptides, polypeptides, antibodies, structural or functional mimetics of the aforementioned. In a seventh aspect, the invention provides a compound that is effective to alter the expression of a natural gene which encodes a polypeptide of the first aspect of the invention or to regulate the activity of a polypeptide of the first aspect of the invention or to regulate the activity of a multimeric complex of the fifteenth aspect of the invention. A compound of the seventh aspect of the invention may either increase (agonise) or decrease (antagonise) the level of expression of the gene or the activity of the polypeptide or the activity of the multimeric complex.

Importantly, the identification of the function of the INPIONCH07, INPIONCH08, LNPIONCH09 and INPIONCHIO polypeptides allows for the design of screening methods capable of identifying compounds that are effective in the treatment and/or diagnosis of disease or for use as a contraceptive. As used herein, the term "disease" also includes disorders. Ligands and compounds according to the sixth and seventh aspects of the invention may be identified using such methods. These methods are included as aspects of the present invention. In a first embodiment of the eighth aspect, the invention provides a polypeptide of the first aspect of the invention, or a nucleic acid molecule of the second or third aspect of the invention, or a vector of the fourth aspect of the invention, or a host cell of the fifth aspect of the invention, or a ligand of the sixth aspect of the invention, or a compound of the seventh aspect of the invention, or a multimeric complex of the fifteenth aspect of the invention, for use in therapy or diagnosis of diseases in which members of the transporter/channel protein family are implicated. Such diseases may include cell proliferative disorders, including neoplasm, melanoma, lung, colorectal, breast, pancreas, head and neck and other solid tumours; myeloproliferative disorders, such as leukemia, non-Hodgkin lymphoma, leukopenia, thrombocytopenia, angiogenesis disorder, Kaposis' sarcoma; autoimmune/inflammatory disorders, including allergy, inflammatory bowel disease, arthritis, psoriasis and respiratory tract inflammation, asthma, and organ transplant rejection; cardiovascular disorders, including hypertension, oedema, angina, atherosclerosis, thrombosis, sepsis, shock, reperfusion injury, and ischemia; neurological disorders including central nervous system disease, Alzheimer's disease, brain injury, amyotrophic lateral sclerosis, and pain; developmental disorders; metabolic disorders including diabetes mellitus, osteoporosis, and obesity, AIDS and renal disease; infections including viral infection, bacterial infection, fungal infection and parasitic infection and other pathological conditions and in particular inflammation, colitis, hypertrophy, fibrosis, heart failure, myocardial infarction, angina, obesity, hyperinsulinemia, vascular disease, renal disease, fertility disorders, infertility, testosterone deficiency, testosterone-related disorder, testicular cancer and sexual dysfunction. These molecules may also be used in the manufacture of a medicament for the treatment of such disorders.

In a second embodiment of the eighth aspect, the invention provides a polypeptide of the first aspect of the invention, or a nucleic acid molecule of the second or third aspect of the invention, or a vector of the fourth aspect of the invention, or a host cell of the fifth aspect of the invention, or a ligand of the sixth aspect of the invention, or a compound of the seventh aspect of the invention, or a multimeric complex of the fifteenth aspect of the invention as a contraceptive agent. These molecules may also be used in the manufacture of a medicament for use in contraception.

In a ninth aspect, the invention provides a method of diagnosing a disease or disorder in a patient, comprising assessing the level of expression of a natural gene encoding a polypeptide of the first aspect of the invention or the activity of a polypeptide of the first aspect of the invention in tissue from said patient and comparing said level of expression or activity to a control level, wherein a level that is different to said control level is indicative of disease or disorder. Such a method will preferably be carried out in vitro. Similar methods may be used for monitoring the therapeutic treatment of disease or disorder in a patient, wherein altering the level of expression or activity of a polypeptide or nucleic acid molecule over the period of time towards a control level is indicative of regression of disease or disorder.

A preferred method for detecting polypeptides of the first aspect of the invention comprises the steps of: (a) contacting a ligand, such as an antibody, of the sixth aspect of the invention with a biological sample under conditions suitable for the formation of a ligand-polypeptide complex or a ligand-multimeric complex complex; and (b) detecting said complex.

A number of different such methods according to the ninth aspect of the invention exist, as the skilled reader will be aware, such as methods of nucleic acid hybridization with short probes, point mutation analysis, polymerase chain reaction (PCR) amplification and methods using antibodies to detect aberrant protein levels. Similar methods may be used on a short or long term basis to allow therapeutic treatment of a disease to be monitored in a patient. The invention also provides kits that are useful in these methods for diagnosing disease. In a tenth aspect, the invention provides for the use of a polypeptide of the first aspect of the invention as transporter/channel proteins. Suitable uses of the polypeptides of the invention as transporter/channel proteins include use as a regulator of cellular growth, metabolism or differentiation, use as part of a receptor/ligand pair and use as a diagnostic marker for a physiological or pathological condition.

In an eleventh aspect, the invention provides a pharmaceutical composition comprising a polypeptide of the first aspect of the invention, or a nucleic acid molecule of the second or third aspect of the invention, or a vector of the fourth aspect of the invention, or a host cell of the fifth aspect of the invention, or a ligand of the sixth aspect of the invention, or a compound of the seventh aspect of the invention, or a multimeric complex of the fifteenth aspect of the invention in conjunction with a pharmaceutically-acceptable carrier.

In a twelfth aspect, the present invention provides a polypeptide of the first aspect of the invention, or a nucleic acid molecule of the second or third aspect of the invention, or a vector of the fourth aspect of the invention, or a host cell of the fifth aspect of the invention, or a ligand of the sixth aspect of the invention, or a compound of the seventh aspect of the invention, or a multimeric complex of the fifteenth aspect of the invention for use in the manufacture of a medicament for the diagnosis or treatment of a disease or disorder.

In a thirteenth aspect, the invention provides a method of treating a disease in a patient comprising administering to the patient a polypeptide of the first aspect of the invention, or a nucleic acid molecule of the second or third aspect of the invention, or a vector of the fourth aspect of the invention, or a host cell of the fifth aspect of the invention, or a ligand of the sixth aspect of the invention, or a compound of the seventh aspect of the invention, or a multimeric complex of the fifteenth aspect of the invention.

For diseases or disorders in which the expression of a natural gene encoding a polypeptide of the first aspect of the invention, or in which the activity of a polypeptide of the first aspect of the invention, or in which the activity of a multimeric complex of the fifteenth aspect of the invention is lower in a diseased patient or a patient affected by a disorder when compared to the level of expression or activity in a healthy patient, the polypeptide, nucleic acid molecule, ligand. compound or multimeric complex administered to the patient should be an agonist. Conversely, for diseases or disorders in which the expression of the natural gene or activity of the polypeptide, or activity of the multimeric complex is higher in a diseased patient or in a patient affected by a disorder when compared to the level of expression or activity in a healthy patient, the polypeptide, nucleic acid molecule, ligand, compound or multimeric complex administered to the patient should be an antagonist. Examples of such antagonists include antisense nucleic acid molecules, ribozymes and ligands, such as antibodies.

In a fourteenth aspect, the invention provides transgenic or knockout non-human animals that have been transformed to express higher, lower or absent levels of a polypeptide of the first aspect of the invention. Such transgenic animals are very useful models for the study of disease/disorders and may also be used in screening regimes for the identification of compounds that are effective in the treatment or diagnosis of such a disease/disorder.

In a fifteenth aspect, the invention provides multimeric complexes of a polypeptide according to the first aspect of the invention. These multimeric complexes may consist of two or more polypeptides of the first aspect of the present invention and preferably consist of two or four polypeptides of the first aspect of the present invention. The multimers of this aspect of the invention may also comprise one or more polypeptides of the first aspect of the invention complexed together with a heterologous polypeptide or molecule. In a first embodiment of the fifteenth aspect of the present invention, there is a provided a multimeric complex, wherein the multimeric complex comprises either a) a dimer comprising either i) two LNPIONCH07 monomers or ii) one LNPIONCH07 monomer and one monomer of a heterologous polypeptide, or b) a tetramer comprising either i) four LNPIONCH07 monomers, ii) a trimer of LNPIONCH07 and a monomer of a heterologous polypeptide, iii) a homodimer of LNPIONCH07 and a homodimer of a heterologous polypeptide, iv) a homodimer of LNPIONCH07 and two monomers of two heterologous polypeptides, v) a monomer of LNPIONCH07 and a trimer of a heterologous polypeptide, vi) a monomer of INPIONCH07, a dimer of a heterologous polypeptide and a monomer of a further heterologous polypeptide, or vii) a monomer of INPIONCH07 and one monomer each of three heterologous polypeptides.

A 'heterologous polypeptide' according to the first embodiment of the fifteenth aspect of the present invention is preferably an LNPIONCH09 polypeptide but may alternatively be any other polypeptide which is capable of forming a multimeric complex with this polypeptide.

Thus a dimer according to the first embodiment of the fifteenth aspect of the present invention preferably comprises: LNPIONCH07-LNPIONCH07; or INPIONCH07-INPIONCH09

Thus a tetramer according to the first embodiment of the fifteenth aspect of the invention preferably comprises: INPIONCH07-rNPIONCH07-LNPIONCH07-INPIONCH07; LNPIONCH07-LNPIONCH07-LNPIONCH07-ΓNPIONCH09; LNPIONCH07-LNPIONCH07-LNPIONCH09-LNPIONCH09; or ΓNPIONCH07-ΓNPIONCH09-LNPIONCH09-INPIONCH09.

In a second embodiment of the fifteenth aspect of the present invention, there is a provided a multimeric complex, wherein the multimeric complex comprises either a) a dimer comprising either i) two LNPIONCH08 monomers or ii) one LNPIONCH08 monomer and one monomer of a heterologous polypeptide, or b) a tetramer comprising either i) four LNPIONCH08 monomers, ii) a trimer of LNPIONCH08 and a monomer of a heterologous polypeptide, iii) a homodimer of LNPIONCH08 and a homodimer of a heterologous polypeptide, iv) a homodimer of LNPIONCH08 and two monomers of two heterologous polypeptides, v) a monomer of LNPIONCH08 and a trimer of a heterologous polypeptide, vi) a monomer of LNPIONCH08, a dimer of a heterologous polypeptide and a monomer of a further heterologous polypeptide, or vii) a monomer of LNPIONCH08 and one monomer each of three heterologous polypeptides. A 'heterologous polypeptide' according to the second embodiment of the fifteenth aspect of the present invention is preferably an INPIONCHIO polypeptide but may alternatively be any other polypeptide which is capable of fomiing a multimeric complex with this polypeptide.

Thus a dimer according to the second embodiment of the fifteenth aspect of the present invention preferably comprises: LNPIONCH08-INPIONCH08; or LNPIONCH08-LNPIONCH10

Thus a tetramer according to the second embodiment of the fifteenth aspect of the invention preferably comprises:

LNPIONCH08-ΓNPIONCH08-ΓNPIONCH08-INPIONCH08; ΓNPIONCH08-ΓNPIONCH08-LNPIONCH08-INPIONCH10; LNPIONCH08-LNPIONCH08-INPIONCH10-INPIONCHl 0; or LNPIONCH08-LNPIONCH10-LNPIONCHl 0-INPIONCHl 0.

In a third embodiment of the fifteenth aspect of the present invention, there is a provided a multimeric complex, wherein the multimeric complex comprises either a) a dimer comprising either i) two NPIONCH09 monomers or ii) one LNPIONCH09 monomer and one monomer of a heterologous polypeptide, or b) a tetramer comprising either i) four INPIONCH09 monomers, ii) a trimer of 1NPIONCH09 and a monomer of a heterologous polypeptide, iii) a homodimer of LNPIONCH09 and a homodimer of a heterologous polypeptide, iv) a homodimer of LNPIONCH09 and two monomers of two heterologous polypeptides, v) a monomer of LNPIONCH09 and a trimer of a heterologous polypeptide, vi) a monomer of LNPIONCH09, a dimer of a heterologous polypeptide and a monomer of a further heterologous polypeptide, or vii) a monomer of LNPIONCH09 and one monomer each of three heterologous polypeptides.

A 'heterologous polypeptide' according to the third embodiment of the fifteenth aspect of the present invention is preferably an LNPIONCH07 polypeptide but may alternatively be any other polypeptide which is capable of forming a multimeric complex with this polypeptide.

Thus a dimer according to the third embodiment of the fifteenth aspect of the present invention preferably comprises:

LNPIONCH09-INPIONCH09; or INPIONCH09-LNPIONCH07 Thus a tetramer according to the third embodiment of the fifteenth aspect of the invention preferably comprises:

LNPIONCH09-INPIONCH09-LNPIONCH09-LNPIONCH09; ΓNPIONCH09-INPIONCH09-LNPIONCH09-LNPIONCH07; LNPIONCH09-rNPIONCH09-LNPIONCH07-LNPIONCH07; or LNPIONCH09-INPIONCH07-LNPIONCH07-INPIONCH07.

In a fourth embodiment of the fifteenth aspect of the present invention, there is a provided a multimeric complex, wherein the multimeric complex comprises either a) a dimer comprising either i) two INPIONCHIO monomers or ii) one INPIONCHIO monomer and one monomer of a heterologous polypeptide, or b) a tetramer comprising either i) four INPIONCHIO monomers, ii) a trimer of INPIONCHl 0 and a monomer of a heterologous polypeptide, iii) a homodimer of INPIONCHIO and a homodimer of a heterologous polypeptide, iv) a homodimer of INPIONCHIO and two monomers of two heterologous polypeptides, v) a monomer of INPIONCHIO and a trimer of a heterologous polypeptide, vi) a monomer of INPIONCHIO, a dimer of a heterologous polypeptide and a monomer of a further heterologous polypeptide, or vii) a monomer of INPIONCHIO and one monomer each of three heterologous polypeptides.

A 'heterologous polypeptide' according to the fourth embodiment of the fifteenth aspect of the present invention is preferably an LNPIONCH08 polypeptide but may alternatively be any other polypeptide which is capable of forming a multimeric complex with this polypeptide.

Thus a dimer according to the fourth embodiment of the fifteenth aspect of the present invention preferably comprises :

INPIONCHl 0-INPIONCHlO; or INPIONCHl 0-LNPIONCH08

Thus a tetramer according to the fourth embodiment of the fifteenth aspect of the invention preferably comprises: INPIONCHl 0-INPIONCHl 0-LNPIONCHl 0-INPIONCHl 0; INPIONCHl 0-INPIONCHl 0-LNPIONCHl 0-LNPIONCH08; INPIONCHl 0-INPIONCHl 0-INPIONCH08-INPIONCH08; or LNPIONCH10-INPIONCH08-INPIONCH08-ΓNPIONCH08.

In the multimeric complexes according to this aspect of the invention, any one or more of the polypeptides according to first aspect of the invention may be substituted by a splice variant in the multimeric complex.

Preferably, multimeric complexes comprising one or more polypeptides according to the first and third embodiments of the first aspect of the invention will be applicable to humans whilst multimeric complexes comprising polypeptides according to the second and fourth embodiments of the first aspect of the invention will be applicable to mice. It will be known to those skilled in the art that a human multimeric complex will preferably comprise the human homologues of its respective subunits whilst a mouse multimeric complex will preferably comprise the mouse homologues of its respective subunits. However, multimeric complexes comprising a combination of human and mouse subunits also form part of the present invention and may be useful, for example, in research into stincture/function relationships. 27 A summary of standard techniques and procedures which may be employed in order to utilise the invention is given below. It will be understood that this invention is not limited to the particular methodology, protocols, cell lines, vectors and reagents described. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and it is not intended that this terminology should limit the scope of the present invention. The extent of the invention is limited only by the terms of the appended claims.

Standard abbreviations for nucleotides and amino acids are used in this specification.

The practice of the present invention will employ, unless otherwise indicated, conventional techniques of molecular biology, microbiology, recombinant DNA technology and immunology, which are within the skill of those working in the art.

Such techniques are explained fully in the literature. Examples of particularly suitable texts for consultation include the following: Sambrook Molecular Cloning; A Laboratory Manual, Second Edition (1989); DNA Cloning, Volumes I and II (D.N Glover ed. 1985); Oligonucleotide Synthesis (M.J. Gait ed. 1984); Nucleic Acid Hybridization (B.D. Hames & SJ. Higgins eds. 1984); Transcription and Translation (B.D. Hames & SJ. Higgins eds. 1984); Animal Cell Culture (R.I. Freshney ed. 1986); Immobilized Cells and Enzymes (IRL Press, 1986); B. Perbal, A Practical Guide to Molecular Cloning (1984); the Methods in Enzymology series (Academic Press, Inc.), especially volumes 154 & 155; Gene Transfer Vectors for Mammalian Cells (J.H. Miller and M.P. Calos eds. 1987, Cold Spring Harbor Laboratory); Immunochemical Methods in Cell and Molecular Biology (Mayer and Walker, eds. 1987, Academic Press, London); Scopes, (1987) Protein Purification: Principles and Practice, Second Edition (Springer Verlag, N.Y.); and Handbook of Experimental Immunology, Volumes I-IV (D.M. Weir and C. C. Blackwell eds. 1986). As used herein, the term "polypeptide" includes any peptide or protein comprising two or more amino acids joined to each other by peptide bonds or modified peptide bonds, i.e. peptide isosteres. This term refers both to short chains (peptides and oligopeptides) and to longer chains (proteins).

The polypeptide of the present invention may be in the form of a mature protein or may be a pre-, pro- or prepro- protein that can be activated by cleavage of the pre-, pro- or prepro- portion to produce an active mature polypeptide. In such polypeptides, the pre-, pro- or prepro- sequence may be a leader or secretory sequence or may be a sequence that is employed for purification of the mature polypeptide sequence.

The polypeptide of the first aspect of the invention may form part of a fusion protein. For example, it is often advantageous to include one or more additional amino acid sequences which may contain secretory or leader sequences, pro-sequences, sequences which aid in purification, or sequences that confer higher protein stability, for example during recombinant production. Alternatively or additionally, the mature polypeptide may be fused with another compound, such as a compound to increase the half-life of the polypeptide (for example, polyethylene glycol).

Polypeptides may contain amino acids other than the 20 gene-encoded amino acids, modified either by natural processes, such as by post-translational processing or by chemical modification techniques which are well known in the art. Among the known modifications which may commonly be present in polypeptides of the present invention are glycosylation, lipid attachment, sulphation, gamma-carboxylation, for instance of glutamic acid residues, hydroxylation and ADP-ribosylation. Other potential modifications include acetylation, acylation, amidation, covalent attachment of flavin, covalent attachment of a haeme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid derivative, covalent attachment of phosphatidylinositol, cross-linking, cyclization, disulphide bond formation, demethylation, formation of covalent cross-links, fonnation of cysteine, formation of pyroglutamate, formylation, GPI anchor formation, iodination, methylation, myristoylation, oxidation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, transfer-RNA mediated addition of amino acids to proteins such as arginylation, and ubiquitination.

Modifications can occur anywhere in a polypeptide, including the peptide backbone, the amino acid side-chains and the amino or carboxyl termini. In fact, blockage of the amino or cai'boxyl terminus in a polypeptide, or both, by a covalent modification is common in naturally-occurring and synthetic polypeptides and such modifications may be present in polypeptides of the present invention.

The modifications that occur in a polypeptide often will be a function of how the polypeptide is made. For polypeptides that are made recombinantly, the nature and extent of the modifications in large part will be determined by the post-translational modification capacity of the particular host cell and the modification signals that are present in the amino acid sequence of the polypeptide in question. For instance, glycosylation patterns vary between different types of host cell.

The polypeptides of the present invention can be prepared in any suitable manner. Such polypeptides include isolated naturally-occurring polypeptides (for example purified from cell culture), recombinantly-produced polypeptides (including fusion proteins), synthetically- produced polypeptides or polypeptides that are produced by a combination of these methods.

The functionally-equivalent polypeptides of the first aspect of the invention may be polypeptides that are homologous to the INPIONCH07, INPIONCH08, INPIONCH09 and INPIONCHIO polypeptides. Two polypeptides are said to be "homologous", as the term is used herein, if the sequence of one of the polypeptides has a high enough degree of identity or similarity to the sequence of the other polypeptide. "Identity" indicates that at any particular position in the aligned sequences, the amino acid residue is identical between the sequences. "Similarity" indicates that, at any particular position in the aligned sequences, the amino acid residue is of a similar type between the sequences. Degrees of identity and similarity can be readily calculated (Computational Molecular Biology, Lesk, A.M., ed., Oxford University Press, New York, 1988; Biocomputing. Informatics and Genome Projects, Smith, D.W., ed., Academic Press, New York, 1993; Computer Analysis of Sequence Data, Part 1, Griffin, A.M., and Griffin, H.G., eds., Humana Press, New Jersey, 1994; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; and Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M Stockton Press, New York, 1991). Homologous polypeptides therefore include natural biological variants (for example, allelic variants or geographical variations within the species from which the polypeptides are derived) and mutants (such as mutants containing amino acid substitutions, insertions or deletions) of the INPIONCH07, INPIONCH08, LNPIONCH09 and INPIONCHIO polypeptides. Such mutants may include polypeptides in which one or more of the amino acid residues are substituted with a conserved or non-conserved amino acid residue (preferably a conserved amino acid residue) and such substituted amino acid residue may or may not be one encoded by the genetic code. Typical such substitutions are among Ala, Val, Leu and lie; among Ser and Thr; among the acidic residues Asp and Glu; among Asn and Gin; among the basic residues Lys and Arg; or among the aromatic residues Phe and Tyr. Particularly preferred are variants in which several, i.e. between 5 and 10, 1 and 5, 1 and 3, 1 and 2 or just 1 amino acids are substituted, deleted or added in any combination. Especially preferred are silent substitutions, additions and deletions, which do not alter the properties and activities of the protein. Also especially preferred in this regard are conservative substitutions. Such mutants also include polypeptides in which one or more of the amino acid residues includes a substituent group.

Typically, greater than 30% identity between two polypeptides is considered to be an indication of functional equivalence. Preferably, functionally equivalent polypeptides of the first aspect of the invention have a degree of sequence identity with the INPIONCH07, LNPIONCH08, LNPIONCH09 and INPIONCHIO polypeptides, or with active fragments thereof, of greater than 80%. More preferred polypeptides have degrees of identity of greater than 85%, 90%, 95%, 98% or 99%, respectively. The functionally-equivalent polypeptides of the first aspect of the invention may also be polypeptides which have been identified using one or more techniques of structural aligmnent. For example, the Inpharmatica Genome Threader technology that forms one aspect of the search tools used to generate the Biopendium™ search database may be used (see PCT application WO 01/69507) to identify polypeptides of presently-unknown function which, while having low sequence identity as compared to the LNPIONCH07, LNPIONCH08, INPIONCH09 and INPIONCHIO polypeptides, are predicted to be members of the transporter/channel protein family, by virtue of sharing significant structural homology with the INPIONCH07, LNPIONCH08, LNPIONCH09 and INPIONCHIO polypeptide sequences. By "significant structural homology" is meant that the Inpharmatica Genome Threader predicts two proteins to share structural homology with a certainty of 10% and above.

The polypeptides of the first aspect of the invention also include fragments of the INPIONCH07, INPIONCH08, LNPIONCH09 and INPIONCHIO polypeptides and fragments of the functional equivalents of the INPIONCH07, LNPIONCH08, INPIONCH09 and INPIONCHIO polypeptides, provided that those fragments are members of the transporter/channel protein family or have an antigenic determinant in common with the LNPIONCH07, INPIONCH08, INPIONCH09 and INPIONCHIO polypeptides.

As used herein, the term "fragment" refers to a polypeptide having an amino acid sequence that is the same as part, but not all, of the amino acid sequence of the INPIONCH07, LNPIONCH08, INPIONCH09 and INPIONCHIO polypeptides or one of their functional equivalents. The fragments should comprise at least n consecutive amino acids from the sequence and, depending on the particular sequence, n preferably is 7 or more (for example, 8, 10, 12, 14, 16, 18, 20 or more). Small fragments may form an antigenic determinant. Fragments of the full length LNPIONCH07 polypeptides may comprise combinations of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 neighbouring exon sequences in the LNPIONCH07 polypeptide sequences (for example, they may consist of a fragment having the sequence given in exons 1 and 2, in exons 6, 7 and 8, in exons 10, 11, 12, 13, 14, 15 and 16 and so forth).

Fragments of the full length LNPIONCH08 polypeptides may comprise combinations of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21 neighbouring exon sequences in the LNPIONCH08 polypeptide sequences.

Fragments of the full length LNPIONCH09 polypeptides may comprise combinations of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21 neighbouring exon sequences in the LNPIONCH09 polypeptide sequences.

Fragments of the full length INPIONCHIO polypeptides may comprise combinations of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21 neighbouring exon sequences in the INPIONCHIO polypeptide sequences. Such fragments may be "free-standing", i.e. not part of or fused to other amino acids or polypeptides, or they may be comprised within a larger polypeptide of which they form a part or region. When comprised within a larger polypeptide, the fragment of the invention most preferably forms a single continuous region. For instance, certain preferred embodiments relate to a fragment having a pre- and/or pro- polypeptide region fused to the amino terminus of the fragment and/or an additional region fused to the carboxyl terminus of the fragment. However, several fragments may be comprised within a single larger polypeptide.

The polypeptides of the present invention or their immunogenic fragments (comprising at least one antigenic determinant) can be used to generate ligands, such as polyclonal or monoclonal antibodies, that are immunospecific for the polypeptides. Such antibodies may be employed to isolate or to identify clones expressing the polypeptides of the invention or to purify the polypeptides by affinity chromatography. The antibodies may also be employed as diagnostic or therapeutic aids, amongst other applications, as will be apparent to the skilled reader.

The term "immunospecific" means that the antibodies have substantially greater affinity for the polypeptides of the invention than their affinity for other related polypeptides in the prior art. As used herein, the term "antibody" refers to intact molecules as well as to fragments thereof, such as Fab, F(ab')₂ and Fv, which are capable of binding to the antigenic determinant in question. Such antibodies thus bind to the polypeptides of the first aspect of the invention.

By "substantially greater affinity" we mean that there is a measurable increase in the affinity for a polypeptide of the invention as compared with the affinity for known transporter/channel proteins.

Preferably, the affinity is at least 1.5-fold, 2-fold, 5-fold 10-fold, 100-fold, 10³-fold, 10⁴-fold, 10⁵-fold, 10⁶-fold or greater for a polypeptide of the invention than for known transporter/channel proteins.

If polyclonal antibodies are desired, a selected mammal, such as a mouse, rabbit, goat or horse, may be immunised with a polypeptide of the first aspect of the invention. The polypeptide used to immunise the animal can be derived by recombinant DNA technology or can be synthesized chemically. If desired, the polypeptide can be conjugated to a carrier protein. Commonly used carriers to which the polypeptides may be chemically coupled include bovine serum albumin, thyroglobulin and keyhole limpet haemocyanin. The coupled polypeptide is then used to immunise the animal. Serum from the immunised animal is collected and treated according to known procedures, for example by immunoaffinity chromatography.

Monoclonal antibodies to the polypeptides of the first aspect of the invention can also be readily produced by one skilled in the art. The general methodology for making monoclonal antibodies using hybridoma technology is well known (see, for example, Kohler, G. and Milstein, C, Nature 256: 495-497 (1975); Kozbor et al, Immunology Today 4: 72 (1983); Cole et al, 11-96 in Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc. (1985).

Panels of monoclonal antibodies produced against the polypeptides of the first aspect of the invention can be screened for various properties, i.e., for isotype, epitope, affinity, etc. Monoclonal antibodies are particularly useful in purification of the individual polypeptides against which they are directed. Alternatively, genes encoding the monoclonal antibodies of interest may be isolated from hybridomas, for instance by PCR techniques known in the art, and cloned and expressed in appropriate vectors.

Chimeric antibodies, in which non-human variable regions are joined or fused to human constant regions (see, for example, Liu et al., Proc. Natl. Acad. Sci. USA, 84, 3439 (1987)), may also be of use. The antibody may be modified to make it less immunogenic in an individual, for example by humanisation (see Jones et al., Nature, 321, 522 (1986); Verhoeyen et al., Science, 239, 1534 (1988); Kabat et al., J. Immunol., 147, 1709 (1991); Queen et al, Proc. Natl Acad. Sci. USA, 86, 10029 (1989); Gorman et al, Proc. Natl Acad. Sci. USA, 88, 34181 (1991); and Hodgson et al., Bio/Technology, 9, 421 (1991)). The term "humanised antibody", as used herein, refers to antibody molecules in which the CDR amino acids and selected other amino acids in the variable domains of the heavy and/or light chains of a non-human donor antibody have been substituted in place of the equivalent amino acids in a human antibody. The humanised antibody thus closely resembles a human antibody but has the binding ability of the donor antibody.

In a further alternative, the antibody may be a "bispecific" antibody, that is an antibody having two different antigen binding domains, each domain being directed against a different epitope.

Phage display technology may be utilised to select genes which encode antibodies with binding activities towards the polypeptides of the invention either from repertoires of PCR amplified V-genes of lymphocytes from humans screened for possessing the relevant antibodies, or from naive libraries (McCafferty, J. et al, (1990), Nature 348, 552-554; Marks, J. et al, (1992) Biotechnology 10, 779-783). The affinity of these antibodies can also be improved by chain shuffling (Clackson, T. et al, (1991) Nature 352, 624-628). Antibodies generated by the above techniques, whether polyclonal or monoclonal, have additional utility in that they may be employed as reagents in immunoassays, radioimmunoassays (RIA) or enzyme-linked immunosorbent assays (ELISA). In these applications, the antibodies can be labelled with an analytically-detectable reagent such as a radioisotope, a fluorescent molecule or an enzyme. Preferred nucleic acid molecules of the second and third aspects of the invention are those which encode a polypeptide sequence as recited in SEQ LD NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO: 18, SEQ ID NO:20, SEQ ID NO:22, SEQ LD NO:24, SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:42, SEQ JD NO:44, SEQ ID NO:46, SEQ LD NO:48, SEQ ID NO:50, SEQ ID NO:52, SEQ JD NO:54, SEQ JD NO:56, SEQ ID NO:58, SEQ ID NO:60, SEQ ID NO:62, SEQ ID NO:64, SEQ JD NO:66, SEQ ID NO:68, SEQ ID NO:70, SEQ ID NO:72, SEQ ID NO:74, SEQ ID NO:76, SEQ ID NO:78, SEQ ID NO:80, SEQ ID NO:82, SEQ ID NO:84, SEQ ID NO:86, SEQ ID NO:88, SEQ JD NO:90, SEQ ID NO:92, SEQ ID NO:94, SEQ ID NO:96, SEQ ID NO:98, SEQ JD NO:100, SEQ ID NO:102, SEQ ID NO:104, SEQ ID NO:106, SEQ JD NO.108, SEQ JD NO: 110, SEQ JD N0:112, SEQ JD NO:114, SEQ JD NO:116, SEQ ID N0.-118, SEQ JD NO:120, SEQ ID NO: 122, SEQ JD NO: 124, SEQ ID NO:126, SEQ ID NO.-128, SEQ ID NO:130, SEQ ID NO:132, SEQ ID NO: 134, SEQ ID NO:136, SEQ ID NO: 138, SEQ ID NO: 140, SEQ ID NO: 142, SEQ ID NO: 144, SEQ ID NO: 146, SEQ JD NO:148, SEQ ID NO:150, SEQ ID NO:152, SEQ ID NO:154, SEQ ID NO:156, SEQ ID NO:158, SEQ JD NO:160, SEQ ID NO:162, SEQ ID NO:164, SEQ ID NO:166, SEQ ID NO:168, SEQ JD NO:170, SEQ JD NO:172, SEQ ID NO:174, SEQ ID NO:176, SEQ ID NO:178, SEQ ID NO:180 and/or SEQ ID NO:182 and functionally equivalent polypeptides. These nucleic acid molecules may be used in the methods and applications described herein. The nucleic acid molecules of the invention preferably comprise at least n consecutive nucleotides from the sequences disclosed herein where, depending on the particular sequence, n is 10 or more (for example, 12, 14, 15, 18, 20, 25, 30, 35, 40 or more).

The nucleic acid molecules of the invention also include sequences that are complementary to nucleic acid molecules described above (for example, for antisense or probing purposes).

Nucleic acid molecules of the present invention may be in the form of RNA, such as mRNA, or in the form of DNA, including, for instance cDNA, synthetic DNA or genomic DNA. Such nucleic acid molecules may be obtained by cloning, by chemical synthetic techniques or by a combination thereof. The nucleic acid molecules can be prepared, for example, by chemical synthesis using techniques such as solid phase phosphoramidite chemical synthesis, from genomic or cDNA libraries or by separation from an organism. RNA molecules may generally be generated by the in vitro or in vivo transcription of DNA sequences. The nucleic acid molecules may be double-stranded or single-stranded. Single-stranded DNA may be the coding strand, also known as the sense strand, or it may be the non-coding strand, also referred to as the anti-sense strand.

The term "nucleic acid molecule" also includes analogues of DNA and RNA, such as those containing modified backbones, and peptide nucleic acids (PNA). The term "PNA", as used herein, refers to an antisense molecule or an anti-gene agent which comprises an oligonucleotide of at least five nucleotides in length linked to a peptide backbone of amino acid residues, which preferably ends in lysine. The terminal lysine confers solubility to the composition. PNAs may be pegylated to extend their lifespan in a cell, where they preferentially bind complementary single stranded DNA and RNA and stop transcript elongation (Nielsen, P.E. et al. (1993) Anticancer Drug Des. 8:53-63).

A nucleic acid molecule which encodes a polypeptide of this invention may be identical to the coding sequence of one or more of the nucleic acid molecules disclosed herein.

These molecules also may have a different sequence which, as a result of the degeneracy of the genetic code, encodes a polypeptide SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ JD NO:8, SEQ JD NO:10, SEQ JD NO: 12, SEQ ID NO:14, SEQ JD NO:16, SEQ JD NO.T8, SEQ ID NO:20, SEQ JD NO:22, SEQ ID NO:24, SEQ JD NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:36, SEQ JD NO:38, SEQ ID NO:40, SEQ JD NO:42, SEQ ID NO:44, SEQ ID NO:46, SEQ ID NO:48, SEQ ID NO:50, SEQ JD NO:52, SEQ ID NO:54, SEQ ID NO:56, SEQ ID NO:58, SEQ ID NO:60, SEQ ID NO:62, SEQ JD NO:64, SEQ ID NO:66, SEQ ID NO:68, SEQ ID NO:70, SEQ ID NO:72, SEQ ID NO:74, SEQ ID NO:76, SEQ ID NO:78, SEQ JD NO:80, SEQ JD NO:82, SEQ ID NO:84, SEQ JD NO:86, SEQ ID NO:88, SEQ JD NO:90, SEQ JD NO:92, SEQ JD NO:94, SEQ ID NO:96, SEQ ID NO:98, SEQ ID NO:100, SEQ ID NO:102, SEQ ID NO:104, SEQ D NO:106, SEQ ID NO:108, SEQ ID NO:110, SEQ ID NO:112, SEQ ID NO:114, SEQ ID NO:116, SEQ JD NO:118, SEQ JD

NO: 120, SEQ ID NO :122, SEQ ID NO: 124, SEQ ID NO: 126, SEQ ID NO 128, SEQ JD NO.-130, SEQ ID NO :132, SEQ ID NO: 134, SEQ ID NO: 136, SEQ ID NO 138, SEQ ID NO: 140, SEQ ID NO :142, SEQ ID NO: 144, SEQ ID NO: 146, SEQ ID NO 148, SEQ ID NO: 150, SEQ ID NO :152, SEQ ID NO: 154, SEQ ID NO: 156, SEQ ID NO 158, SEQ ID NO:160, SEQ LD NO :162, SEQ ID NO: 164, SEQ JD NO: 166, SEQ ID NO 168, SEQ JD NO:170, SEQ JD NO :172, SEQ JD NO:174, SEQ ID NO: 176, SEQ JD NO 178, SEQ ID NO: 180 and/or SEQ ID NO: 182. Such nucleic acid molecules may include, but are not limited to, the coding sequence for the mature polypeptide by itself; the coding sequence for the mature polypeptide and additional coding sequences, such as those encoding a leader or secretory sequence, such as a pro-, pre- or prepro- polypeptide sequence; the coding sequence of the mature polypeptide, with or without the aforementioned additional coding sequences, together with further additional, non-coding sequences, including non-coding 5' and 3' sequences, such as the transcribed, non-translated sequences that play a role in transcription (including termination signals), ribosome binding and mRNA stability. The nucleic acid molecules may also include additional sequences which encode additional amino acids, such as those which provide additional functionalities. The nucleic acid molecules of the second and third aspects of the invention may also encode the fragments or the functional equivalents of the polypeptides and fragments of the first aspect of the invention. Such a nucleic acid molecule may be a naturally-occurring variant such as a naturally-occurring allelic variant, or the molecule may be a variant that is not known to occur naturally. Such non-naturally occurring variants of the nucleic acid molecule may be made by mutagenesis techniques, including those applied to nucleic acid molecules, cells or organisms.

Among variants in this regard are variants that differ from the aforementioned nucleic acid molecules by nucleotide substitutions, deletions or insertions. The substitutions, deletions or insertions may involve one or more nucleotides. The variants may be altered in coding or non- coding regions or both. Alterations in the coding regions may produce conservative or non- conservative amino acid substitutions, deletions or insertions.

The nucleic acid molecules of the invention can also be engineered, using methods generally known in the art, for a variety of reasons, including modifying the cloning, processing, and/or expression of the gene product (the polypeptide). DNA shuffling by random fragmentation and PCR reassembly of gene fragments and synthetic oligonucleotides are included as techniques which may be used to engineer the nucleotide sequences. Site-directed mutagenesis may be used to insert new restriction sites, alter glycosylation patterns, change codon preference, produce splice variants, introduce mutations and so forth. Nucleic acid molecules which encode a polypeptide of the first aspect of the invention may be ligated to a heterologous sequence so that the combined nucleic acid molecule encodes a fusion protein. Such combined nucleic acid molecules are included within the second or third aspects of the invention. For example, to screen peptide libraries for inhibitors of the activity of the polypeptide, it may be useful to express, using such a combined nucleic acid molecule, a fusion protein that can be recognised by a commercially-available antibody. A fusion protein may also be engineered to contain a cleavage site located between the sequence of the polypeptide of the invention and the sequence of a heterologous protein so that the polypeptide may be cleaved and purified away from the heterologous protein.

The nucleic acid molecules of the invention also include antisense molecules that are partially complementary to nucleic acid molecules encoding polypeptides of the present invention and that therefore hybridize to the encoding nucleic acid molecules (hybridization). Such antisense molecules, such as oligonucleotides, can be designed to recognise, specifically bind to and prevent transcription of a target nucleic acid encoding a polypeptide of the invention, as will be known by those of ordinary skill in the art (see, for example, Cohen, J.S., Trends in Pharm. Sci., 10, 435 (1989), Okano, J. Neurochem. 56, 560 (1991); O'Connor, J. Neurochem 56, 560 (1991); Lee et al, Nucleic Acids Res 6, 3073 (1979); Cooney et al., Science 241, 456 (1988); Dervan et al., Science 251, 1360 (1991).

The term "hybridization" as used here refers to the association of two nucleic acid molecules with one another by hydrogen bonding. Typically, one molecule will be fixed to a solid support and the other will be free in solution. Then, the two molecules may be placed in contact with one another under conditions that favour hydrogen bonding. Factors that affect this bonding include: the type and volume of solvent; reaction temperature; time of hybridization; agitation; agents to block the non-specific attachment of the liquid phase molecule to the solid support (Denhardt's reagent or BLOTTO); the concentration of the molecules; use of compounds to increase the rate of association of molecules (dextran sulphate or polyethylene glycol); and the stringency of the washing conditions following hybridization (see Sambrook et al. [supra]).

The inhibition of hybridization of a completely complementary molecule to a target molecule may be examined using a hybridization assay, as known in the art (see, for example, Sambrook et al. [supra]). A substantially homologous molecule will then compete for and inhibit the binding of a completely homologous molecule to the target molecule under various conditions of stringency, as taught in Wahl, G.M. and S.L. Berger (1987; Methods Enzymol. 152:399-407) and Kimmel, A.R. (1987; Methods Enzymol. 152:507-511).

"Stringency" refers to conditions in a hybridization reaction that favour the association of very similar molecules over association of molecules that differ. High stringency hybridisation conditions are defined as overnight incubation at 42°C in a solution comprising 50% formamide, 5XSSC (150mM NaCl, 15mM trisodium citrate), 50mM sodium phosphate (pH7.6), 5x Denhardts solution, 10% dextran sulphate, and 20 microgram/ml denatured, sheared salmon sperm DNA, followed by washing the filters in 0.1X SSC at approximately 65°C. Low stringency conditions involve the hybridisation reaction being carried out at 35°C (see Sambrook et al. [supra]). Preferably, the conditions used for hybridization are those of high stringency.

Preferred embodiments of this aspect of the invention are nucleic acid molecules that are at least 70% identical over their entire length to a nucleic acid molecule encoding the LNPIONCH07, INPIONCH08, INPIONCH09 or INPIONCHIO polypeptides and nucleic acid molecules that are substantially complementary to such nucleic acid molecules. Preferably, a nucleic acid molecule according to this aspect of the invention comprises a region that is at least 80% identical over its entire length to such coding sequences, or is a nucleic acid molecule that is complementary thereto. In this regard, nucleic acid molecules at least 90%, preferably at least 95%, more preferably at least 98%, 99% or more identical over their entire length to the same are particularly preferred. Preferred embodiments in this respect are nucleic acid molecules that encode polypeptides which retain substantially the same biological function or activity as the INPIONCH07, INPIONCH08, INPIONCH09 or INPIONCHl 0 polypeptides.

The invention also provides a process for detecting a nucleic acid molecule of the invention, comprising the steps of: (a) contacting a nucleic probe according to the invention with a biological sample under hybridizing conditions to form duplexes; and (b) detecting any such duplexes that are formed. As discussed additionally below in connection with assays that may be utilised according to the invention, a nucleic acid molecule as described above may be used as a hybridization probe for RNA, cDNA or genomic DNA, in order to isolate full-length cDNAs and genomic clones encoding the INPIONCH07, LNPIONCH08, INPIONCH09 or INPIONCHIO polypeptides and to isolate cDNA and genomic clones of homologous or orthologous genes that have a high sequence similarity to the gene encoding this polypeptide.

In this regard, the following techniques, among others known in the art, may be utilised and are discussed below for purposes of illustration. Methods for DNA sequencing and analysis are well known and are generally available in the art and may, indeed, be used to practice many of the embodiments of the invention discussed herein. Such methods may employ such enzymes as the Klenow fragment of DNA polymerase I, Sequenase (US Biochemical Corp, Cleveland, OH), Taq polymerase (Perkin Elmer), thermostable T7 polymerase (Amersham, Chicago, IL), or combinations of polymerases and proof-reading exonucleases such as those found in the ELONGASE Amplification System marketed by Gibco/BRL (Gaithersburg, MD). Preferably, the sequencing process may be automated using machines such as the Hamilton Micro Lab 2200 (Hamilton, Reno, NV), the Peltier Thermal Cycler (PTC200; MJ Research, Watertown, MA) and the ABI Catalyst and 373 and 377 DNA Sequencers (Perkin Elmer). One method for isolating a nucleic acid molecule encoding a polypeptide with an equivalent function to that of the LNPIONCH07, INPIONCH08, INPIONCH09 or INPIONCHIO polypeptides is to probe a genomic or cDNA library with a natural or artificially-designed probe using standard procedures that are recognised in the art (see, for example, "Current Protocols in Molecular Biology", Ausubel et al. (eds). Greene Publishing Association and John Wiley Interscience, New York, 1989,1992). Probes comprising at least 15, preferably at least 30, and more preferably at least 50, contiguous bases that correspond to, or are complementary to, nucleic acid sequences from the appropriate encoding gene (SEQ ID NO:l, SEQ ID NO:3, SEQ JD NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:ll, SEQ JD NO:13, SEQ ID NO:15, SEQ JD NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ JD NO:23, SEQ JD NO:25, SEQ ID NO:27, SEQ JD NO:29, SEQ ID NO:31, SEQ JD NO:33, SEQ JD NO:35, SEQ ID NO:37, SEQ ID NO:39, SEQ ID NO:41, SEQ JD NO:43, SEQ JD NO:45, SEQ ID NO:47 SEQ JD NO:49, SEQ ID NO:51, SEQ JD NO:53, SEQ ID NO:55, SEQ ID NO:57, SEQ JD NO:59, SEQ ID NO:61, SEQ ID NO:63, SEQ ID NO:65, SEQ ID NO:67, SEQ ID NO:69, SEQ ID NO:71, SEQ ID NO:73, SEQ JD NO:75, SEQ ID NO:77, SEQ ID NO:79, SEQ ID NO:81, SEQ ID NO:83, SEQ JD NO:85, SEQ ID NO:87, SEQ ID NO:89, SEQ JD NO:91, SEQ JD NO:93, SEQ ID NO:95, SEQ ID NO:97, SEQ ID NO:99, SEQ JD NO:101, SEQ ID NO:103, SEQ ID NO:105, SEQ ID NO:107, SEQ JD NO:109, SEQ ID NO:lll, SEQ JD NO:113, SEQ ID NO:115, SEQ ID NO:117, SEQ ID NO:119, SEQ ID NO:121, SEQ ID NO:123, SEQ ID NO:125, SEQ ID NO:127, SEQ JD NO :129, SEQ ID NO:131, SEQ ID NO:133, SEQ ID NO:135, SEQ JD NO:137, SEQ JD NO :139, SEQ ID NO:141, SEQ JD NO:143, SEQ ID NO:145, SEQ ID NO:147, SEQ JD NO :149, SEQ JD NO:151, SEQ JD NO:153, SEQ ID NO: 155, SEQ ID NO: 157, SEQ JD NO :159, SEQ ID NO:161, SEQ JD NO.T63, SEQ ID NO: 165, SEQ ID NO.T67, SEQ ID NO :169, SEQ JD NO.T71, SEQ ID NO:173, SEQ ID NO: 175, SEQ ID NO: 177, SEQ ID NO :179 and SEQ ID NO: 181) are particularly useful probes. Such probes may be labelled with an analytically-detectable reagent to facilitate their identification. Useful reagents include, but are not limited to, radioisotopes, fluorescent dyes and enzymes that are capable of catalysing the formation of a detectable product. Using these probes, the ordinarily skilled artisan will be capable of isolating complementary copies of genomic DNA, cDNA or RNA polynucleotides encoding proteins of interest from human, mammalian or other animal sources and screening such sources for related sequences, for example, for additional members of the family, type and or subtype. In many cases, isolated cDNA sequences will be incomplete, in that the region encoding the polypeptide will be cut short, normally at the 5' end. Several methods are available to obtain full length cDNAs, or to extend short cDNAs. Such sequences may be extended utilising a partial nucleotide sequence and employing various methods known in the art to detect upstream sequences such as promoters and regulatory elements. For example, one method which may be employed is based on the method of Rapid Amplification of cDNA Ends (RACE; see, for example, Frohman et al., PNAS USA 85, 8998-9002, 1988). Recent modifications of this technique, exemplified by the Marathon™ technology (Clontech Laboratories Inc.), for example, have significantly simplified the search for longer cDNAs. A slightly different technique, termed "restriction-site" PCR, uses universal primers to retrieve unknown nucleic acid sequence adjacent a known locus (Sarkar, G. (1993) PCR Methods Applic. 2:318-322). Inverse PCR may also be used to amplify or to extend sequences using divergent primers based on a known region (Triglia, T. et al. (1988) Nucleic Acids Res. 16:8186). Another method which may be used is capture PCR which involves PCR amplification of DNA fragments adjacent a known sequence in human and yeast artificial chromosome DNA (Lagerstrom, M. et al. (1991) PCR Methods Applic, 1, 111-119). Another method which may be used to retrieve unknown sequences is that of Parker, JD. et al. (1991); Nucleic Acids Res. 19:3055-3060). Additionally, one may use PCR, nested primers, and PromoterFinder™ libraries to walk genomic DNA (Clontech, Palo Alto, CA). This process avoids the need to screen libraries and is useful in finding intron/exon junctions.

When screening for full-length cDNAs, it is preferable to use libraries that have been size- selected to include larger cDNAs. Also, random-primed libraries are preferable, in that they will contain more sequences that contain the 5' regions of genes. Use of a randomly primed library may be especially preferable for situations in which an oligo d(T) library does not yield a full-length cDNA. Genomic libraries may be useful for extension of sequence into 5' non-transcribed regulatory regions.

In one embodiment of the invention, the nucleic acid molecules of the present invention may be used for chromosome localisation. In this technique, a nucleic acid molecule is specifically targeted to, and can hybridize with, a particular location on an individual human chromosome. The mapping of relevant sequences to chromosomes according to the present invention is an important step in the confirmatory correlation of those sequences with the gene-associated disease. Once a sequence has been mapped to a precise chromosomal location, the physical position of the sequence on the chromosome can be correlated with genetic map data. Such data are found in, for example, V. McKusick, Mendelian Inheritance in Man (available online through Johns Hopkins University Welch Medical Library). The relationships between genes and diseases that have been mapped to the same chromosomal region are then identified through linkage analysis (coinheritance of physically adjacent genes). This provides valuable information to investigators searching for disease genes using positional cloning or other gene discovery techniques. Once the disease or syndrome has been crudely localised by genetic linkage to a particular genomic region, any sequences mapping to that area may represent associated or regulatory genes for further investigation. The nucleic acid molecule may also be used to detect differences in the chromosomal location due to translocation, inversion, etc. among normal, carrier, or affected individuals.

The nucleic acid molecules of the present invention are also valuable for tissue localisation. Such techniques allow the determination of expression patterns of the polypeptide in tissues by detection of the mRNAs that encode them. These techniques include in situ hybridization techniques and nucleotide amplification techniques, such as PCR. Results from these studies provide an indication of the normal functions of the polypeptide in the organism. In addition, comparative studies of the normal expression pattern of mRNAs with that of mRNAs encoded by a mutant gene provide valuable insights into the role of mutant polypeptides in disease/disorders. Such inappropriate expression may be of a temporal, spatial or quantitative nature. The vectors of the present invention comprise nucleic acid molecules of the invention and may be cloning or expression vectors. The host cells of the invention, which may be transformed, transfected or transduced with the vectors of the invention may be prokaryotic or eukaryotic.

The polypeptides of the invention may be prepared in recombinant form by expression of their encoding nucleic acid molecules in vectors contained within a host cell. Such expression methods are well known to those of skill in the art and many are described in detail by Sambrook et al. (supra) and Fernandez & Hoeffler (1998, eds. "Gene expression systems. Using nature for the art of expression". Academic Press, San Diego, London, Boston, New York, Sydney, Tokyo, Toronto). Generally, any system or vector that is suitable to maintain, propagate or express nucleic acid molecules to produce a polypeptide in the required host may be used. The appropriate nucleotide sequence may be inserted into an expression system by any of a variety of well- known and routine techniques, such as, for example, those described in Sambrook et al., (supra). Generally, the encoding gene can be placed under the control of a control element such as a promoter, ribosome binding site (for bacterial expression) and, optionally, an operator, so that the DNA sequence encoding the desired polypeptide is transcribed into RNA in the transformed host cell.

Examples of suitable expression systems include, for example, chromosomal, episomal and virus-derived systems, including, for example, vectors derived from: bacterial plasmids, bacteriophage, transposons, yeast episomes, insertion elements, yeast chromosomal elements, viruses such as baculoviruses, papova viruses such as SV40, vaccinia viruses, adenoviruses, fowl pox viruses, pseudorabies viruses and retroviruses, or combinations thereof, such as those derived from plasmid and bacteriophage genetic elements, including cosmids and phagemids. Human artificial chromosomes (HACs) may also be employed to deliver larger fragments of DNA than can be contained and expressed in a plasmid.

Particularly suitable expression systems include microorganisms such as bacteria transformed with recombinant bacteriophage, plasmid or cosmid DNA expression vectors; yeast transformed with yeast expression vectors; insect cell systems infected with virus expression vectors (for example, baculovirus); plant cell systems transformed with virus expression vectors (for example, cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) or with bacterial expression vectors (for example, Ti or pBR322 plasmids); or animal cell systems. Cell-free translation systems can also be employed to produce the polypeptides of the invention.

Introduction of nucleic acid molecules encoding a polypeptide of the present invention into host cells can be effected by methods described in many standard laboratory manuals, such as Davis et al., Basic Methods in Molecular Biology (1986) and Sambrook et ah, (supra). Particularly suitable methods include calcium phosphate transfection, DEAE-dextran mediated transfection, transfection, microinjection, cationic lipid-mediated transfection, electroporation, transduction, scrape loading, ballistic introduction or infection (see Sambrook et al, 1989 [supra]; Ausubel et al., 1991 [supra]; Spector, Goldman & Leinwald, 1998). In eukaryotic cells, expression systems may either be transient (for example, episomal) or permanent (chromosomal integration) according to the needs of the system.

The encoding nucleic acid molecule may or may not include a sequence encoding a control sequence, such as a signal peptide or leader sequence, as desired, for example, for secretion of the translated polypeptide into the lumen of the endoplasmic reticulum, into the periplasmic space or into the extracellular environment. These signals may be endogenous to the polypeptide or they may be heterologous signals. Leader sequences can be removed by the bacterial host in post-translational processing. In addition to control sequences, it may be desirable to add regulatory sequences that allow for regulation of the expression of the polypeptide relative to the growth of the host cell. Examples of regulatory sequences are those which cause the expression of a gene to be increased or decreased in response to a chemical or physical stimulus, including the presence of a regulatory compound or to various temperature or metabolic conditions. Regulatory sequences are those non-translated regions of the vector, such as enhancers, promoters and 5' and 3' untranslated regions. These interact with host cellular proteins to carry out transcription and translation. Such regulatory sequences may vary in their strength and specificity. Depending on the vector system and host utilised, any number of suitable transcription and translation elements, including constitutive and inducible promoters, may be used. For example, when cloning in bacterial systems, inducible promoters such as the hybrid lacZ promoter of the Bluescript phagemid (Sfratagene, LaJolla, CA) or pSportl™ plasmid (Gibco BRL) and the like may be used. The baculovirus polyhedrin promoter may be used in insect cells. Promoters or enhancers derived from the genomes of plant cells (for example, heat shock, RUBISCO and storage protein genes) or from plant viruses (for example, viral promoters or leader sequences) may be cloned into the vector. In mammalian cell systems, promoters from mammalian genes or from mammalian viruses are preferable. If it is necessary to generate a cell line that contains multiple copies of the sequence, vectors based on S V40 or EBV may be used with an appropriate selectable marker.

An expression vector is constructed so that the particular nucleic acid coding sequence is located in the vector with the appropriate regulatory sequences, the positioning and orientation of the coding sequence with respect to the regulatory sequences being such that the coding sequence is transcribed under the "control" of the regulatory sequences, i.e., RNA polymerase which binds to the DNA molecule at the control sequences transcribes the coding sequence. In some cases it may be necessary to modify the sequence so that it may be attached to the control sequences with the appropriate orientation; i.e., to maintain the reading frame. The control sequences and other regulatory sequences may be ligated to the nucleic acid coding sequence prior to insertion into a vector. Alternatively, the coding sequence can be cloned directly into an expression vector that already contains the control sequences and an appropriate restriction site. For long-term, high-yield production of a recombinant polypeptide, stable expression is preferred. For example, cell lines which stably express the polypeptide of interest may be transformed using expression vectors which may contain viral origins of replication and/or endogenous expression elements and a selectable marker gene on the same or on a separate vector. Following the introduction of the vector, cells may be allowed to grow for 1-2 days in an enriched media before they are switched to selective media. The purpose of the selectable marker is to confer resistance to selection, and its presence allows growth and recovery of cells that successfully express the introduced sequences. Resistant clones of stably transformed cells may be proliferated using tissue culture techniques appropriate to the cell type. Mammalian cell lines available as hosts for expression are known in the art and include many immortalised cell lines available from the American Type Culture Collection (ATCC) including, but not limited to, Chinese hamster ovary (CHO), HeLa, baby hamster kidney (BHK), monkey kidney (COS), C127, 3T3, BHK, HEK 293, Bowes melanoma and human hepatocellular carcinoma (for example Hep G2) cells and a number of other cell lines. In the baculovirus system, the materials for baculovirus/insect cell expression systems are commercially available in kit form from, ter alia, Invitrogen, San Diego CA (the "MaxBac" kit). These techniques are generally known to those skilled in the art and are described fully in Summers and Smith, Texas Agricultural Experiment Station Bulletin No. 1555 (1987). Particularly suitable host cells for use in this system include insect cells such as Drosophila S2 and Spodoptera Sf9 cells.

There are many plant cell culture and whole plant genetic expression systems known in the art. Examples of suitable plant cellular genetic expression systems include those described in US 5,693,506; US 5,659,122; and US 5,608,143. Additional examples of genetic expression in plant cell culture has been described by Zenk, Phytochemistry 30, 3861-3863 (1991). In particular, all plants from which protoplasts can be isolated and cultured to give whole regenerated plants can be utilised, so that whole plants are recovered which contain the transferred gene. Practically all plants can be regenerated from cultured cells or tissues, including but not limited to all major species of sugar cane, sugar beet, cotton, fruit and other trees, legumes and vegetables.

Examples of particularly preferred bacterial host cells include streptococci, staphylococci, E. coli, Streptomyces and Bacillus subtilis cells. Examples of particularly suitable host cells for fungal expression include yeast cells (for example, S. cerevisiae) and Aspergillus cells.

Any number of selection systems are known in the art that may be used to recover transformed cell lines. Examples include the herpes simplex virus thymidine kinase (Wigler, M. et al. (1977) Cell 11:223-32) and adenine phosphoribosyltransferase (Lowy, I. et al. (1980) Cell 22:817-23) genes that can be employed in tk^" or aprt* cells, respectively.

Also, antimetabolite, antibiotic or herbicide resistance can be used as the basis for selection; for example, dihydrofolate reductase (DHFR) that confers resistance to methotrexate (Wigler, M. et al. (1980) Proc. Natl. Acad. Sci. 77:3567-70); npt, which confers resistance to the aminoglycosides neomycin and G-418 (Colbere-Garapin, F. et al. (1981) J. Mol. Biol. 150:1- 14) and als or pat, which confer resistance to chlorsulfuron and phosphinotricin acetyltransferase, respectively. Additional selectable genes have been described, examples of which will be clear to those of skill in the art.

Although the presence or absence of marker gene expression suggests that the gene of interest is also present, its presence and expression may need to be confirmed. For example, if the relevant sequence is inserted within a marker gene sequence, transfonned cells containing the appropriate sequences can be identified by the absence of marker gene function. Alternatively, a marker gene can be placed in tandem with a sequence encoding a polypeptide of the invention under the control of a single promoter. Expression of the marker gene in response to induction or selection usually indicates expression of the tandem gene as well. Alternatively, host cells that contain a nucleic acid sequence encoding a polypeptide of the invention and which express said polypeptide may be identified by a variety of procedures known to those of skill in the art. These procedures include, but are not limited to, DNA-DNA or DNA-RNA hybridizations and protein bioassays, for example, fluorescence activated cell sorting (FACS) or immunoassay techniques (such as the enzyme-linked immunosorbent assay [ELISA] and radioimmunoassay [RIA]), that include membrane, solution, or chip based technologies for the detection and/or quantification of nucleic acid or protein (see Hampton, R. et al. (1990) Serological Methods, a Laboratory Manual, APS Press, St Paul, MN) and Maddox, D.E. et al. (1983) J. Exp. Med, 158, 1211-1216).

A wide variety of labels and conjugation techniques are known by those skilled in the art and may be used in various nucleic acid and amino acid assays. Means for producing labelled hybridization or PCR probes for detecting sequences related to nucleic acid molecules encoding polypeptides of the present invention include oligolabelling, nick translation, end- labelling or PCR amplification using a labelled polynucleotide. Alternatively, the sequences encoding the polypeptide of the invention may be cloned into a vector for the production of an mRNA probe. Such vectors are known in the art, are commercially available, and may be used to synthesise RNA probes in vitro by addition of an appropriate RNA polymerase such as T7, T3 or SP6 and labelled nucleotides. These procedures may be conducted using a variety of commercially available kits (Pharmacia & Upjohn, (Kalamazoo, MI); Promega (Madison WI); and U.S. Biochemical Corp., Cleveland, OH)).

Suitable reporter molecules or labels, which may be used for ease of detection, include radionuclides, enzymes and fluorescent, chemiluminescent or chromogenic agents as well as substrates, cofactors, inhibitors, magnetic particles, and the like.

Nucleic acid molecules according to the present invention may also be used to create transgenic animals, particularly rodent animals. Such transgenic animals form a further aspect of the present invention. This may be done locally by modification of somatic cells, or by germ line therapy to incorporate heritable modifications. Such transgenic animals may be particularly useful in the generation of animal models for drug molecules effective as modulators of the polypeptides of the present invention.

The polypeptide can be recovered and purified from recombinant cell cultures by well-known methods including ammonium sulphate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography and lectin chromatography. High performance liquid chromatography is particularly useful for purification. Well known techniques for refolding proteins may be employed to regenerate an active conformation when the polypeptide is denatured during isolation and or purification. Specialised vector constructions may also be used to facilitate purification of proteins, as desired, by joining sequences encoding the polypeptides of the invention to a nucleotide sequence encoding a polypeptide domain that will facilitate purification of soluble proteins. Examples of such purification-facilitating domains include metal chelating peptides such as histidine-tryptophan modules that allow purification on immobilised metals, protein A domains that allow purification on immobilised immunoglobulin, and the domain utilised in the FLAGS extension affinity purification system (Immunex Corp., Seattle, WA). The inclusion of cleavable linker sequences such as those specific for Factor XA or enterokinase (Invitrogen, San Diego, CA) between the purification domain and the polypeptide of the invention may be used to facilitate purification. One such expression vector provides for expression of a fusion protein containing the polypeptide of the invention fused to several histidine residues preceding a thioredoxin or an enterokinase cleavage site. The histidine residues facilitate purification by IMAC (immobilised metal ion affinity chromatography as described in Porath, J. et al. (1992), Prot. Exp. Purif. 3: 263-281) while the thioredoxin or enterokinase cleavage site provides a means for purifying the polypeptide from the fusion protein. A discussion of vectors which contain fusion proteins is provided in Kroll, D.J. et al. (1993; DNA Cell Biol. 12:441-453). If the polypeptide is to be expressed for use in screening assays, generally it is preferred that it be produced at the surface of the host cell in which it is expressed. In this event, the host cells may be harvested prior to use in the screening assay, for example using techniques such as fluorescence activated cell sorting (FACS) or immunoaffinity techniques. If the polypeptide is secreted into the medium, the medium can be recovered in order to recover and purify the expressed polypeptide. If polypeptide is produced intracellularly, the cells must first be lysed before the polypeptide is recovered.

The polypeptide of the invention can be used to screen libraries of compounds in any of a variety of drug screening techniques. Such compounds may activate (agonise) or inhibit (antagonise) the level of expression of the gene or the activity of the polypeptide of the invention and form a further aspect of the present invention. Preferred compounds are effective to alter the expression of a natural gene which encodes a polypeptide of the first aspect of the invention or to regulate the activity of a polypeptide of the first aspect of the invention.

Agonist or antagonist compounds may be isolated from, for example, cells, cell-free preparations, chemical libraries or natural product mixtures. These agonists or antagonists may be natural or modified substrates, ligands, enzymes, receptors or structural or functional mimetics. For a suitable review of such screening techniques, see Coligan et al, Current Protocols in Immunology l(2):Chapter 5 (1991).

Compounds that are most likely to be good antagonists are molecules that bind to the polypeptide of the invention without inducing the biological effects of the polypeptide upon binding to it. Potential antagonists include small organic molecules, peptides, polypeptides and antibodies that bind to the polypeptide of the invention and thereby inhibit or extinguish its activity. In this fashion, binding of the polypeptide to normal cellular binding molecules may be inhibited, such that the normal biological activity of the polypeptide is prevented.

The polypeptide of the invention that is employed in such a screening technique may be free in solution, affixed to a solid support, borne on a cell surface or located intracellularly. In general, such screening procedures may involve using appropriate cells or cell membranes that express the polypeptide that are contacted with a test compound to observe binding, or stimulation or inhibition of a functional response. The functional response of the cells contacted with the test compound is then compared with control cells that were not contacted with the test compound. Such an assay may assess whether the test compound results in a signal generated by activation of the polypeptide, using an appropriate detection system. Inhibitors of activation are generally assayed in the presence of a known agonist and the effect on activation by the agonist in the presence of the test compound is observed.

A preferred method for identifying an agonist or antagonist compound of a polypeptide or a multimeric complex of the present invention comprises: (a) contacting a cell expressing on the surface thereof the polypeptide according to the first aspect of the invention, the polypeptide being associated with a second component capable of providing a detectable signal in response to the binding of a compound to the polypeptide, with a compound to be screened under conditions to permit binding to the polypeptide; and

(b) determining whether the compound binds to and activates or inhibits the polypeptide by measuring the level of a signal generated from the interaction of the compound with the polypeptide.

A further preferred method for identifying an agonist or antagonist of a polypeptide or a multimeric complex of the invention comprises:

(a) contacting a cell expressing on the surface thereof the polypeptide, the polypeptide being associated with a second component capable of providing a detectable signal in response to the binding of a compound to the polypeptide, with a compound to be screened under conditions to permit binding to the polypeptide; and

(b) determining whether the compound binds to and activates or inhibits the polypeptide by comparing the level of a signal generated from the interaction of the compound with the polypeptide with the level of a signal in the absence of the compound. In further preferred embodiments, the general methods that are described above may further comprise conducting the identification of agonist or antagonist in the presence of labelled or unlabelled ligand for the polypeptide or multimeric complex.

In another embodiment of the method for identifying an agonist or antagonist of a polypeptide or multimeric complex of the present invention comprises: determining the inhibition of binding of a ligand to cells which have a polypeptide of the invention on the surface thereof, or to cell membranes containing such a polypeptide, in the presence of a candidate compound under conditions to permit binding to the polypeptide, and determining the amount of ligand bound to the polypeptide. A compound capable of causing reduction of binding of a ligand is considered to be an agonist or antagonist. Preferably the ligand is labelled.

More particularly, a method of screening for a polypeptide antagonist or agonist compound comprises the steps of:

(a) incubating a labelled ligand with a whole cell expressing a polypeptide according to the invention on the cell surface, or a cell membrane containing a polypeptide of the invention, (b) measuring the amount of labelled ligand bound to the whole cell or the cell membrane;

(c) adding a candidate compound to a mixture of labelled ligand and the whole cell or the cell membrane of step (a) and allowing the mixture to attain equilibrium;

(d) measuring the amount of labelled ligand bound to the whole cell or the cell membrane after step (c); and (e) comparing the difference in the labelled ligand bound in step (b) and (d), such that the compound which causes the reduction in binding in step (d) is considered to be an agonist or antagonist.

In certain of the embodiments described above, simple binding assays may be used, in which the adherence of a test compound to a surface bearing the polypeptide is detected by means of a label directly or indirectly associated with the test compound or in an assay involving competition with a labelled competitor. In another embodiment, competitive drug screening assays may be used, in which neutralising antibodies that are capable of binding the polypeptide or multimeric complex specifically compete with a test compound for binding. In this manner, the antibodies can be used to detect the presence of any test compound that possesses specific binding affinity for the polypeptide or multimeric complex.

Assays may also be designed to detect the effect of added test compounds on the production of mRNA encoding the polypeptide in cells. For example, an ELISA may be constructed that measures secreted or cell-associated levels of polypeptide using monoclonal or polyclonal antibodies by standard methods known in the art, and this can be used to search for compounds that may inhibit or enhance the production of the polypeptide or multimeric complex from suitably manipulated cells or tissues. The formation of binding complexes between the polypeptide or multimeric complex and the compound being tested may then be measured.

Another technique for drug screening which may be used provides for high throughput screening of compounds having suitable binding affinity to the polypeptide or multimeric complex of interest (see International patent application WO84/03564). In this method, large numbers of different small test compounds are synthesised on a solid substrate, which may then be reacted with the polypeptide or multimeric complex of the invention and washed. One way of immobilising the polypeptide or multimeric complex is to use non-neutralising antibodies. Bound polypeptide may then be detected using methods that are well known in the art. Purified polypeptide can also be coated directly onto plates for use in the aforementioned drug screening techniques.

The polypeptide of the invention may be used to identify membrane-bound or soluble receptors, through standard receptor binding techniques that are known in the art, such as ligand binding and crosslmking assays in which the polypeptide is labelled with a radioactive isotope, is chemically modified, or is fused to a peptide sequence that facilitates its detection or purification, and incubated with a source of the putative receptor (for example, a composition of cells, cell membranes, cell supernatants, tissue extracts, or bodily fluids). The efficacy of binding may be measured using biophysical techniques such as surface plasmon resonance and spectroscopy. Binding assays may be used for the purification and cloning of the receptor, but may also identify agonists and antagonists of the polypeptide, that compete with the binding of the polypeptide to its receptor. Standard methods for conducting screening assays are well understood in the art.

The invention also includes a screening kit useful in the methods for identifying agonists, antagonists, ligands, receptors, substrates, enzymes, that are described above.

The invention includes the agonists, antagonists, ligands, receptors, substrates and enzymes, and other compounds which modulate the activity or antigenicity of the polypeptide or multimeric complex of the invention discovered by the methods that are described above.

The invention also provides pharmaceutical compositions comprising a polypeptide, nucleic acid, ligand, compound or multimeric complex of the invention in combination with a suitable pharmaceutical carrier. These compositions may be suitable as therapeutic or diagnostic reagents, as vaccines, or as other immunogenic compositions, as outlined in detail below.

According to the terminology used herein, a composition containing a polypeptide, nucleic acid, ligand or compound [X] is "substantially free of impurities [herein, Y] when at least 85% by weight of the total X+Y in the composition is X. Preferably, X comprises at least about 90% by weight of the total of X+Y in the composition, more preferably at least about 95%, 98% or even 99% by weight.

The pharmaceutical compositions should preferably comprise a therapeutically effective amount of the polypeptide, nucleic acid molecule, ligand, compound or multimeric complex of the invention. The term "therapeutically effective amount" as used herein refers to an amount of a therapeutic agent needed to treat, ameliorate, or prevent a targeted disease or condition, or to exhibit a detectable therapeutic or preventative effect. For any compound, the therapeutically effective dose can be estimated initially either in cell culture assays, for example, of neoplastic cells, or in animal models, usually mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.

The precise effective amount for a human subject will depend upon the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. This amount can be determined by routine experimentation and is within the judgement of the clinician. Generally, an effective dose will be from 0.01 mg/kg to 50 mg/kg, preferably 0.05 mg/kg to 10 mg/kg. Compositions may be administered individually to a patient or may be administered in combination with other agents, drugs or hormones.

A pharmaceutical composition may also contain a pharmaceutically acceptable carrier, for administration of a therapeutic agent. Such carriers include antibodies and other polypeptides, genes and other therapeutic agents such as liposomes, provided that the carrier does not itself induce the production of antibodies harmful to the individual receiving the composition, and which may be administered without undue toxicity. Suitable carriers may be large, slowly metabolised macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers and inactive virus particles. Pharmaceutically acceptable salts can be used therein, for example, mineral acid salts such as hydrochlorides, hydrobromides, phosphates, sulphates, and the like; and the salts of organic acids such as acetates, propionates, malonates, benzoates, and the like. A thorough discussion of pharmaceutically acceptable carriers is available in Remington's Pharmaceutical Sciences (Mack Pub. Co., N.J. 1991). Pharmaceutically acceptable carriers in therapeutic compositions may additionally contain liquids such as water, saline, glycerol and ethanol. Additionally, auxiliary substances, such as wetting or emulsifying agents, pH buffering substances, and the like, may be present in such compositions. Such carriers enable the pharmaceutical compositions to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for ingestion by the patient.

Once formulated, the compositions of the invention can be administered directly to the subject. The subjects to be treated can be animals; in particular, human subjects can be treated.

The pharmaceutical compositions utilised in this invention may be administered by any number of routes including, but not limited to, oral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, intraventricular, transdermal or transcutaneous applications (for example, see WO98/20734), subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, intravaginal or rectal means. Gene guns or hyposprays may also be used to administer the pharmaceutical compositions of the invention. Typically, the therapeutic compositions may be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection may also be prepared. Direct delivery of the compositions will generally be accomplished by injection, subcutaneously, intraperitoneally, intravenously or intramuscularly, or delivered to the interstitial space of a tissue. The compositions can also be administered into a lesion. Dosage treatment may be a single dose schedule or a multiple dose schedule. If the activity of the polypeptide of the invention is in excess in a particular disease state, several approaches are available. One approach comprises administering to a subject an inhibitor compound (antagonist) as described above, along with a pharmaceutically acceptable carrier in an amount effective to inhibit the function of the polypeptide, such as by blocking the binding of ligands, substrates, enzymes, receptors, or by inhibiting a second signal, and thereby alleviating the abnormal condition. Preferably, such antagonists are antibodies. Most preferably, such antibodies are chimeric and/or humanised to minimise their immunogenicity, as described previously.

In another approach, soluble forms of the polypeptide that retain binding affinity for the ligand, substrate, enzyme, receptor, in question, may be administered. Typically, the polypeptide may be administered in the form of fragments that retain the relevant portions.

In an alternative approach, expression of the gene encoding the polypeptide can be inhibited using expression blocking techniques, such as the use of antisense nucleic acid molecules (as described above), either internally generated or separately administered. Modifications of gene expression can be obtained by designing complementary sequences or antisense molecules (DNA, RNA, or PNA) to the control, 5' or regulatory regions (signal sequence, promoters, enhancers and introns) of the gene encoding the polypeptide. Similarly, inhibition can be achieved using "triple helix" base-pairing methodology. Triple helix pairing is useful because it causes inhibition of the ability of the double helix to open sufficiently for the binding of polymerases, transcription factors, or regulatory molecules. Recent therapeutic advances using triplex DNA have been described in the literature (Gee, J.E. et al. (1994) In: Huber, B.E. and B.I. Carr, Molecular and Immunologic Approaches, Futura Publishing Co., Mt. Kisco, NY). The complementary sequence or antisense molecule may also be designed to block translation of mRNA by preventing the transcript from binding to ribosomes. Such oligonucleotides may be administered or may be generated in situ from expression in vivo. In addition, expression of the polypeptide of the invention may be prevented by using ribozymes specific to its encoding mRNA sequence. Ribozymes are catalytically active RNAs that can be natural or synthetic (see for example Usman, N, et al, Curr. Opin. Struct. Biol (1996) 6(4), 527-33). Synthetic ribozymes can be designed to specifically cleave mRNAs at selected positions thereby preventing translation of the mRNAs into functional polypeptide. Ribozymes may be synthesised with a natural ribose phosphate backbone and natural bases, as normally found in RNA molecules. Alternatively the ribozymes may be synthesised with non-natural backbones, for example, 2'-O-methyl RNA, to provide protection from ribonuclease degradation and may contain modified bases.

RNA molecules may be modified to increase intracellular stability and half-life. Possible modifications include, but are not limited to, the addition of flanking sequences at the 5' and/or 3' ends of the molecule or the use of phosphorothioate or 2' O-methyl rather than phosphodiesterase linkages within the backbone of the molecule. This concept is inherent in the production of PNAs and can be extended in all of these molecules by the inclusion of non- traditional bases such as inosine, queosine and butosine, as well as acetyl-, methyl-, thio- and similarly modified forms of adenine, cytidine, guanine, thymine and uridine which are not as easily recognised by endogenous endonucleases. For treating abnormal conditions related to an under-expression of the polypeptide of the invention and its activity, several approaches are also available. One approach comprises administering to a subject a therapeutically effective amount of a compound that activates the polypeptide or multimeric complex, i.e., an agonist as described above, to alleviate the abnormal condition. Alternatively, a therapeutic amount of the polypeptide or multimeric complex in combination with a suitable pharmaceutical carrier may be administered to restore the relevant physiological balance of polypeptide or multimeric complex.

Gene therapy may be employed to effect the endogenous production of the polypeptide by the relevant cells in the subject. Gene therapy is used to treat permanently the inappropriate production of the polypeptide by replacing a defective gene with a corrected therapeutic gene. Gene therapy of the present invention can occur in vivo or ex vivo. Ex vivo gene therapy requires the isolation and purification of patient cells, the introduction of a therapeutic gene and introduction of the genetically altered cells back into the patient. In contrast, in vivo gene therapy does not require isolation and purification of a patient's cells.

The therapeutic gene is typically "packaged" for administration to a patient. Gene delivery vehicles may be non- viral, such as liposomes, or replication-deficient viruses, such as adenovirus as described by Berkner, K.L., in Curr. Top. MicrobioL Immunol., 158, 39-66

(1992) or adeno-associated virus (AAV) vectors as described by Muzyczka, N., in Curr. Top. MicrobioL Immunol., 158, 97-129 (1992) and U.S. Patent No. 5,252,479. For example, a nucleic acid molecule encoding a polypeptide of the invention may be engineered for expression in a replication-defective retroviral vector. This expression construct may then be isolated and introduced into a packaging cell transduced with a retroviral plasmid vector containing RNA encoding the polypeptide, such that the packaging cell now produces infectious viral particles containing the gene of interest. These producer cells may be administered to a subject for engineering cells in vivo and expression of the polypeptide in vivo (see Chapter 20, Gene Therapy and other Molecular Genetic-based Therapeutic Approaches, (and references cited therein) in Human Molecular Genetics (1996), T Strachan and A P Read, BIOS Scientific Publishers Ltd).

Another approach is the administration of "naked DNA" in which the therapeutic gene is directly injected into the bloodstream or muscle tissue.

In situations in which the polypeptides or nucleic acid molecules of the invention are disease- causing agents, the invention provides that they can be used in vaccines to raise antibodies against the disease causing agent.

Vaccines according to the invention may either be prophylactic (i.e. to prevent infection) or therapeutic (i.e. to treat disease after infection). Such vaccines comprise immunising antigen(s), immunogen(s), polypeptide(s), protein(s) or nucleic acid, usually in combination with pharmaceutically-acceptable carriers as described above, which include any carrier that does not itself induce the production of antibodies harmful to the individual receiving the composition. Additionally, these carriers may function as immunostimulating agents ("adjuvants"). Furthermore, the antigen or immunogen may be conjugated to a bacterial toxoid, such as a toxoid from diphtheria, tetanus, cholera, H. pylori, and other pathogens.

Since polypeptides may be broken down in the stomach, vaccines comprising polypeptides are preferably administered parenterally (for instance, subcutaneous, intramuscular, intravenous, or intradermal injection). Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the recipient, and aqueous and non-aqueous sterile suspensions which may include suspending agents or thickening agents.

The vaccine formulations of the invention may be presented in unit-dose or multi-dose containers. For example, sealed ampoules and vials and may be stored in a freeze-dried condition requiring only the addition of the sterile liquid carrier immediately prior to use. The dosage will depend on the specific activity of the vaccine and can be readily determined by routine experimentation.

Genetic delivery of antibodies that bind to polypeptides according to the invention may also be effected, for example, as described in International patent application WO98/55607.

The technology referred to as jet injection (see, for example, www.powderject.com) may also be useful in the formulation of vaccine compositions.

A number of suitable methods for vaccination and vaccine delivery systems are described in International patent application WO00/29428. This invention also relates to the use of nucleic acid molecules according to the present invention as diagnostic reagents. Detection of a mutated form of the gene characterised by the nucleic acid molecules of the invention which is associated with a dysfunction will provide a diagnostic tool that can add to, or define, a diagnosis of a disease, or susceptibility to a disease, which results from under-expression, over-expression or altered spatial or temporal expression of the gene. Individuals carrying mutations in the gene may be detected at the DNA level by a variety of techniques.

Nucleic acid molecules for diagnosis may be obtained from a subject's cells, such as from blood, urine, saliva, tissue biopsy or autopsy material. The genomic DNA may be used directly for detection or may be amplified enzymatically by using PCR, ligase chain reaction (LCR), strand displacement amplification (SDA), or other amplification techniques (see Saiki et al., Nature, 324, 163-166 (1986); Bej, et al., Crit. Rev. Biochem. Molec. Biol., 26, 301-334 (1991); Birkenmeyer et al., J. Virol. Meth., 35, 117-126 (1991); Van Brunt, J., Bio/Technology, 8, 291-294 (1990)) prior to analysis.

In one embodiment, this aspect of the invention provides a method of diagnosing a disease or disorder in a patient, comprising assessing the level of expression of a natural gene encoding a polypeptide according to the invention and comparing said level of expression to a control level, wherein a level that is different to said control level is indicative of disease. The method may comprise the steps of: a)contacting a sample of tissue from the patient with a nucleic acid probe under stringent conditions that allow the formation of a hybrid complex between a nucleic acid molecule of the invention and the probe; b)contacting a control sample with said probe under the same conditions used in step a); c)and detecting the presence of hybrid complexes in said samples; wherein detection of levels of the hybrid complex in the patient sample that differ from levels of the hybrid complex in the control sample is indicative of disease. A further aspect of the invention comprises a diagnostic method comprising the steps of: a)obtaining a tissue sample from a patient being tested for a disease; b)isolating a nucleic acid molecule according to the invention from said tissue sample; and c)diagnosing the patient for disease by detecting the presence of a mutation in the nucleic acid molecule which is associated with disease. To aid the detection of nucleic acid molecules in the above-described methods, an amplification step, for example using PCR, may be included.

Deletions and insertions can be detected by a change in the size of the amplified product in comparison to the normal genotype. Point mutations can be identified by hybridizing amplified DNA to labelled RNA of the invention or alternatively, labelled antisense DNA sequences of the invention. Perfectly-matched sequences can be distinguished from mismatched duplexes by RNase digestion or by assessing differences in melting temperatures. The presence or absence of the mutation in the patient may be detected by contacting DNA with a nucleic acid probe that hybridises to the DNA under stringent conditions to form a hybrid double-stranded molecule, the hybrid double-stranded molecule having an unhybridised portion of the nucleic acid probe strand at any portion corresponding to a mutation associated with disease; and detecting the presence or absence of an unhybridised portion of the probe strand as an indication of the presence or absence of a disease-associated mutation in the corresponding portion of the DNA strand.

Such diagnostics are particularly useful for prenatal and even neonatal testing. Point mutations and other sequence differences between the reference gene and "mutant" genes can be identified by other well-known techniques, such as direct DNA sequencing or single-strand conformational polymorphism, (see Orita et al., Genomics, 5, 874-879 (1989)). For example, a sequencing primer may be used with double-stranded PCR product or a single-stranded template molecule generated by a modified PCR. The sequence determination is performed by conventional procedures with radiolabelled nucleotides or by automatic sequencing procedures with fluorescent-tags. Cloned DNA segments may also be used as probes to detect specific DNA segments. The sensitivity of this method is greatly enhanced when combined with PCR. Further, point mutations and other sequence variations, such as polymorphisms, can be detected as described above, for example, through the use of allele- specific oligonucleotides for PCR amplification of sequences that differ by single nucleotides.

DNA sequence differences may also be detected by alterations in the electrophoretic mobility of DNA fragments in gels, with or without denaturing agents, or by direct DNA sequencing (for example, Myers et al, Science (1985) 230:1242). Sequence changes at specific locations may also be revealed by nuclease protection assays, such as RNase and SI protection or the chemical cleavage method (see Cotton et al, Proc. Natl. Acad. Sci. USA (1985) 85: 4397- 4401).

In addition to conventional gel electrophoresis and DNA sequencing, mutations such as microdeletions, aneuploidies, translocations, inversions, can also be detected by in situ analysis (see, for example, Keller et al. , DNA Probes, 2nd Ed., Stockton Press, New York, N.Y., USA (1993)), that is, DNA or RNA sequences in cells can be analysed for mutations without need for their isolation and/or immobilisation onto a membrane. Fluorescence in situ hybridization (FISH) is presently the most commonly applied method and numerous reviews of FISH have appeared (see, for example, Trachuck et al, Science, 250, 559-562 (1990), and Trask et al, Trends, Genet, 7, 149-154 (1991)). In another embodiment of the invention, an array of oligonucleotide probes comprising a nucleic acid molecule according to the invention can be constructed to conduct efficient screening of genetic variants, mutations and polymorphisms. Array technology methods are well known and have general applicability and can be used to address a variety of questions in molecular genetics including gene expression, genetic linkage, and genetic variability (see for example: M.Chee et al, Science (1996), Vol 274, pp 610-613).

In one embodiment, the array is prepared and used according to the methods described in PCT application WO95/11995 (Chee et al); Lockhart, D. J. et al. (1996) Nat. Biotech. 14: 1675- 1680); and Schena, M. et al. (1996) Proc. Natl. Acad. Sci. 93: 10614-10619). Oligonucleotide pairs may range from two to over one million. The oligomers are synthesized at designated areas on a substrate using a light-directed chemical process. The substrate may be paper, nylon or other type of membrane, filter, chip, glass slide or any other suitable solid support. In another aspect, an oligonucleotide may be synthesized on the surface of the substrate by using a chemical coupling procedure and an ink jet application apparatus, as described in PCT application W095/25116 (Baldeschweiler et al). In another aspect, a "gridded" array analogous to a dot (or slot) blot may be used to arrange and link cDNA fragments or oligonucleotides to the surface of a substrate using a vacuum system, thermal, UV, mechanical or chemical bonding procedures. An array, such as those described above, may be produced by hand or by using available devices (slot blot or dot blot apparatus), materials (any suitable solid support), and machines (including robotic instruments), and may contain 8, 24, 96, 384, 1536 or 6144 oligonucleotides, or any other number between two and over one million which lends itself to the efficient use of commercially-available instrumentation. In addition to the methods discussed above, diseases may be diagnosed by methods comprising determining, from a sample derived from a subject, an abnormally decreased or increased level of polypeptide or mRNA. Decreased or increased expression can be measured at the RNA level using any of the methods well known in the art for the quantitation of polynucleotides, such as, for example, nucleic acid amplification, for instance PCR, RT-PCR, RNase protection, Northern blotting and other hybridization methods.

Assay techniques that can be used to determine levels of a polypeptide of the present invention in a sample derived from a host are well-known to those of skill in the art and are discussed in some detail above (including radioimmunoassays, competitive-binding assays, Western Blot analysis and ELISA assays). This aspect of the invention provides a diagnostic method which comprises the steps of: (a) contacting a ligand as described above with a biological sample under conditions suitable for the formation of a ligand-polypeptide complex; and (b) detecting said complex.

Protocols such as ELISA, RIA, and FACS for measuring polypeptide levels may additionally provide a basis for diagnosing altered or abnormal levels of polypeptide expression. Normal or standard values for polypeptide expression are established by combining body fluids or cell extracts taken from normal mammalian subjects, preferably humans, with antibody to the polypeptide under conditions suitable for complex formation The amount of standard complex formation may be quantified by various methods, such as by photometric means.

Antibodies which specifically bind to a polypeptide of the invention may be used for the diagnosis of conditions or diseases characterised by expression of the polypeptide, or in assays to monitor patients being treated with the polypeptides, nucleic acid molecules, ligands and other compounds of the invention. Antibodies useful for diagnostic purposes may be prepared in the same manner as those described above for therapeutics. Diagnostic assays for the polypeptide include methods that utilise the antibody and a label to detect the polypeptide in human body fluids or extracts of cells or tissues. The antibodies may be used with or without modification, and may be labelled by joining them, either covalently or non- covalently, with a reporter molecule. A wide variety of reporter molecules known in the art may be used, several of which are described above.

Quantities of polypeptide expressed in subject, control and disease samples from biopsied tissues are compared with the standard values. Deviation between standard and subject values establishes the parameters for diagnosing disease. Diagnostic assays may be used to distinguish between absence, presence, and excess expression of polypeptide and to monitor regulation of polypeptide levels during therapeutic intervention. Such assays may also be used to evaluate the efficacy of a particular therapeutic treatment regimen in animal studies, in clinical trials or in monitoring the treatment of an individual patient.

A diagnostic kit of the present invention may comprise: (a) a nucleic acid molecule of the present invention;

(b) a polypeptide of the present invention;

(c) a multimeric complex of the present invention; or

(c) a ligand of the present invention.

In one aspect of the invention, a diagnostic kit may comprise a first container containing a nucleic acid probe that hybridises under stringent conditions with a nucleic acid molecule according to the invention; a second container containing primers useful for amplifying the nucleic acid molecule; and instructions for using the probe and primers for facilitating the diagnosis of disease. The kit may further comprise a third container holding an agent for digesting unhybridised RNA. In an alternative aspect of the invention, a diagnostic kit may comprise an array of nucleic acid molecules, at least one of which may be a nucleic acid molecule according to the invention.

To detect polypeptide according to the invention, a diagnostic kit may comprise one or more antibodies that bind to a polypeptide according to the invention; and a reagent useful for the detection of a binding reaction between the antibody and the polypeptide. Such kits will be of use in diagnosing a disease or susceptibility to disease in which members of the transporter/channel protein family are implicated. Such diseases may include cell proliferative disorders, including neoplasm, melanoma, lung, colorectal, breast, pancreas, head and neck and other solid tumours; myeloproliferative disorders, such as leukemia, non- Hodgkin lymphoma, leukopenia, thrombocytopenia, angiogenesis disorder, Kaposis' sarcoma; autoimmune/inflammatory disorders, including allergy, inflammatory bowel disease, arthritis, psoriasis and respiratory tract inflammation, asthma, and organ transplant rejection; cardiovascular disorders, including hypertension, oedema, angina, atherosclerosis, thrombosis, sepsis, shock, reperfusion injury, and ischemia; neurological disorders including central nervous system disease, Alzheimer's disease, brain injury, amyotrophic lateral sclerosis, and pain; developmental disorders; metabolic disorders including diabetes mellitus, osteoporosis, and obesity, AIDS and renal disease; infections including viral infection, bacterial infection, fungal infection and parasitic infection and other pathological conditions and in particular inflammation, colitis, hypertrophy, fibrosis, heart failure, myocardial infarction, angina, obesity, hyperinsulinemia, vascular disease, renal disease, fertility disorders, infertility, testosterone deficiency, testosterone-related disorder, testicular cancer and sexual dysfunction.

Various aspects and embodiments of the present invention will now be described in more detail by way of example, with particular reference to the INPIONCH07, INPIONCH08, INPIONCH09 and INPIONCHl 0 polypeptides.

It will be appreciated that modification of detail may be made without departing from the scope of the invention.

Brief description of the Figures Figure 1: Top 5 annotated hits from BLAST against NCBI non-redundant database using the full length INPIONCH07 polypeptide sequence;

Figure 2: Alignment generated by BLAST between the full-length INPIONCH07 polypeptide sequence and the sequence of the annotated protein, (NM_126259) putative Na⁺/H⁺ antiporter from Arabidopsis fhaliana; Figure 3: Alignment generated by BLAST between the full-length INPIONCH07 polypeptide sequence and the sequence of the annotated known protein, (AF368920) voltage-dependent calcium channel alphal3 subunit from Caenorhabditis elegans;

Figure 4: Conserved domain search results for INPIONCH07; Figure 5: Top 5 annotated hits from BLAST against NCBI non-redundant database using the full length INPIONCH08 polypeptide sequence;

Figure 6: Alignment generated by BLAST between the full-length INPIONCH08 polypeptide sequence and the sequence of the annotated protein, (NM_126259) putative Na⁺/H⁺ antiporter from Arabidopsis thaliana; Figure 7: Alignment generated by BLAST between the full-length INPIONCH08 polypeptide sequence and the sequence of the annotated known protein, (AF368920) voltage-dependent calcium channel alphal3 subunit from Caenorhabditis elegans;

Figure 8: Conserved domain search results for INPIONCH08;

Figure 9: Top 5 annotated hits from BLAST against NCBI non-redundant database using the full length INPIONCH09 polypeptide sequence;

Figure 10: Alignment generated by BLAST between the full-length INPIONCH09 polypeptide sequence and the sequence of the annotated protein, (AL359217) possible Na⁺/H⁺ antiporter from Leishmania major;

Figure 11: Alignment generated by BLAST between the full-length INPIONCH09 polypeptide sequence and the sequence of the annotated known protein, (AL022319) calcium channel, voltage-dependent, alpha II subunit from Homo sapiens;

Figure 12: Conserved domain search results for INPIONCH09;

Figure 13: Top 5 annotated hits from BLAST against NCBI non-redundant database using the full length unmasked INPIONCHIO polypeptide sequence; Figure 14: Alignment generated by BLAST between the full-length INPIONCHIO polypeptide sequence and the sequence of the annotated protein, (NM_126259) putative Na^4"/!!^1" antiporter from Arabidopsis thaliana;

Figure 15: Alignment generated by BLAST between the full-length INPIONCHIO polypeptide sequence and the sequence of the annotated known protein, (D31718) voltage-dependent calcium channel alpha- 1 subunit from Blattella germanica; Figure 16: Conserved domain search results for INPIONCHIO;

Figure 17: Multiple sequence alignment of JNPIONCH07, INPIONCH08, INPIONCH09 and INPIONCHIO;

Figure 18: Multiple sequence alignment of INPIONCH07, JNPIONCH08, INPIONCH09 and INPIONCHIO with ion channel sequences containing the ion transport domain regions S1-S4;

Figure 19: Multiple sequence alignment of INPIONCH07, INPIONCH08, INPIONCH09 and INPIONCHIO with sequences of selected cyclic nucleotide binding domains;

Figure 20: Multiple sequence alignment of INPIONCH07, JNPIONCH08, INPIONCH09 and INPIONCHIO with sequences of the latter half of NaVH^4" antiporter transmembrane domains; Figure 21 : Normalised expression of INPIONCH07 in 22 normal human tissues; and

Figure 22: Normalised expression of INPIONCH09 in 22 normal human tissues.

Examples

Example 1: INPIONCH07 The polypeptide sequence given in SEQ JD NO:42, which represents the translation of consecutive exons of INPIONCH07, was used as a BLAST query against the NCBI non- redundant Sequence database.

Low-complexity or coiled-coil regions can match many sequences in the database, thus causing "matrix drift", permitting large numbers of unrelated sequences to be dragged into the sequence profile of the query. It is for this reason that these regions are often masked. By 'masked' it is meant that where there exists a long row of hydrophobic residues, these have been replaced ('masked') by a row of Xs. However, the sequences used as BLAST queries against the NCBI non-redundant Sequence database in the present application are unmasked sequences.

The top five annotated matches are shown in Figure 1. The top five annotated matches are, in the order of the closest match to the fiftli closest match, to i) a putative Na⁺/H⁺ antiporter, ii) a voltage-dependent calcium channel alphal3 subunit, iii) a cation channel of sperm, iv) a skeletal muscle calcium channel alpha- 1 subunit, and v) a possible Na⁺/H⁺ antiporter. The top five hits all have a highly significant expectation value of 6e⁴ or less. These very low expectation values reinforce the high degree of confidence functional prediction of INPIONCH07.

Figure 2 shows the alignment of the INPIONCH07 query sequence to the sequence of the top annotated protein, a putative Na⁺/H⁺ antiporter from Arabidopsis thaliana. Figure 3 shows the alignment of the INPIONCH07 query sequence to the sequence of the top annotated known protein, a voltage-dependent calcium channel alphal3 subunit from Caenorhabditis elegans.

The amino acid sequence of LNPIONCH07 (SEQ ID NO:42) was submitted into the 3D- PSSM (position specific scoring matrix) search tool database (http://www.sbg.bio.ic.ac.uk/~3dpssm ) in an attempt to predict its 3 -dimensional structure and possible function. Significant alignments were, in the order of the closest match to the third closest match, to the amino acid sequence of: i) pfam00999, Na_H_Exchanger, Sodium/Hydrogen exchanger, ii) pfam00027, cNMP_binding, Cyclic nucleotide-binding, and iii) pfam00520, ion-trans, Ion transport protein, and are shown in Figure 4. These three alignments are to different sections of the INPONCH07 sequence; the N-terminal region of the INPIONCH07 sequence closely matches the sequence of the sodium/hydrogen exchanger, the middle region of the INPIONCH07 sequence closely matches the sequences of an ion transport protein and a region in the C-terminal half of the LNPIONCH07 sequence closely matches the sequence of a cyclic nucleotide-binding domain. These results provide further evidence that the LNPIONCH07 protein is a transporter/channel protein.

Example 2: INPIONCH08

The polypeptide sequence given in SEQ JD NO:86, which represents the translation of consecutive exons from INPIONCH08, was used as a BLAST query against the NCBI non- redundant Sequence database.

The top five annotated matches are shown in Figure 5. The top five annotated matches are, in the order of the closest match to the fifth closest match, to i) a putative Na^'TH^1" antiporter, ii) a voltage-dependent calcium channel alphal3 subunit, iii) a skeletal muscle calcium channel alpha- 1 subunit, iv) a possible Na⁺/H⁺ antiporter and v) a sodium hydrogen exchanger. The top five hits all have an expectation of 4e^"4 or less. This very low expectation value reinforces the functional prediction of INPIONCH08. Figure 6 shows the alignment of the INPIONCH08 query sequence to the sequence of the top annotated protein, a putative Na⁺/H⁺ antiporter from Arabidopsis thaliana. Figure 7 shows the alignment of the INPIONCH08 query sequence to the sequence of the top annotated known protein, a voltage-dependent calcium channel alphal 3 subunit from Caenorhabditis elegans. The amino acid sequence of LNPIONCH08 (SEQ ID NO:86) was submitted into the 3D- PSSM (position specific scoring matrix) search tool database (http://www.sbg.bio.ic.ac.uk/~3dpssm ) in an attempt to predict its 3 -dimensional structure and possible function. Significant alignments were, in the order of the closest match to the second closest match, to the amino acid sequence of: i) pfam00999, Na_H_Exchanger, Sodium/Hydrogen exchanger, and ii) pfam00027, cNMP_binding, Cyclic nucleotide-binding, and are shown in Figure 8. These three alignments are to different sections of the INPONCH08 sequence; the N-terminal region of the LNPIONCH08 sequence closely matches the sequence of the sodium/hydrogen exchanger and a region in the C-terminal half of the INPIONCH08 sequence closely matches the sequence of a cyclic nucleotide-binding domain. These results provide further evidence that the INPIONCH08 protein is a transporter/channel protein.

Example 3: INPIONCH09

The polypeptide sequence given in SEQ JD NO: 130, which represents the translation of consecutive exons of LNPIONCH09, was used as a BLAST query against the NCBI non- redundant Sequence database.

The top five annotated matches are shown in Figure 9. The top five annotated matches are, in the order of the closest match to the fifth closest match, to i) a possible Na⁺/H⁺ antiporter, ii) a voltage-dependent calcium channel, alpha II subunit, iii) a voltage-dependent calcium channel T-type alpha II subunit, iv) a T-type calcium channel alphal subunit Alphall-a isoform, and v) a voltage-dependent alpha II subunit.

The top five hits all have a highly significant expectation value of le^"6 or less. These very low expectation values reinforce the high degree of confidence functional prediction of 1NPIONCH09. Figure 10 shows the alignment of the INPIONCH09 query sequence to the sequence of the top annotated protein, a possible NaYH^"1" antiporter from Leishmania major. Figure 11 shows the alignment of the LNPIONCH09 query sequence to the sequence of the top annotated known protein, a voltage-dependent calcium channel alpha II subunit from Homo sapiens.

The amino acid sequence of INPIONCH09 (SEQ ID NO: 130) was submitted into the 3D- PSSM (position specific scoring matrix) search tool database (http://www.sbg.bio.ic.ac.uk/~3dpssm/) in an attempt to predict its 3 -dimensional structure and possible function. Significant alignments were, in the order of the closest match to the second closest match, to the amino acid sequence of: i) pfam00027, cNMP_binding, Cyclic nucleotide-binding, and ii) pfam.00520, ion-trans, Ion transport protein, and are shown in Figure 12. These two alignments are to different sections of the INPONCH09 sequence; the middle region of the LNPIONCH09 sequence closely matches the sequences of an ion transport protein and a region in the C-terminal half of the INPIONCH09 sequence closely matches the sequence of a cyclic nucleotide-binding domain. These results provide further evidence that the LNPIONCH09 protein is a transporter/channel protein.

Example 4: INPIONCHl 0

The polypeptide sequence given in SEQ ID NO: 174, which represents the translation of consecutive exons of INPIONCHIO, was used as a BLAST query against the NCBI non- redundant Sequence database.

The top five annotated matches are shown in Figure 13. The top five annotated matches are, in the order of the closest match to the fifth closest match, to i) a putative Na⁺/H⁺ antiporter, ii) a possible Na+ H+ antiporter, iii) a voltage-dependent calcium channel alpha- 1 subunit, iv) a cation channel of sperm, and v) a putative Na⁺/H⁺ antiporter.

The top five hits all have a highly significant expectation value of 2e^"5 or less. These very low expectation values reinforce the high degree of confidence functional prediction of INPIONCHIO.

Figure 14 shows the alignment of the INPIONCHIO query sequence to the sequence of the top annotated protein, a putative Na⁺/H⁺ antiporter from Arabidopsis thaliana. Figure 15 shows the alignment of the INPIONCHIO query sequence to the sequence of the top annotated known protein, a voltage-dependent calcium channel alpha- 1 subunit from Blattella germanica. The amino acid sequence of INPIONCHIO (SEQ ID NO:174) was submitted into the 3D- PSSM (position specific scoring matrix) search tool database (http://www.sbg.bio.ic.ac.uk/~3dpssmΛ in an attempt to predict its 3-dimensional structure and possible function. Significant alignments were, in the order of the closest match to the second closest match, to the amino acid sequence of: i) pfam.00027, cNMP_binding, Cyclic nucleotide-binding, and ii) pfam00999, NaJHJExchanger, Sodium/Hydrogen exchanger, and are shown in Figure 16. These two alignments are to different sections of the INPONCH10 sequence; the N-terminal region of the INPIONCHIO sequence closely matches the sequence of the sodium/hydrogen exchanger and a region in the C-terminal half of the INPIONCHIO sequence closely matches the sequence of a cyclic nucleotide-binding domain. These results provide further evidence that the INPIONCHIO protein is a transporter/channel protein.

Example 5: domain structure

Figure 17 shows a multiple alignment of the INPIONCH07, INPIONCH08, INPIONCH09 and INPIONCHIO sequences. The location of the transporter-like domain, voltage sensor ion channel-like domain and the cyclic nucleotide binding domain are indicated. Figure 18 shows the INPIONCH07, INPIONCH08, INPIONCH09 and INPIONCHIO polypeptides aligned with ion channel sequences containing the ion transport domain regions S1-S4. The alignment clearly shows the presence of the entire voltage sensor domain with the S4 transmembrane region containing 3-4 charged amino acid residues. Figure 18 therefore provides further evidence that the middle regions of the INPIONCH07, INPIONCH08, INPIONCH09 and INPIONCHIO polypeptides contains an ion transport domain.

Figure 19 shows the INPIONCH07, INPIONCH08, INPIONCH09 and INPIONCHIO polypeptides aligned with the sequences of selected cyclic nucleotide binding domains. Alignment of the sequences from a region in the C-terminal half of INPIONCH07, INPIONCH08, INPIONCH09 and INPIONCHIO with other well defined cyclic nucleotide binding domains shows a high degree of conservation over all regions of secondary structure, and the presence of the three Glycine residues necessary for maintaining the structural scaffold. Figure 19 therefore provides further evidence that a region in the C-terminal half of the LNPIONCH07, LNPIONCH08, LNPIONCH09 and INPIONCHIO polypeptides contains a cyclic nucleotide monophosphate binding domain. Figure 20 shows the INPIONCH07, INPIONCH08, INPIONCH09 and INPIONCHIO polypeptides aligned with the sequences of the latter half of selected Na⁺/H⁺ antiporter transmembrane domains. The region covers the last 6-12 transmembrane regions of the domain and sequence conservation is high between members of the Na^"1"/!!^4" antiporter family. Alignment of the sequences from the N-terminal region of INPIONCH07, INPIONCH08, INPIONCH09 and INPIONCHIO with these regions shows a high degree of conservation. Figure 20 therefore provides further evidence that the N-terminal region of the INPIONCH07, LNPIONCH08, INPIONCH09 and INPIONCHIO polypeptides contains a transporter-like domain.

Example 6: Tissue Profiling Data for INPIONCH07 Expression profiling confirmed the existence of the transcript for the LNPIONCH07 gene prediction. High levels of expression were found in the human testis. Very low levels of transcript expression were also found in the cervix and the brain. Expression in all other tissues tested was extremely low or absent. The finding that the gene is expressed in significant levels only in the testis implies that it is involved in spermatogenesis in terms of sperm maturation or sperm motility. This finding is consistent with the prediction that this gene possesses motifs that are responsive to pH and cyclic nucleotides. The localised expression of this gene prediction supports the finding that it is a good target for the treatment of fertility in man.

In order to determine the tissue expression of the proposed transporter/channel protein, Taqman RT-PCR quantitation was used. The TaqMan 3'- 5' exonuclease assay signals the formation of PCR amplicons by a process involving the nucleolytic degradation of a doublelabeled fiuorogenie probe that hybridises to the target template at a site between the two primer recognition sequences (cf. U. S. Patent 5,876,930). The ABI Prism 7700 automates the detection and quantitative measurement of these signals, which are stoichiometrically related to the quantities of amplicons produced, during each cycle of amplification. In addition to providing a substantial reduction in the time and labour required for PCR analyses, this technology permits simplified and potentially highly accurate quantification of target sequences in the reactions.

Taqman RT-PCR was carried out using 15ng of the indicated cDNA using primers/probes specific for LNPIONCH07 and 18s rRNA as described below. A standard curve for target and internal control was also carried out, using between 25ng to 0.39ng of cDNA template of a typical tissue sample. Cycle threshold (Ct) determinations, i.e. non-integer calculations of the number of cycles required for reporter dye fluorescence resulting from the synthesis of PCR products to become significantly higher than background fluorescence levels, were performed by the instrument for each reaction using default parameters. Using linear regression analysis of the standard curves, the Ct values were used to calculate the amount of actual starting target or 18s cDNA in each test sample.

The levels of target cDNA in each sample were normalised to the level of expression of target in a comparative sample, in this case testis. The level of 18s cDNA in each sample was also normalised to the level of expression of 18s cDNA in testis. The expression levels of INPIONCH07 were then normalised to the expression levels of 18s cDNA. Figure 21 represents the fold expression of normalised INPIONCH07 target sequence in 22 normal human tissues relative to the level of expression in testis cDNA, which was set arbitrarily to 1. Each sample was quantitated in 2 individual experiments. Figure 21 shows the mean ± SEM for the multiple experiments.

Tissues RNA samples: Human RNA prepared from non-diseased organs was purchased from either Ambion Europe (Huntingdon, UK), Biochain - AMS technology (Abingdon, UK), Clinomics biosciences (Fredrick, Marynland, US), Clontech (BD, Franklin Lakes, NJ) or Sfratagene (La Jolla, California, US).

Oligo Design: Oligonucleotide primers and probes were designed using Primer Express software (Applied Biosystems, Foster City CA) with a GC-content of 40-60%, no G-nucleotide at the 5'-end of the probe, and no more than 4 contiguous Gs.

Each primer and probe was analysed using BLAST^® (Basic Local Alignment Search Tool, Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ.: J Mol Biol 1990 Oct 5;215(3):403- 10). The results confirmed that each oligonucleotide recognised the target sequence with a specificity >3 bp when compared to other known cDNAs or genomic sequence represented in the Unigene and GoldenPath publicly available databases. The sequence of the primers and probes that were used are:

INPIONCH07 Fwd TTTGCACCTTGCATTATACCTACAA INPIONCH07 Probe TTAAATCAGAAGTTCCCTGAACCTGCTCACAG INPIONCH07 Rev AGATGCTTGGATTATCAGCAGCTT

The 18s pre-optimised primers and probe were purchased from Applied Biosystems, Foster City, CA.

The probes were covalently conjugated with a fluorescent reporter dye (e.g. 6carboxy- fluorescein [FAM]; Xem = 518nm) and a fluorescent quencher dye (6carboxytetram-ethyl- rhodamine [TAMRA]; Mem = 582nm) at the most 5' and most 3' base, respectively. Primers were obtained from Sigma Genosys, UK and probes were obtained from Eurogentec, Belgium.

The primers and probe concentrations that were used were 900nM and lOOnM, respectively. cDNA reaction: cDNA was prepared using components from Applied Biosystems, Foster City CA. 50μl reactions were prepared in 0.5ml RNase free tubes. The reactions contained 500ng total RNA; lx reverse transcriptase buffer; 5.5mM MgCl₂; ImM dNTPs; 2.5μl random hexamers; 20U RNase inhibitor; and 62.5U reverse transcriptase. PCR reactions:

25 μl reactions were prepared in 0.5 ml thin-walled, optical grade PCR 96 well plates (Applied Biosystems, Foster City CA). The reactions contained: lx final concentration of TaqMan Universal Master Mix (a proprietary mixture of AmpliTaq Gold DNA polymerase, AmpEraseX UNG, dNTPs with UTP, passive reference dye and optimised buffer components, Applied Biosystems, Foster City CA); lOOnM Taqman probe; 900nM forward primer; 900nM reverse primer and either 15ng (for human tissues) or 25ng (for cells or foetal tissues) of cDNA template. Performance of Assay:

Standard procedures for the operation of the ABI Prism 7700 or similar detection system were used. This included, for example with the ABI Prism 7700, use of all default program settings with the exception of reaction volume which was changed from 50 to 25 ul. Thermal cycling conditions consisted of two min at 50°C, 10 min at 95°C, followed by 40 cycles of 15 sec at 95°C and 1 min at 60°C. Cycle threshold (Ct) determinations, i.e. non-integer calculations of the number of cycles required for reporter dye fluorescence resulting from the synthesis of PCR products to become significantly higher than background fluorescence levels were automatically performed by the instrument for each reaction using default parameters. Assays for target sequences and ribosomal 18s (reference) sequences in the same cDNA samples were performed in separate reaction tubes.

Within each experiment, a standard curve was carried out of a typical tissue sample (in this case testis), from 25ng to 0.39ng of cDNA template. From this standard curve, the amount of actual starting target or 18s cDNA in each test sample was determined. The levels of target cDNA in each sample were normalised to the level of expression of target in a comparative sample. The levels of internal control cDNA in each sample were normalised to the level of expression of internal control in a comparative sample. The data was then represented as fold expression of normalised target sequence relative to the level of expression in the comparative sample, which was set arbitrarily to 1.

Example 7: Tissue Profiling Data for INPIONCH09

Expression profiling confirmed the existence of the transcript for the INPIONCH09 gene prediction. High levels of expression were found in the human testis. Very low levels of transcript expression were also found in heart, placenta and thymus. Expression in all other tissues tested was extremely low or absent. The finding that the gene is expressed in significant levels only in the testis implies that it is involved in spermatogenesis in terms of sperm maturation or sperm motility. This finding is consistent with the prediction that this gene possesses motifs that are responsive to pH and cyclic nucleotides. The localised expression of this gene prediction supports the finding that it will be a good target for the treatment of fertility in man. In order to determine the tissue expression of the proposed transporter/channel protein, Taqman RT-PCR quantitation was used. The TaqMan 3'- 5' exonuclease assay signals the formation of PCR amplicons by a process involving the nucleolytic degradation of a doublelabeled fluorogenic probe that hybridises to the target template at a site between the two primer recognition sequences (cf. U.S. Patent 5,876,930). The ABI Prism 7700 automates the detection and quantitative measurement of these signals, which are stoichiometrically related to the quantities of amplicons produced, during each cycle of amplification. In addition to providing substantial reductions in the time and labour requirements for PCR analyses, this technology permits simplified and potentially highly accurate quantification of target sequences in the reactions.

Taqman RT-PCR was carried out using 15ng of the indicated cDNA using primers/probes specific for INPIONCH09 and 18s rRNA as described below. A standard curve for target and internal control was also carried out, using between 25ng to 0.39ng of cDNA template of a typical tissue sample. Cycle threshold (Ct) determinations, i.e. non-integer calculations of the number of cycles required for reporter dye fluorescence resulting from the synthesis of PCR products to become significantly higher than background fluorescence levels were performed by the instrument for each reaction using default parameters. Using linear regression analysis of the standard curves, the Ct values were used to calculate the amount of actual starting target or 18s cDNA in each test sample. The levels of target cDNA in each sample were normalised to the level of expression of target in a comparative sample, in this case, testis. The levels of 18s cDNA in each sample were also normalised to the level of expression of 18s cDNA in testis. The expression levels of INPIONCH09 were then normalised to the expression levels of 18s cDNA.

Figure 22 represents the fold expression of normalised target sequence relative to the level of expression in testis cDNA, which was set arbitrarily to 1. Each sample was quantitated in 2 individual experiments. Figure 22 shows the mean ± SEM for the multiple experiments.

Tissues RNA samples:

Human RNA prepared from non-diseased organs was purchased from either Ambion Europe (Huntingdon, UK), Biochain - AMS technology (Abingdon, UK), Clinomics biosciences (Fredrick, Marynland, US), Clontech (BD, Franklin Lakes, NJ) or Sfratagene (La JoUa, California, US). Oligo Design:

Oligonucleotide primers and probes were designed using Primer Express software (Applied Biosystems, Foster City CA) with a GC-content of 40-60%, no G-nucleotide at the 5'-end of the probe, and no more than 4 contiguous Gs.

Each primer and probe was analysed using BLAST^® (Basic Local Alignment Search Tool, Altschul SF, Gish W, Miller W, Myers EW, Lipman DL: J Mol Biol 1990 Oct 5;215(3):403- 10). The results confirmed that each oligonucleotide recognised the target sequence with a specificity >3 bp when compared to other known cDNAs or genomic sequence represented in the Unigene and GoldenPath publicly available databases.

The sequence of the primers and probes that were used are:

INPIONCH09 Fwd AGGAATGAGATTCTGTCCCAGAGT LNPIONCH09 Probe CTGCTGCACCAACCAACACCTGGA INPIONCH09 Rev TTTCCCTTCTTCTCACCAAAACTT

18s pre-optimised primers and probe were purchased from Applied Biosystems, Foster City, CA.

The probes were covalently conjugated with a fluorescent reporter dye (e.g. όcarboxy- fluorescein [FAM]; Xem = 518nm) and a fluorescent quencher dye (6carboxytetram-ethyl- rhodamine [TAMRA]; Mem = 582nm) at the most 5' and most 3' base, respectively. Primers were obtained from Sigma Genosys, UK and probes were obtained from Eurogentec, Belgium.

The primer and probe concentrations that were used were 900nM and lOOnM respectively. cDNA reaction: cDNA was prepared using components from Applied Biosystems, Foster City CA. 50μl reactions were prepared in 0.5ml RNase free tubes. The reactions contained 500ng total RNA; lx reverse transcriptase buffer; 5.5mM MgCl₂; ImM dNTPs; 2.5μl random hexamers; 20U RNase inhibitor; and 62.5U reverse transcriptase. PCR reactions:

25μl reactions were prepared in 0.5 ml thin-walled, optical grade PCR 96 well plates (Applied Biosystems, Foster City CA). The reactions contained: lx final concentration of TaqMan Universal Master Mix (a proprietary mixture of AmpliTaq Gold DNA polymerase, AmpEraseX UNG, dNTPs with UTP, passive reference dye and optimised buffer components, Applied Biosystems, Foster City CA); lOOnM Taqman probe; 900nM forward primer; 900nM reverse primer and either 15ng (for human tissues) or 25ng (for cells or foetal tissues) of cDNA template.

Performance of Assay: Standard procedures for the operation of the ABI Prism 7700 or similar detection system were used. This included, for example with the ABI Prism 7700, use of all default program settings with the exception of reaction volume which was changed from 50 to 25 ul. Thermal cycling conditions consisted of two min at 50°C, 10 min at 95°C, followed by 40 cycles of 15 sec at 95°C and 1 min at 60°C. Cycle threshold (Ct) determinations, i.e. non-integer calculations of the number of cycles required for reporter dye fluorescence resulting from the synthesis of PCR products to become significantly higher than background fluorescence levels, were automatically performed by the instrument for each reaction using default parameters. Assays for target sequences and ribosomal 18s (reference) sequences in the same cDNA samples were performed in separate reaction tubes. Within each experiment, a standard curve was carried out of a typical tissue sample (in this case testis), from 25ng to 0.39ng of cDNA template. From this standard curve, the amount of actual starting target or 18s cDNA in each test sample was determined.

The levels of target cDNA in each sample were normalised to the level of expression of target in a comparative sample. The levels of internal control cDNA in each sample were normalised to the level of expression of internal control in a comparative sample. The data was then represented as fold expression of normalised target sequence relative to the level of expression in the comparative sample, which was set arbitrarily to 1. Sequences

Note: for amino acids encoded by exon-exon junctions, the amino acid will be assigned to the more 5' exon.

SEQ ID NO:l INPIONCH07 exon 1 nucleotide sequence

1 ATGCTGACTA ATATCATTCT CTGCTTTTCA ATGGTGTACA TGACTTTCTA TATTG

SEQ ID NO:2 INPIONCH07 exon 1 amino acid sequence

1 MLTNIILCFS MVYMTFYIV

SEQ ID NO:3 INPIONCH07 exon 2 nucleotide sequence

1 TGGAATTTTT AGGAATGTCA GGCACTCTTG CCTTAGCCGC TGTAGGACTG AATTTAGATT 61 CTTTAACTTT TAAACCGAAG ATCGAACTTG TAATTACTAA SEQ ID NO:4 INPIONCH07 exon 2 amino acid sequence

1 EFLGMSGTLA LAAVGLNLDS LTFKPKIELV ITK

SEQ ID NO:5 INPIONCH07 exon 3 nucleotide sequence

1 GTTCTTAAGA ATTTTTTCAT CTGTATATGA ACATTTAATA TATGCTTTCT TTGGCATTGT 61 GATTGGATGT GGAGAACTCA GCCACTATGA ATTTCACACT ATACCTTTCA TATTCATTTT 121 ATTTACAACA GTGAATTTGG TAAG

SEQ ID NO:6 INPIONCH07 exon 3 amino acid sequence

1 FLRIFSSVYE HLIYAFFGIV IGCGELSHYE FHTIPFI FIL FTTVNLVR

SEQ ID NO:7 INPIONCH07 exon 4 nucleotide sequence

1 GTTGCTTACT ATTTTGTTAG TGAGCCCTAT TTTGATGCAT TCAAATTATG AATATAATTG 61 GCGATGGGGA GTTGTAATCA CGTGGTCTGG AATTAAAGGA GTTTTTAATT TACTCTGGGC 21 TCCTGATGTT TATAATCTCG CTGAACGAAA AGTGGAAGTA CCACAAATG

SEQ ID NO:8 INPIONCH07 exon 4 amino acid sequence

1 LLTILLVSPl LMHSNYEYN R GVVIT SG IKGVFNLLWA PDVYNLAERK VEVPQM

SEQ ID NO:9 INPIONCH07 exon 5 nucleotide sequence 1 TTTATACTCT ATGTACAAGT AATATCATTA TTGACAATGG GAATAAATTC ATACGTGATG

61 ACTCAGTCAG CCAGGAAGTT AG

SEQ ID NO:10 INPIONCH07 exon 5 amino acid sequence

1 FILYVQVISL LTMGINSYVM TQSARKLD

SEQ ID NO:ll INPIONCH07 exon 6 nucleotide sequence

1 ATTTGTGTGT TCTTTCCCTC CCAAGACAAA TGATCTTGCA AAATGCCACT CAGCACATAC 61 AGGAGATAGT ACAGAACACA ATAACTTTAT TTAAAACAGA AAAAATTTTG ACAAATGTTA 121 ACTGGACCTT AGTAGAAGAT AAAACGAGGA TCGAATACAT TCCT

SEQ ID NO.12 INPIONCH07 exon 6 amino acid sequence

1 LCVLSLPRQ ILQNATQHIQ EIVQNTITLF KTEKILTNVN TLVEDKTRI EYIPN SEQ ID NO: 13 INPIONCH07 exon 7 nucleotide sequence

1 TTTTCCCACG TTTCACATAA TGATATGAAG ACAGAATCCA CAACAGATGA AGCTTTAATG 61 GAGGAAGCCA GATTGCATGT AGCTGCAATA CAAATG SEQ ID NO.14 INPIONCH07 exon 7 amino acid sequence

1 FSHVSHNDMK TESTTDEALM EEARLHVAAI QM

SEQ ID NO:15 INPIONCH07 exon 8 nucleotide sequence

1 AGTAGCTTTG AAAAACAGCG TAACAATGGA ATTCTTGAAA TAGAGGCAGC CCGGATATTA 61 ATTGGTGCAG CAAAATGCTA TTACTCCATC CAAGGAAA

SEQ ID NO: 16 INPIONCH07 exon 8 amino acid sequence

1 SSFEKQRNNG ILEIEAARIL IGAAKCYYSI QGK SEQ ID NO:17 INPIONCH07 exon 9 nucleotide sequence

1 AGGTTTAAAT GTATCAGCAC TGATATCAAT AAACTACTAT TTTATGTTTT TATATGTATT 61 AGAATCAACA TTGAAG

SEQ ID NO: 18 INPIONCH07 exon 9 amino acid sequence

1 GLNVSALISI NYYFMFLYVL ESTLK

SEQ ID NO:19 INPIONCH07 exon 10 nucleotide sequence

1 ATAATAATTT TGAAAAGGAA ATATTTTCAA CAATGTTGGA ATACTTTGGA ATTTTTTATC 61 CTGGTTATTG GAATCATTGA TATCTTTTGT GTATACTTTG TGAAATTGAG ACCAGACAAC

121 TTGGCTCTTA TACAGCTTAC AGTAATAATG GGATATTTAA GAATAATTAG GTTTCTTCCT

181 CTCTTCAAG

SEQ ID NO:20 INPIONCH07 exon 10 amino acid sequence 1 II1LKRKYFQ QC NTLEFFI LVIGIIDIFC VYFVKLRPDN LALIQLTVIM GYLRIIRFLP

61 LFK

SEQ ID NO:21 INPIONCH07 exon 11 nucleotide sequence

1 ATAATAGTAC CAATACTGAT AAGAATTGCA GATGTGCAGA TCAAAAAGCG CCTCAGCTTG 61 ATGTATAGTA TTACAAAAGG CTATATCAAA AGTCAAGAAG ATGCCAAACT TCTAATAAAA 121 CAAATAGCTG TCTGTGAATC AATATATCAG

SEQ ID NO:22 INPIONCH07 exon 11 amino acid sequence 1 IIVPILIRIA DVQIKKRLSL YSITKGYIK SQEDAKLLIK QIAVCESIYQ

SEQ ID NO:23 INPIONCH07 exon 12 nucleotide sequence

1 AAACTATGTG AAATTTTGGA AACCAACAAA CAGGATGCTG TCAAAGAATT AG SEQ ID NO:24 INPIONCH07 exon 12 amino acid sequence

1 KLCEILETNK QDAVKELV

SEQ ID NO:25 INPIONCH07 exon 13 nucleotide sequence

1 TACTCATGGA GCATGAGGGT CGTGATGTTG TCATTGCTTT GAAGACTAAA CAGGCAATCC 61 GGAATGTGAT TGCTAAAGCT CTAAAAAATC TCACCTTCCT TTGTTCAAGA GGCATTATTG 121 ATAAGCATGA AGTCATTGAG ATAAATAAG

SEQ ID NO:26 INPIONCH07 exon 13 amino acid sequence

1 LMEHEGRDVV IALKTKQAIR NVIAKALKNL TFLCSRGIID KHEVIEINK SEQ ID NO:27 INPIONCH07 exon 14 nucleotide sequence

1 GTACTTCTTA AAAAATTAAA AGCACTAAAT AACTTTCCAA AGGCAATCCC ACCCCCAACT 61 CCTGACATAT ACCTTCACAA CATCATTTGG CTGGAAGGTA AAGATGTTCT CATTGACTTC 121 TTCAAG

SEQ ID NO:28 INPIONCH07 exon 14 amino acid sequence

1 VLLKKLKALN NFPKAIPPPT PDIYLHNI IW LEGKDVLIDF FK

SEQ ID NO:29 INPIONCH07 exon 15 nucleotide sequence

1 GAAAGAGCCA AACTTGCCTG TTTTGACTCT GGAGATACCA TTTGTAAAGG AGGTGAAATG 61 CCACAAGGAA TCTACTTAAT TATTTCAGGA ATGGCAATT

SEQ ID NO:30 INPIONCH07 exon 15 amino acid sequence

1 ERAKLACFDS GDTICKGGEM PQGIYLIISG MAI

SEQ ID NO:31 INPIONCH07 exon 16 nucleotide sequence

1 TTGCATAGTT TATCTCCTAC CTTTGGAATA GAGAGTAATC AAAGGTGTGA TAGAGGGTCC 61 AGAGACATGT TTACAGAGTT CTGTACTACT GGGGACATAA TTGGAGAGCT AAGCTGTCTG 121 CTTAAGCGTG AAATTGAATA TACCGTCATC TGTGAAACTA GTTTACAG SEQ ID NO:32 INPIONCH07 exon 16 amino acid sequence

1 LHSLSPTFGI ESNQRCDRGS RDMFTEFCTT GDI IGELSCL LKREIEYTVI CETSLQ

SEQ ID NO: 33 INPIONCH07 exon 17 nucleotide sequence

1 GCCTGCTTTA TCTCCCTGGA GGATTTATAT GAAGGCTTTG ATGCCTTCTG GCCATCTCTG 61 GAATATAAAA TATGGCTAAA GCTTGCTCTC AGTACTGCCT ATCAGTATTT TGAATCAAGT 121 CTTATTGATG AG

SEQ ID NO:34 INPIONCH07 exon 17 amino acid sequence

1 ACFISLEDLY EGFDAF PSL EYKIWLKLAL STAYQYFESS LIDE

SEQ ID NO: 35 INPIONCH07 exon 18 nucleotide sequence

1 GACTTAAGGT TTCAGAACTG TGTGATGTTC AATCAAGCAT ATGTGGAAAC TTTATCAAGC

61 TATAGTGACA TGATTATTGA TAATATGACC ATGAAATTTG TTATCATTGT GTATGGCAGT

121 GTAATTGATA CTAAGACAGA GGAACCATAT TTTGCACCTT GCATTATACC TACAACCTGT 181 GAGCAG

SEQ ID NO:36 INPIONCH07 exon 18 amino acid sequence

1 DLRFQNCVMF NQAYVETLSS YSDMIIDNMT MKFVIIVYGS VIDTKTEEPY FAPCIIPTTC 61 EQ

SEQ ID NO: 37 INPIONCH07 exon 19 nucleotide sequence

1 GTTCAGGGAA CTTCTGATTT AAGCAAGCTG CTGATAATCC AAGCATCTGA GCTTACCCAA 61 AGAAATAGTA ACACCAATGT CATGG SEQ ID NO:38 INPIONCH07 exon 19 amino acid sequence

1 VQGTSDLSK LIIQASELTQ RNSNTNVMG

SEQ ID NO: 39 INPIONCH08 exon 20 nucleotide sequence

1 GTGGTTTAGT GCAGATTGAA GCCTGA SEQ ID NO:40 INPIONCH07 exon 20 amino acid sequence

1 GLVQIEA SEQ ID NO: 41 INPIONCH07 nucleotide sequence

1 ATGCTGACTA ATATCATTCT CTGCTTTTCA ATGGTGTACA TGACTTTCTA TATTGTGGAA

61 TTTTTAGGAA TGTCAGGCAC TCTTGCCTTA GCCGCTGTAG GACTGAATTT AGATTCTTTA

121 ACTTTTAAAC CGAAGATCGA ACTTGTAATT ACTAAGTTCT TAAGAATTTT TTCATCTGTA

181 TATGAACATT TAATATATGC TTTCTTTGGC ATTGTGATTG GATGTGGAGA ACTCAGCCAC 241 TATGAATTTC ACACTATACC TTTCATATTC ATTTTATTTA CAACAGTGAA TTTGGTAAGG

301 TTGCTTACTA TTTTGTTAGT GAGCCCTATT TTGATGCATT CAAATTATGA ATATAATTGG

361 CGATGGGGAG TTGTAATCAC GTGGTCTGGA ATTAAAGGAG TTTTTAATTT ACTCTGGGCT

421 CCTGATGTTT ATAATCTCGC TGAACGAAAA GTGGAAGTAC CACAAATGTT TATACTCTAT

481 GTACAAGTAA TATCATTATT GACAATGGGA ATAAATTCAT ACGTGATGAC TCAGTAGTAA 541 TATCATTATT GACAATGGGA ATAAATTCAT ACGTGATGAC TCAGTCAGCC AGGAAGTTAG

601 ATTTGTGTGT TCTTTCCCTC CCAAGACAAA TGATCTTGCA AAATGCCACT CAGCACATAC

661 AGGAGATAGT ACAGAACACA ATAACTTTAT TTAAAACAGA AAAAATTTTG ACAAATGTTA

721 ACTGGACCTT AGTAGAAGAT AAAACGAGGA TCGAATACAT TCCTTTTTCC CACGTTTCAC

781 ATAATGATAT GAAGACAGAA TCCACAACAG ATGAAGCTTT AATGGAGGAA GCCAGATTGC 841 ATGTAGCTGC AATACAAATG AGTAGCTTTG AAAAACAGCG TAACAATGGA ATTCTTGAAA

901 TAGAGGCAGC CCGGATATTA ATTGGTGCAG CAAAATGCTA TTACTCCATC CAAGGAAAAG

961 GTTTAAATGT ATCAGCACTG ATATCAATAA ACTACTATTT TATGTTTTTA TATGTATTAG

1021 AATCAACATT GAAGATAATA ATTTTGAAAA GGAAATATTT TCAACAATGT TGGAATACTT

1081 TGGAATTTTT TATCCTGGTT ATTGGAATCA TTGATATCTT TTGTGTATAC TTTGTGAAAT 1141 TGAGACCAGA CAACTTGGCT CTTATACAGC TTACAGTAAT AATGGGATAT TTAAGAATAA

1201 TTAGGTTTCT TCCTCTCTTC AAGATAATAG TACCAATACT GATAAGAATT GCAGATGTGC

1261 AGATCAAAAA GCGCCTCAGC TTGATGTATA GTATTACAAA AGGCTATATC AAAAGTCAAG

1321 AAGATGCCAA ACTTCTAATA AAACAAATAG CTGTCTGTGA ATCAATATAT CAGAAACTAT

1381 GTGAAATTTT GGAAACCAAC AAACAGGATG CTGTCAAAGA ATTAGTACTC ATGGAGCATG 1441 AGGGTCGTGA TGTTGTCATT GCTTTGAAGA CTAAACAGGC AATCCGGAAT GTGATTGCTA

1501 AAGCTCTAAA AAATCTCACC TTCCTTTGTT CAAGAGGCAT TATTGATAAG CATGAAGTCA

1561 TTGAGATAAA TAAGGTACTT CTTAAAAAAT TAAAAGCACT AAATAACTTT CCAAAGGCAA

1621 TCCCACCCCC AACTCCTGAC ATATACCTTC ACAACATCAT TTGGCTGGAA GGTAAAGATG

1681 TTCTCATTGA CTTCTTCAAG GAAAGAGCCA AACTTGCCTG TTTTGACTCT GGAGATACCA 1741 TTTGTAAAGG AGGTGAAATG CCACAAGGAA TCTACTTAAT TATTTCAGGA ATGGCAATTT

1801 TGCATAGTTT ATCTCCTACC TTTGGAATAG AGAGTAATCA AAGGTGTGAT AGAGGGTCCA

1861 GAGACATGTT TACAGAGTTC TGTACTACTG GGGACATAAT TGGAGAGCTA AGCTGTCTGC

1921 TTAAGCGTGA AATTGAATAT ACCGTCATCT GTGAAACTAG TTTACAGGCC TGCTTTATCT

1981 CCCTGGAGGA TTTATATGAA GGCTTTGATG CCTTCTGGCC ATCTCTGGAA TATAAAATAT 2041 GGCTAAAGCT TGCTCTCAGT ACTGCCTATC AGTATTTTGA ATCAAGTCTT ATTGATGAGG

2101 ACTTAAGGTT TCAGAACTGT GTGATGTTCA ATCAAGCATA TGTGGAAACT TTATCAAGCT

2161 ATAGTGACAT GATTATTGAT AATATGACCA TGAAATTTGT TATCATTGTG TATGGCAGTG

2221 TAATTGATAC TAAGACAGAG GAACCATATT TTGCACCTTG CATTATACCT ACAACCTGTG

2281 AGCAGGTTCA GGGAACTTCT GATTTAAGCA AGCTGCTGAT AATCCAAGCA TCTGAGCTTA 2341 CCCAAAGAAA TAGTAACACC AATGTCATGG GTGGTTTAGT GCAGATTGAA GCCTGA

SEQ ID NO: 42 INPIONCH07 amino acid sequence

1 MLTNIILCFS MVYMTFYIVE FLGMSGTLAL AAVGLNLDSL TFKPK1ELVI TKF RIFSSV

61 YEH IYAFFG IVIGCGELSH YEFHTIPFIF ILFTTVNLVR LTILLVSPI LMHSNYEYNW 121 RWGWITWSG IKGVFNLLWA PDVYNLAERK VEVPQMFILY VQVIS LTMG INSYVMTQSA

181 RK D CVLSL PRQMILQNAT QHIQEXVQNT IT FKTEKIL TNVNWTLVED KTRIEYIPFS

241 HVSHNDMKTE STTDEALMEE AR HVAAIQM SSFEKQRNNG ILEIEAARIL IGAAKCYYSI

301 QGKGLNVSAL ISINYYF FL YV ESTLKII ILKRKYFQQC WNTLEFFI V IGIIDIFCVY

361 FVKLRPDNLA LIQLTVIMGY LRIIRFLPLF KIIVPI IRI ADVQIKKRLS LMYSITKGYI 421 KSQEDAK LI KQIAVCESIY QK CEILETN KQDAVKELVL EHEGRDWI A KTKQAIRN

481 VIAKALKNLT FLCSRGIIDK HEVIEINKV LKKLKA NNF PKAIPPPTPD IYLHNII LE

541 GKDVLIDFFK ERAKLACFDS GDTICKGGEM PQGIYLIISG MAILHS SPT FGIESNQRCD

601 RGSRDMFTEF CTTGDIIGE SCLLKREIEY TVICETSLQA CFISLEDLYE GFDAFWPS E

661 YKIWLK ALS TAYQYFESSL IDEDLRFQNC VMFNQAYVET LSSYSDMIID NMTMKFVIIV 721 YGSVIDTKTE EPYFAPCIIP TTCEQVQGTS DLSK IIQA SELTQRNSNT NVMGGLVQ1E

781 A

SEQ ID NO:43 INPIONCH08 exon 1 nucleotide sequence

1 ATGTACACGG ATATCATCAG AGGGGAGTCG CTGATCATTT GTAGTTTCAC ATGCATTTTC 61 TTTGGAATTT TTCGAGGTCA CTCAACTGAC ACGTCCATGT TCAGAG

SEQ ID NO:44 INPIONCH08 exon 1 amino acid sequence

1 MYTDIIRGES LIICSFTCIF FGIFRGHSTD TSMFRE

SEQ ID NO:45 INPIONCH08 exon 2 nucleotide sequence

1 AGTTACACAT AATCATCGGA CTCAGCTTTG ATGTTTTTGG AAGCACCATA TGTGGCTATT 61 GGTGTACGAG AGTCATCCAG ATTATATTGA CCGACCTCTT TAGCAACACA CTGACGAACG 121 TTGTTCTCTG TTTCTCACTG GTGTACATGA CGTTTTACCT TG

SEQ ID NO:46 INPIONCH08 exon 2 amino acid sequence

1 LHIIIGLSFD VFGSTICGY CTRVIQIILT DLFSNTLTNV VLCFSLVYMT FYLV

SEQ ID NO:47 INPIONCH08 exon 3 nucleotide sequence 1 TGGAATATTT CGGAATGTCA GGCATTGTTG CTTTGGTCAC GGTAGGCCTG AATTTGGATT

61 CTTTAAGCTT TAAACCGAGG ATGGAGTTCA TCATTACTAA

SEQ ID NO:48 INPIONCH08 exon 3 amino acid sequence

1 EYFGMSGIVA LVTVGLNLDS LSFKPRMEFI ITK

SEQ ID NO:49 INPIONCH08 exon 4 nucleotide sequence

1 GTTCTTAATA ATGTGCTCAT CTGTATATGA ACACTTAATA TATGCTTTCT TTGGCATTGT 61 CATTGGCTGT GGAGAAATCA AGTATTTCAA ATTTCACTCC ATAGTTTTCA CTGTGACTTT 121 ATTCATAACA GTGAATTTTG TAAG

SEQ ID NO:50 INPIONCH08 exon 4 amino acid sequence

1 FLIMCSSVYE HLIYAFFGIV IGCGEIKYFK FHSIVFTVTL FITVNFVR

SEQ ID NO:51 INPIONCH08 exon 5 nucleotide sequence 1 GCTGCTTACT ATCATTTTAG TGAGCCCAAT TTTGATGCAT TCAAGTTATG AGTATGACTG

61 GCGTTGGGGA TTCGTCATCG CATGGTCTGG GATCAGAGGT GTTTTCAGCT TACTCTTGGC 121 TCCCGATATT TACAATATTT CTCGATTTAA ATTACCAGCA CCACATATG

SEQ ID NO:52 INPIONCH08 exon 5 amino acid sequence 1 LLTIILVSPI LMHSSYEYDW RWGFVIAWSG IRGVFSLLLA PDIYNISRFK LPAPHM

SEQ ID NO:53 INPIONCH08 exon 6 nucleotide sequence

1 TTTATCTTCT ATATACAAGT ACTATCGTTA TTGACAACAG GAATAAATTC ACATATGATG 61 CTTCGTTCAG CCAAAACACT AG

SEQ ID NO:54 INPIONCH08 exon 6 amino acid sequence

1 FIFYIQVLSL LTTGINSHMM LRSAKTLG

SEQ ID NO:55 INPIONCH08 exon 7 nucleotide sequence 1 GTTTGTGTGC TCTCTCCCTC CCAAGACAAA TGGCTGTTCG GAATGCCATT GAACACATAC

61 AGGAGATTAT ACGGAACACA ATAACTTTAT TTAAGACAGA AAAAATTTTG ACAAATGTTA 121 ACTGGAATGT AGTAGAAGAA AAAGCAAAAA TCGAATACAA TCCT

SEQ ID NO:56 INPIONCH08 exon 7 amino acid sequence 1 LCALSLPRQM AVRNAIEHIQ EIIRNTITLF KTEKILTNV N VEEKAKI EYNP

SEQ ID NO:57 INPIONCH08 exon 8 nucleotide sequence

1 ACTCACGTTC AAGTTTCCCA CAGTCCAAAA GAGGAGTCCC CAACCGATGA AGTTTTAATA 61 GAAGAGGCCA GATTGCATGT AGCTATAATA CAAATG SEQ ID NO:58 INPIONCH08 exon 8 amino acid sequence

1 THVQVSHSPK EESPTDEVLI EEARLHVAI I QM SEQ ID NO:59 INPIONCH08 exon 9 nucleotide sequence

1 AGTAGCTTTG AAAAGCAGTG TAACGATGGT ACCCTTGGAG TAGAGGCAGC TCGAATATTA 61 ATTGGTGCCA CCAAAAGTTA CTGCCCCATC CACGGAAA

SEQ ID NO.-60 INPIONCH08 exon 9 amino acid sequence 1 SSFEKQCNDG TLGVEAARIL IGATKSYCPI HGK

SEQ ID NO:61 INPIONCH08 exon 10 nucleotide sequence

1 AGAGTTAAAT GTATCAGCAC TGACATCCAT AAACTACTAT TTTATGTTTT TATATATATT 61 AGAATCAGCA CTGAAG

SEQ ID NO:62 INPIONCH08 exon 10 amino acid sequence

1 ELNVSALTSI NYYFMFLY1L ESALK

SEQ ID NO:63 INPIONCH08 exon 11 nucleotide sequence 1 ATACTAATTT TAAAAAGGAA ATATTTTCTT CAGAATTGGA ATACTTTGGA CTTTTTTATC 61 ATAGTCATCG GAATCACTGA TATACTGTGC ATGTACTTTG TCAAGCTGAG ACCAGACAGC 121 TTGATTCTCA TCCAGTTTAC GGTGGTGATA GGATATTTAA GAGTGATTAG GTTTCTTCCC 181 ATCTTCAAG SEQ ID NO:64 INPIONCH08 exon 11 amino acid sequence

1 ILILKRKYFL QN NTLDFFI IVIGITDILC MYFVKLRPDS LILIQFTVVI GYLRVIRFLP 61 IFK

SEQ ID NO:65 INPIONCH08 exon 12 nucleotide sequence 1 ATTATAATAC CAATACTAAT AAATATGGCA GATGTTCAGA TCAAAAAGAG CCTCAGCTTG

61 ATGTACAGTA TTACAAAAGG CTATGTCAAA AGTCAGGAAG ATGCCAAGCT TTTGATAAGG 121 CAAATTTCTG GACGTGAATC AATCTATCGG

SEQ ID NO:66 INPIONCH08 exon 12 amino acid sequence 1 IIIPILINMA DVQIKKSLSL MYS1T GYVK SQEDAKLLIR QISGRESIYR

SEQ ID NO:67 INPIONCH08 exon 13 nucleotide sequence

1 AAATTATATG ACATTTTAGA AAAAAACAAA CGAGAGGCTA TTAGAGAACT AG SEQ ID NO:68 INPIONCH08 exon 13 amino acid sequence

1 KLYDILEKNK REAIRELG

SEQ ID NO:69 INPIONCH08 exon 14 nucleotide sequence

1 GACTCATAGA GCATGAAGGC CGTGATGTTG TCATAGCTCT GAAGACGAAG CAGACAATCC 61 GCAACGTGAT TGCCAAAGCC CTGAAAAACC TCACCTTTCT TTGGTCAAGA GGCATTATTG 121 ACAAGCACGA GGGTATTGAG ATGAACAAG

SEQ ID NO:70 INPIONCH08 exon 14 amino acid sequence

1 LIEHEGRDVV IALKTKQTIR NVIAKALKNL TFLWSRGIID KHEGIEMNK

SEQ ID NO:71 INPIONCH08 exon 15 nucleotide sequence

1 GTACTTCTTA CAAAAATAAA AGCCTTGAAT AACTTTCCAA TGGCGATCCC ACCTCCCACC 61 CCTGACAAAT ACCTTCCCAA CATTGTTTGG ATGGAAAATA AGGATGTTCT CATTGAGTTC 121 TTCAAG SEQ ID NO:72 INPIONCH08 exon 15 amino acid sequence

1 VLLT IKA N NFPMAIPPPT PDKYLPNIVW MENKDVLIEF FK

SEQ ID NO:73 INPIONCH08 exon 16 nucleotide sequence 1 GAAAGAACCA AACTCACCTA CTTTGACTAT GGGGACATCA TCTGTAGAGA AGGTGAAATG

61 TCTCAAGGAA TCTTCTTAAT TATCTCAGGA ATGGCAAGT

SEQ ID NO:74 INPIONCH08 exon 16 amino acid sequence

1 ERTKLTYFDY GDIICREGEM SQGIF1IISG MAS

SEQ ID NO:75 INPIONCH08 exon 17 nucleotide sequence

1 TTACATAGCT CATCTCCCAC CTTTGGGATA GACTCAACCC AGAGGACTGA CAGACAGTTC 61 AAGACTATGT ATACAGAGTA CTGTACCAGT GGGGATGTAC TTGGTGAACT AAGCTGTTTG 121 CTGAAGCGTG AAATTGAATA TACGGCCATC TGTGAAACTA CGTTGCAG

SEQ ID NO:76 INPIONCH08 exon 17 amino acid sequence

1 LHSSSPTFGI DSTQRTDRQF KTMYTEYCTS GDVLGELSCL L REIEYTAI CETTLQ

SEQ ID NO:77 INPIONCH08 exon 18 nucleotide sequence 1 GCCTTCTTCA TCTCCTTGGA GGATTTATAT GAAGGTTTTG ATGTCTTCTG GCCATCTCTA

61 GAATATAAAA TGTGGCTCAA GCTTGCTCTT AGTATTGCAA ATCAGTATTT TGAACCAAAT 121 ATTGCTGGTG AG

SEQ ID NO:78 INPIONCH08 exon 18 amino acid sequence 1 AFFISLEDLY EGFDVFWPSL EYKM LKLAL SIANQYFEPN IAGE

SEQ ID NO:79 INPIONCH08 exon 19 nucleotide sequence

1 GATTTAAAGT TTCACAAGTG TGTGTTGTAC AATCACGCAT ATGTGGAGAC TCTGTCAAGC 61 TATAATGAGA TGACTCTTAA TCACGTGATC ATGAAACTCA TTATTCTGGT GTACGGCATT 121 GTGATCAATA GCAAGACGGA AGAAACATTT GTGGCACCCA GCATCATCCC TAAGTCTTGT 181 GAGCAG

SEQ ID NO:80 INPIONCH08 exon 19 amino acid sequence

1 DLKFHKCVLY NHAYVETLSS YNEMTLNHVI MKLIILVYGI VINSKTEETF VAPSIIPKSC 61 EQ

SEQ ID NO:81 INPIONCH08 exon 20 nucleotide sequence

1 ATCCAGGGGA TTTCGGATGT AAGCAAGCTC CTCATAATCC CGACATCTGA TCCTGCCAAA 61 AACGATGCGA CCTCCCATGC CATGG

SEQ ID NO:82 INPIONCH08 exon 20 amino acid sequence

1 IQGISDVSKL LIIPTSDPAK NDATSHAMG

SEQ ID NO:83 INPIONCH08 exon 21 nucleotide sequence 1 GTATAGGTGG AATAGATGTA CTAGAAAAAG GCATAAGCTT TATGGCCTTG CCTAGGAGGC

61 ATA TAGCAT GTAG

SEQ ID NO:84 INPIONCH08 exon 21 amino acid sequence

1 IGGIDVLEKG ISFMALPRRH ISM

SEQ lD NO:85 INPIONCH08 nucleotide sequence

1 ATGTACACGG ATATCATCAG AGGGGAGTCG CTGATCATTT GTAGTTTCAC ATGCATTTTC

61 TTTGGAATTT TTCGAGGTCA CTCAACTGAC ACGTCCATGT TCAGAGAGTT ACACATAATC

121 ATCGGACTCA GCTTTGATGT TTTTGGAAGC ACCATATGTG GCTATTGGTG TACGAGAGTC 181 ATCCAGATTA TATTGACCGA CCTCTTTAGC AACACACTGA CGAACGTTGT TCTCTGTTTC 241 TCACTGGTGT ACATGACGTT TTACCTTGTG GAATATTTCG GAATGTCAGG CATTGTTGCT

301 TTGGTCACGG TAGGCCTGAA TTTGGATTCT TTAAGCTTTA AACCGAGGAT GGAGTTCATC

361 ATTACTAAGT TCTTAATAAT GTGCTCATCT GTATATGAAC ACTTAATATA TGCTTTCTTT

421 GGCATTGTCA TTGGCTGTGG AGAAATCAAG TATTTCAAAT TTCACTCCAT AGTTTTCACT 481 GTGACTTTAT TCATAACAGT GAATTTTGTA AGGCTGCTTA CTATCATTTT AGTGAGCCCA

541 ATTTTGATGC ATTCAAGTTA TGAGTATGAC TGGCGTTGGG GATTCGTCAT CGCATGGTCT

601 GGGATCAGAG GTGTTTTCAG CTTACTCTTG GCTCCCGATA TTTACAATAT TTCTCGATTT

661 AAATTACCAG CACCACATAT GTTTATCTTC TATATACAAG TACTATCGTT ATTGACAACA

721 GGAATAAATT CACATATGAT GCTTCGTTCA GCCAAAACAC TAGGTTTGTG TGCTCTCTCC 781 CTCCCAAGAC AAATGGCTGT TCGGAATGCC ATTGAACACA TACAGGAGAT TATACGGAAC

841 ACAATAACTT TATTTAAGAC AGAAAAAATT TTGACAAATG TTAACTGGAA TGTAGTAGAA

901 GAAAAAGCAA AAATCGAATA CAATCCTACT CACGTTCAAG TTTCCCACAG TCCAAAAGAG

961 GAGTCCCCAA CCGATGAAGT TTTAATAGAA GAGGCCAGAT TGCATGTAGC TATAATACAA

1021 ATGAGTAGCT TTGAAAAGCA GTGTAACGAT GGTACCCTTG GAGTAGAGGC AGCTCGAATA 1081 TTAATTGGTG CCACCAAAAG TTACTGCCCC ATCCACGGAA AAGAGTTAAA TGTATCAGCA

1141 CTGACATCCA TAAACTACTA TTTTATGTTT TTATATATAT TAGAATCAGC ACTGAAGATA

1201 CTAATTTTAA AAAGGAAATA TTTTCTTCAG AATTGGAATA CTTTGGACTT TTTTATCATA

1261 GTCATCGGAA TCACTGATAT ACTGTGCATG TACTTTGTCA AGCTGAGACC AGACAGCTTG

1321 ATTCTCATCC AGTTTACGGT GGTGATAGGA TATTTAAGAG TGATTAGGTT TCTTCCCATC 1381 TTCAAGATTA TAATACCAAT ACTAATAAAT ATGGCAGATG TTCAGATCAA AAAGAGCCTC

1441 AGCTTGATGT ACAGTATTAC AAAAGGCTAT GTCAAAAGTC AGGAAGATGC CAAGCTTTTG

1501 ATAAGGCAAA TTTCTGGACG TGAATCAATC TATCGGAAAT TATATGACAT TTTAGAAAAA

1561 AACAAACGAG AGGCTATTAG AGAACTAGGA CTCATAGAGC ATGAAGGCCG TGATGTTGTC

1621 ATAGCTCTGA AGACGAAGCA GACAATCCGC AACGTGATTG CCAAAGCCCT GAAAAACCTC 1681 ACCTTTCTTT GGTCAAGAGG CATTATTGAC AAGCACGAGG GTATTGAGAT GAACAAGGTA

1741 CTTCTTACAA AAATAAAAGC CTTGAATAAC TTTCCAATGG CGATCCCACC TCCCACCCCT

1801 GACAAATACC TTCCCAACAT TGTTTGGATG GAAAATAAGG ATGTTCTCAT TGAGTTCTTC

1861 AAGGAAAGAA CCAAACTCAC CTACTTTGAC TATGGGGACA TCATCTGTAG AGAAGGTGAA

1921 ATGTCTCAAG GAATCTTCTT AATTATCTCA GGAATGGCAA GTTTACATAG CTCATCTCCC 1981 ACCTTTGGGA TAGACTCAAC CCAGAGGACT GACAGACAGT TCAAGACTAT GTATACAGAG

2041 TACTGTACCA GTGGGGATGT ACTTGGTGAA CTAAGCTGTT TGCTGAAGCG TGAAATTGAA

2101 TATACGGCCA TCTGTGAAAC TACGTTGCAG GCCTTCTTCA TCTCCTTGGA GGATTTATAT

2161 GAAGGTTTTG ATGTCTTCTG GCCATCTCTA GAATATAAAA TGTGGCTCAA GCTTGCTCTT

2221 AGTATTGCAA ATCAGTATTT TGAACCAAAT ATTGCTGGTG AGGATTTAAA GTTTCACAAG 2281 TGTGTGTTGT ACAATCACGC ATATGTGGAG ACTCTGTCAA GCTATAATGA GATGACTCTT

2341 AATCACGTGA TCATGAAACT CATTATTCTG GTGTACGGCA TTGTGATCAA TAGCAAGACG

2401 GAAGAAACAT TTGTGGCACC CAGCATCATC CCTAAGTCTT GTGAGCAGAT CCAGGGGATT

2461 TCGGATGTAA GCAAGCTCCT CATAATCCCG ACATCTGATC CTGCCAAAAA CGATGCGACC

2521 TCCCATGCCA TGGGTATAGG TGGAATAGAT GTACTAGAAA AAGGCATAAG CTTTATGGCC 2581 TTGCCTAGGA GGCATATTAG CATGTAG

SEQ ID NO:86 INPIONCH08 amino acid sequence

1 MYTDIIRGES LIICSFTCIF FGIFRGHSTD TSMFRELHII IGLSFDVFGS TICGY CTRV

61 IQIILTDLFS NTLTNVVLCF SLVYMTFYLV EYFGMSGIVA LVTVGLNLDS LSFKPRMEFI 121 ITKFLIMCSS VYEHLIYAFF GIVIGCGEIK YFKFHSIVFT VTLFITVNFV RLLTIILVSP

181 ILMHSSYEYD R GFVIAWS GIRGVFSLLL APDIYNISRF KLPAPHMFIF YIQVLSLLTT

241 GINSHMMLRS AKTLGLCALS LPRQMAVRNA IEHIQEIIRN TITLFKTEKI LTNVN NWE

301 EKAKIEYNPT HVQVSHSPKE ESPTDEVLIE EARLHVAIIQ MSSFE QCND GTLGVEAARI

361 LIGATKSYCP IHGKELNVSA LTSINYYFMF LYILESALKI LIL RKYFLQ N NTLDFFII 421 VIGITDILCM YFVKLRPDSL I1IQFTVVIG YLRVIRFLPI FKIIIPILIN MADVQIKKSL

481 SLMYSITKGY VKSQEDAKLL IRQISGRESI YRKLYDILEK NKREAIRELG LIEHEGRDVV

541 IALKTKQTIR NVIAKALKNL TFL SRGIID KHEGIEMNKV LLTKIKALNN FPMAIPPPTP

601 DKYLPNIVWM ENKDVLIEFF KERTKLTYFD YGDIICREGE MSQGIFLIIS GMASLHSSSP

661 TFGIDSTQRT DRQFKTMYTE YCTSGDVLGE LSCLLKREIE YTAICETTLQ AFFISLEDLY 721 EGFDVF PSL EYKMWLKLAL SIANQYFEPN IAGEDLKFHK CVLYNHAYVE TLSSYNEMTL

781 NHVIMKLIIL VYGIVINSKT EETFVAPSII PKSCEQIQGI SDVSKLLIIP TSDPAKNDAT

841 SHAMGIGGID VLEKGISFMA LPRRHISM

SEQ ID NO.-87 INPIONCH09 exon 1 nucleotide sequence 1 ATGGATGATC ATATGGAGAT TGCTTCTAAC ATAAATCTGC ATAAAAATTT TTCTGAAACA 61 TGGCTGGAAT ATTTAAGGA

SEQ ID NO:88 INPIONCH09 exon 1 amino acid sequence

1 MDDHMEIASN INLHKNFSET WLEYLRS

SEQ ID NO.-89 INPIONCH09 exon 2 nucleotide sequence

1 GTGAGTTAGT TGGAATGTCA GGAATATTTA CTCTGGCCAT TGTGGGACTT CTTTTAAATT 61 CTACAAGTTT TAAAGCAGCA ATTGAAGAAA CACTTCTTCT TGA SEQ ID NO:90 INPIONCH09 exon 2 amino acid sequence

1 ELVGMSGIFT LAIVGLLLNS TSFKAAIEET LLLE

SEQ ID NO:91 INPIONCH09 exon 3 nucleotide sequence

1 ATTCTGGACT TTTCTATCAC GTATTGCTTT TCTCATGGTG TTTACTTTCT TTGGACTTCT 61 AATTCCTGCA CATACATATT TGTATATAGA ATTTGTTGAT ATATACTATT CATTAAATAT 121 CTACTTAACA TTGATTGTTT TAAG

SEQ ID NO:92 INPIONCH09 exon 3 amino acid sequence

1 F TFLSRIAF LMVFTFFGLL IPAHTYLYIE FVDIYYSLNI YLTLIVLR

SEQ ID NO:93 INPIONCH09 exon 4 nucleotide sequence

1 ATTTCTGACC CTTCTTTTAA TAAGCCCTGT TTTGTCTCGA GTTGGTCATG AGTTCAGTTG

61 GCGCTGGATA TTCATAATGG TCTGTAGTGA AATGAAGGGG ATGCCTAATA TAAACATGGC

121 CCTTCTGCTT GCCTACTCTG ATCTTTATTT TGGATCTGAC AAAGAAAAAT CTCAAGTAAA 181 GAAAGCT

SEQ ID NO:94 INPIONCH09 exon 4 amino acid sequence

1 FLTLLLISPV LSRVGHEFS R IFIMVCSE MKGMPNINMA LLLAYSDLYF GSDKEKSQVK 61 KA

SEQ ID NO:95 INPIONCH09 exon 5 nucleotide sequence

1 ATATTATTTC ATGGAGTGTT AGTATGCCTA ATAACCCTTG TTGTCAATAG ATTTATTTTG 61 CCAGTGGCAG TTACTATACT AG SEQ ID NO:96 INPIONCH09 exon 5 amino acid sequence

1 ILFHGVLVCL ITLVVNRFIL PVAVTILG

SEQ ID NO:97 INPIONCH09 exon 6 nucleotide sequence

1 GTCTTCGTGA TGCCACATCA ACAAAATATA AATCGGTTTG TTGCACATTT CAACACTTTC 61 AAGAGCTAAC CAAGTCTGCA GCCTCTGCCC TTAAATTTGA CAAAGATCTT GCTAATGCTG

121 ATTGGAACAT GATTGAGAAA GCAATTACAC TTGAAAACCC ATACATG

SEQ ID NO:98 INPIONCH09 exon 6 amino acid sequence

1 LRDATSTKYK SVCCTFQHFQ ELTKSAASAL KFDKDLANAD NMIEKAITL ENPYM

SEQ ID NO:99 INPIONCH09 exon 7 nucleotide sequence

1 ATTGACGCCC ACTCCTCCAA TTATGATTCA CTAGGTCTAA GGTGGGATCT 61 GAGAATGCAC GTTTCTAACA ATTCCCAG SEQ ID NO: 100 INPIONCH09 exon 7 amino acid sequence

1 IDAHSSNYDS LGLR DLRMH VSNNSQ

SEQ ID NO:101 INPIONCH09 exon 8 nucleotide sequence

1 TTGAACGAAG AAGAAACAAC AGAACATCAG AAGGTGAAAT GTCCACACTG TAACAAGGAA 61 ATAGATGAGA TCTTTAACAC TGAAGCAATG GAGCTGGCCA ACAGGCGTCT CTTGTCAGCA 121 CAAATA

SEQ ID NO:102 INPIONCH09 exon 8 amino acid sequence

1 LNEEETTEHQ KVKCPHCNKE IDEIFNTEAM ELANRRLLSA QI

SEQ ID NO.103 INPIONCH09 exon 9 nucleotide sequence

1 CTACCAGAGA CAATACAGGA ATGAGATTCT GTCCCAGAGT GCTGTCCAGG TGTTGGTTGG 61 TGCAGCAGAA AGTTTTGGTG AGAAGAAGGG AAA SEQ ID NO:104 INPIONCH09 exon 9 amino acid sequence

1 YQRQYRNEIL SQSAVQVLVG AAESFGEKKG K

SEQ ID NO: 105 INPIONCH09 exon 10 nucleotide sequence

1 ATGTATGAGT CTTGATACAA TAAAGAATTA TTCTGAAAGC CAAAAAACAG TTACCTTTGC 61 TAGAAAACTA CTACTTAATT GGGTGTATAA TACCAGAAAG GAAAAAGAGG GCCCATCAAA

SEQ ID NO: 106 INPIONCH09 exon 10 amino acid sequence

1 CMSLDTIKNY SESQKTVTFA RKLLLN VYN TRKEKEGPSK SEQ ID NO: 107 INPIONCH09 exon 11 nucleotide sequence

1 ATACTTCTTT TTTCGTATAT GCCATACAAT AGTATTTACT GAGGAATTTG AACATGTTGG

61 ATACCTTGTG ATATTAATGA ATATATTTCC CTTTATAATC TCTTGGATAT CCCAGTTAAA

121 TGTAATCTAC CACAGCGAAT TAAAACACAC TAACTACTGT TTTCTTACAC TTTATATTCT

181 AGAGGCACTA CTTAAG

SEQ ID NO:108 INPIONCH09 exon 11 amino acid sequence

1 YFFFRICHTI VFTEEFEHVG YLVILMNIFP FIISWISQ N VIYHSELKHT NYCFLTLYIL 61 EALLK SEQ ID NO:109 INPIONCH09 exon 12 nucleotide sequence

1 ATAGCAGCAA TGAGGAAGGA CTTTTTTTCA CATGCCTGGA ACATATTCGA GTTAGCAATT 61 ACATTAATTG GCATCTTACA TGTAATACTT ATTGAAATAG ACACCATTAA GTATATTTTT 121 AATGAGACTG AAGTAATAGT CTTTATAAAA GTTGTTCAAT TTTTTCGTAT ACTACGCATT 181 TTCAAG

SEQ ID NO: 110 INPIONCH09 exon 12 amino acid sequence

1 IAAMRKDFFS HANIFELAI TLIGILHVIL IEIDTIKYIF NETEVIVFIK WQFFRILRI 61 FK SEQ ID NO:lll INPIONCH09 exon 13 nucleotide sequence

1 CTCATAGCAC CAAAGTTGCT GCAAATAATA GATAAAAGAA TGAGTCATCA GAAGACCTTT 61 TGGTATGGAA TACTAAAAGG CTATGTCCAA GGCGAAGCAG ACATAATGAC CATAATTGAT 121 CAGATTACAA GTTCTAAACA GATTAAACAG SEQ ID NO:112 INPIONCH09 exon 13 amino acid sequence

1 LIAPKLLQII DKRMSHQ TF WYGILKGYVQ GEADIMTIID QITSSKQIKQ SEQ ID NO:113 INPIONCH09 exon 14 nucleotide sequence

1 ATGTTATTAA AGCAAGTGAT AAGGAATATG GAACATGCTA TAAAAGAGCT AG

SEQ ID NO:114 INPIONCH09 exon 14 amino acid sequence 1 MLLKQVIRNM EHAIKELG

SEQ ID NO:115 INPIONCH09 exon 15 nucleotide sequence

1 GCTACTTAGA GTATGATCAC CCAGAAATTG CTGTCACTGT GAAAACAAAG GAAGAAATTA 61 ATGTTATGCT CAATATGGCT ACAGAAATTC TTAAGGCTTT TGGCTTAAAA GGAATTATTA 121 GTAAAACTGA AGGTGCTGGA ATTAATAAG

SEQ ID NO.116 INPIONCH09 exon 15 amino acid sequence

1 YLEYDHPEIA VTVKTKEEIN VMLNMATEIL KAFGLKGIIS KTEGAGINK SEQ ID NO:117 INPIONCH09 exon 16 nucleotide sequence

1 TTAATCATGG CCAAAAAGAA AGAGGTGCTT GATTCTCAAT CTATTATCAG GCCTCTTACT 61 GTTGAAGAAG TTCTATATCA TATTCCGTGG CTAGATAAAA ACAAAGATTA TATAAACTTC 121 ATTCAG SEQ ID NO:118 INPIONCH09 exon 16 amino acid sequence

1 LIMAKKKEVL DSQSIIRPLT VEEVLYHIPW LDKNKDYINF IQ

SEQ ID NO:119 INPIONCH09 exon 17 nucleotide sequence

1 GCAGCTTCCA GACTTGCTCC AGTCGCTGCA GCTGGGACAA TTAATGAATG CCCCCAAAGA 61 AAATTCAGCA TCTCATCAGC CCTTGGGA

SEQ ID NO: 120 INPIONCH09 exon 17 amino acid sequence

1 AASRLAPVAA AGTINECPQR KFSISSALGR SEQ ID NO-.121 INPIONCH09 exon 18 nucleotide sequence

1 GGATTGATCA AATGGTGGAG TCAAAGGAGA AAGATTTTCC GATAATTGAC ACAGACTATA 61 TGCTCAGTGG AGAAATAATA GGAGAGATAA ACTGCTTAAC TAATGAACCT ATGAAATATT 121 CTGCCACCTG CAAAACTGTA GTGGAG SEQ ID NO:122 INPIONCH09 exon 18 amino acid sequence

1 IDQMVESKEK DFPIIDTDYM LSGEIIGEIN CLTNEPMKYS ATCKTWE

SEQ ID NO: 123 INPIONCH09 exon 19 nucleotide sequence

1 ACATGTTTTA TTCCCAAAAC TCACTTGTAT GATGCTTTTG AGCAATGCTC TCCTCTCATT 61 AAACAAAAAA TGTGGCTAAA ACTTGGACTC GCTATTACAG CCAGAAAAAT CAGAGAACAC 121 TTATCTTATG AG

SEQ ID NO:124 INPIONCH09 exon 19 amino acid sequence

1 TCFIPKTHLY DAFEQCSPLI KQKM LKLGL AITARKIREH LSYE

SEQ ID NO:125 INPIONCH09 exon 20 nucleotide sequence

1 GATTGGAACT ACAATATGCA ACTAAAGCTC TCTAATATTT ATGTAGTAGA TATACCAATG 61 AGTACCAAAA CTGATATTTA TGATGAAAAT CTAATCTATG TTATCCTCAT ACATGGAGCT 121 GTAGAAGATT GTCTGTTACG AAAAACTTAT AGAGCACCTT TCTTAATTCC TATAACATGC 181 CATCAG

SEQ ID NO:126 INPIONCH09 exon 20 amino acid sequence

1 D NYNMQLKL SNIYVVDIPM STKTDIYDEN LIYVILIHGA VEDCLLRKTY RAPFLIPITC 61 HQ SEQ ID NO:127 INPIONCH09 exon 21 nucleotide sequence

1 ATACAAAGTA TTGAAGATTT CACAAAAGTA GTGATTATTC AAACTCCGAT TAACATGAAA

61 ACATTCAGAA GGAATATTAG AAAGTTTGTT CCTAAACATA AAAGTTATCT TACACCAGGA 121 TTAATAGGTG AGTTAGACTT CTTTCAGCAA TTGTGA

SEQ ID NO:128 INPIONCH09 exon 21 amino acid sequence

1 IQSIEDFTKV VIIQTPINMK TFRRNIRKFV PKHKSYLTPG LIGELDFFQQ L SEQ ID NO: 129 INPIONCH09 nucleotide sequence

1 ATGGATGATC ATATGGAGAT TGCTTCTAAC ATAAATCTGC ATAAAAATTT TTCTGAAACA

61 TGGCTGGAAT ATTTAAGGAG TGAGTTAGTT GGAATGTCAG GAATATTTAC TCTGGCCATT

121 GTGGGACTTC TTTTAAATTC TACAAGTTTT AAAGCAGCAA TTGAAGAAAC ACTTCTTCTT

181 GAATTCTGGA CTTTTCTATC ACGTATTGCT TTTCTCATGG TGTTTACTTT CTTTGGACTT 241 CTAATTCCTG CACATACATA TTTGTATATA GAATTTGTTG ATATATACTA TTCATTAAAT

301 ATCTACTTAA CATTGATTGT TTTAAGATTT CTGACCCTTC TTTTAATAAG CCCTGTTTTG

361 TCTCGAGTTG GTCATGAGTT CAGTTGGCGC TGGATATTCA TAATGGTCTG TAGTGAAATG

421 AAGGGGATGC CTAATATAAA CATGGCCCTT CTGCTTGCCT ACTCTGATCT TTATTTTGGA

481 TCTGACAAAG AAAAATCTCA AGTAAAGAAA GCTATATTAT TTCATGGAGT GTTAGTATGC 541 CTAATAACCC TTGTTGTCAA TAGATTTATT TTGCCAGTGG CAGTTACTAT ACTAGGTCTT

601 CGTGATGCCA CATCAACAAA ATATAAATCG GTTTGTTGCA CATTTCAACA CTTTCAAGAG

661 CTAACCAAGT CTGCAGCCTC TGCCCTTAAA TTTGACAAAG ATCTTGCTAA TGCTGATTGG

721 AACATGATTG AGAAAGCAAT TACACTTGAA AACCCATACA TGATTGACGC CCACTCCTCC

781 AATTATGATT CACTAGGTCT AAGGTGGGAT CTGAGAATGC ACGTTTCTAA CAATTCCCAG 841 TTGAACGAAG AAGAAACAAC AGAACATCAG AAGGTGAAAT GTCCACACTG TAACAAGGAA

901 ATAGATGAGA TCTTTAACAC TGAAGCAATG GAGCTGGCCA ACAGGCGTCT CTTGTCAGCA

961 CAAATAGCAA GCTACCAGAG ACAATACAGG AATGAGATTC TGTCCCAGAG TGCTGTCCAG

1021 GTGTTGGTTG GTGCAGCAGA AAGTTTTGGT GAGAAGAAGG GAAAATGTAT GAGTCTTGAT

1081 ACAATAAAGA ATTATTCTGA AAGCCAAAAA ACAGTTACCT TTGCTAGAAA ACTACTACTT 1141 AATTGGGTGT ATAATACCAG AAAGGAAAAA GAGGGCCCAT CAAAATACTT CTTTTTTCGT

1201 ATATGCCATA CAATAGTATT TACTGAGGAA TTTGAACATG TTGGATACCT TGTGATATTA

1261 ATGAATATAT TTCCCTTTAT AATCTCTTGG ATATCCCAGT TAAATGTAAT CTACCACAGC

1321 GAATTAAAAC ACACTAACTA CTGTTTTCTT ACACTTTATA TTCTAGAGGC ACTACTTAAG

1381 ATAGCAGCAA TGAGGAAGGA CTTTTTTTCA CATGCCTGGA ACATATTCGA GTTAGCAATT 1441 ACATTAATTG GCATCTTACA TGTAATACTT ATTGAAATAG ACACCATTAA GTATATTTTT

1501 AATGAGACTG AAGTAATAGT CTTTATAAAA GTTGTTCAAT TTTTTCGTAT ACTACGCATT

1561 TTCAAGCTCA TAGCACCAAA GTTGCTGCAA ATAATAGATA AAAGAATGAG TCATCAGAAG

1621 ACCTTTTGGT ATGGAATACT AAAAGGCTAT GTCCAAGGCG AAGCAGACAT AATGACCATA

1681 ATTGATCAGA TTACAAGTTC TAAACAGATT AAACAGATGT TATTAAAGCA AGTGATAAGG 1741 AATATGGAAC ATGCTATAAA AGAGCTAGGC TACTTAGAGT ATGATCACCC AGAAATTGCT

1801 GTCACTGTGA AAACAAAGGA AGAAATTAAT GTTATGCTCA ATATGGCTAC AGAAATTCTT

1861 AAGGCTTTTG GCTTAAAAGG AATTATTAGT AAAACTGAAG GTGCTGGAAT TAATAAGTTA

1921 ATCATGGCCA AAAAGAAAGA GGTGCTTGAT TCTCAATCTA TTATCAGGCC TCTTACTGTT

1981 GAAGAAGTTC TATATCATAT TCCGTGGCTA GATAAAAACA AAGATTATAT AAACTTCATT 2041 CAGGCAGCTT CCAGACTTGC TCCAGTCGCT GCAGCTGGGA CAATTAATGA ATGCCCCCAA

2101 AGAAAATTCA GCATCTCATC AGCCCTTGGG AGGATTGATC AAATGGTGGA GTCAAAGGAG

2161 AAAGATTTTC CGATAATTGA CACAGACTAT ATGCTCAGTG GAGAAATAAT AGGAGAGATA

2221 AACTGCTTAA CTAATGAACC TATGAAATAT TCTGCCACCT GCAAAACTGT AGTGGAGACA

2281 TGTTTTATTC CCAAAACTCA CTTGTATGAT GCTTTTGAGC AATGCTCTCC TCTCATTAAA 2341 CAAAAAATGT GGCTAAAACT TGGACTCGCT ATTACAGCCA GAAAAATCAG AGAACACTTA

2401 TCTTATGAGG ATTGGAACTA CAATATGCAA CTAAAGCTCT CTAATATTTA TGTAGTAGAT

2461 ATACCAATGA GTACCAAAAC TGATATTTAT GATGAAAATC TAATCTATGT TATCCTCATA

2521 CATGGAGCTG TAGAAGATTG TCTGTTACGA AAAACTTATA GAGCACCTTT CTTAATTCCT

2581 ATAACATGCC ATCAGATACA AAGTATTGAA GATTTCACAA AAGTAGTGAT TATTCAAACT 2641 CCGATTAACA TGAAAACATT CAGAAGGAAT ATTAGAAAGT TTGTTCCTAA ACATAAAAGT

2701 TATCTTACAC CAGGATTAAT AGGTGAGTTA GACTTCTTTC AGCAATTGTG A

SEQ ID NO: 130 INPIONCH09 amino acid sequence

1 MDDHMEIASN INLHKNFSET LEYLRSELV GMSGIFTLAI VGLLLNSTSF KAAIEETLLL 61 EF TFLSRIA FLMVFTFFGL LIPAHTYLYI EFVDIYYSLN IYLTLIVLRF LTLLLISPVL

121 SRVGHEFS R IFIMVCSEM KGMPNINMAL LLAYSDLYFG SDKEKSQVKK AILFHGVLVC

181 LlTLVVNRFl LPVAVTILGL RDATSTKYKS VCCTFQHFQE LTKSAASALK FDKDLANADW

241 NMIEKAITLE NPYMIDAHSS NYDSLGLRWD LRMHVSNNSQ LNEEETTEHQ KVKCPHCNKE 301 IDEIFNTEAM ELANRRLLSA QIASYQRQYR NEILSQSAVQ VLVGAAESFG EKKGKCMSLD

361 TIKNYSESQK TVTFARKLLL NWVYNTRKEK EGPSKYFFFR ICHTIVFTEE FEHVGYLVIL

421 MNIFPFIISW ISQLNVIYHS ELKHTNYCFL TLYILEALLK IAAMRKDFFS HA NIFELAI

481 TLIGILHVIL IEIDTIKYIF NETEVIVFIK VVQFFRILRI FKLIAPKLLQ IIDKRMSHQK

541 TFWYGILKGY VQGEADIMTI IDQITSSKQI KQMLLKQVIR NMEHAIKELG YLEYDHPEIA 601 VTVKTKEEIN VMLNMATEIL KAFGLKGIIS KTEGAGINKL IMAKKKEVLD SQSIIRPLTV

661 EEVLYHIPWL DKNKDYINFI QAASRLAPVA AAGTINECPQ RKFSISSALG RIDQMVESKE

721 KDFPIIDTDY MLSGEIIGEI NCLTNEPMKY SATCKTVVET CFIPKTHLYD AFEQCSPLIK

781 QKMWLKLGLA ITARKIREHL SYEDWNYNMQ LKLSNIYVVD IPMSTKTDIY DENLIYVILI

841 HGAVEDCLLR KTYRAPFLIP ITCHQIQSIE DFTKVVIIQT PINMKTFRRN IRKFVPKHKS 901 YLTPGLIGEL DFFQQL

SEQ ID NO-.131 INPIONCHIO exon 1 nucleotide sequence

1 ATGGCCACCA TCTTTGGTGA TGATGTCAAC CACATCACTC TCATCTTCTC AGTTTTATAC 61 CTCATCTTCT ATGTTT

SEQ ID NO:132 INPIONCHIO exon 1 amino acid sequence

1 MATIFGDDVN HITLIFSVLY LIFYVC

SEQ ID NO:133 INPIONCHIO exon 2 nucleotide sequence 1 GTGAACTAGT TGGAATGTCT GGAATATTTA CTCTGGCCAC CATAGGACTT TTTCTAAATT

61 CTACAAGCTT TAAACCAGGA GTTGAAGCAT TTCTGCTCGA

SEQ H) NO:134 INPIONCHIO exon 2 amino acid sequence

1 ELVGMSGIFT LATIGLFLNS TSFKPGVEAF LLE

SEQ ID NO: 135 INPIONCHIO exon 3 nucleotide sequence

1 ATTCTGGAAC TGCCTGTCTT TTATTGGTTT TCTTATGGTG TTCACTTTCA TTGGACTTCT 61 AATCCCTGCA CACACATACT TACATATATC ATTTTCTGAT GTATATTATT CATTAAATAT 121 CTACTTCACA CTGATTGTTT TAAG

SEQ ID NO: 136 INPIONCHIO exon 3 amino acid sequence

1 FWNCLSFIGF LMVFTFIGLL IPAHTYLHIS FSDVYYSLNI YFTLIVLR

SEQ ID NO-.137 INPIONCHIO exon 4 nucleotide sequence 1 ACTTTTGGTC TTTCTGCTAA TGAGCCCCAT CTTGTCTCGA CTTGGTCACG GGTTCAGCTG

61 GCGCTGGGCG TTCATCATGG TCTGGAGTGA AATGAAAGGA ACACCGAACA TAAATATGGC

121 GCTCCTGCTT GCCTACTCGG ACATTTCTCT CGGTTCTGAG AGGGAAAGAT CTCAAGTAAG

181 GAAAGCTATG TTTTCTTATT TGG SEQ ID NO-.138 INPIONCHIO exon 4 amino acid sequence

1 LLVFLLMSPI LSRLGHGFSW RWAFIMVWSE MKGTPNINMA LLLAYSDISL GSERERSQVR 61 KAMFSYLV

SEQ ID NO: 139 INPIONCHIO exon 5 nucleotide sequence 1 TGTCAGTATG TGTAATTACC CTGATTGTCA ATAGATTTAT TTTGCCAATG GCAGTTACTA 61 AACTAG

SEQ ID NO:140 INPIONCHIO exon 5 amino acid sequence

1 SVCVITLIVN RFILPMAVTK LG SEQ ID NO: 141 INPIONCHIO exon 6 nucleotide sequence

1 GTCTTCGTGA TGTCACATCA ACAAAATATA AATCGGTTTA TTATACATTC CAACACTTTC 61 AAGAGCTAAC CAAATCTACA GCCATGGCAC TCAAATTTGA CAAAGATCTT GCTAATGCTG 121 ACTGGAACAT GGTTGACAAT GCAATTATAC TTCAAAATCC ATATGCA

SEQ ID NO:142 INPIONCHIO exon 6 amino acid sequence

1 LRDVTSTKYK SVYYTFQHFQ ELTKSTAMAL KFDKDLANAD WNMVDNAIIL QNPYA SEQ ID NO: 143 INPIONCHIO exon 7 nucleotide sequence

1 ATGAACCAAG AAGAAATAAC AGAGCATCAG AAGGTGAAAT GTCCAGATTG CAACAAGGAA 61 ATAGATGAGA CCCTCAACAT TGAAGCCATG GAGCTGACCA ACAGACGTCT CCTGTCAGCA 121 CAGATA SEQ ID NO.-144 INPIONCHIO exon 7 amino acid sequence

1 MNQEEITEHQ KVKCPDCNKE IDETLNIEAM ELTNRRLLSA QI

SEQ ID NO: 145 INPIONCHIO exon 8 nucleotide sequence

1 GCGAGCTACC AACGACAGTA CAGGAATGAG GTTCTGTCCC AGAGTGCAGT GCAGGTGTTG 61 GTAGGCGCAG CTGGAAGCTT TGGTGAGAAG AAGGGAGA

SEQ ID NO: 146 INPIONCHIO exon 8 amino acid sequence

1 ASYQRQYRNE VLSQSAVQVL VGAAGSFGEK KGE SEQ ID NO: 147 INPIONCHIO exon 9 nucleotide sequence

1 ATATATGAGT CCTGAGAATA TAAAGAATTT TTCAGAAAGC AAAAAACTCC TCTCCTTTCT 61 TAGAAAATTA CTACTCAACT GGGTGTATAA TACTAAAAAA GATAAAGGGG TTCCATCAAG

SEQ ID NO:148 INPIONCHIO exon 9 amino acid sequence 1 YMSPENIKNF SESKKLLSFL RKLLLNWVYN TKKDKGVPSR

SEQ ID NO: 149 INPIONCHIO exon 10 nucleotide sequence

1 ACCTCATACA GTGACAGCTG CTGTGAGCTC AGTCGTGCAG CAGCTGTTAG ACCTGAAGTC 61 CTTTTCCTAC ACTCCTCTCC CCACTGTCTC TGACCCTTCT CCCATGATGT CCCCTTGGCC 121 TCACAAAGG

SEQ ID NO:150 INPIONCHIO exon 10 amino acid sequence

1 PHTVTAAVSS VVQQLLDLKS FSYTPLPTVS DPSPMMSPWP HKG SEQ ID NO: 151 INPIONCHIO exon 11 nucleotide sequence

1 ATACATGTTT CTTCATGCAT GCCATAGAAT AGTCTTCACA AATGAATTTG AATATACTGG

61 ATACCTTGTG GTATTAATGA GCACATATCC TATGATAATC TGTTGGATTT CCCGACTAAA

121 AGACATCTAT GACAACGAGA TAAAGTGTGC TAACTACTAT TTTCTTGCCT TCTATATTCT

181 AGAGGCTCTA CTTAAG

SEQ ID NO:152 INPIONCHIO exon 11 amino acid sequence

1 YMFLHACHRI VFTNEFEYTG YLVVLMSTYP MIICWISRLK DIYDNEIKCA NYYFLAFYIL 61 EALLK SEQ ID NO:153 INPIONCHIO exon 12 nucleotide sequence

1 GTGGCAGCAA TGAGGAAGGA ATTTTTTTCA CACACCTGGC TCCTGTTTGA GCTGGGGATT

61 ACCTTAGTCG GCGTCCTAGA TATAATACTT ATCGAAACAG ACTCCATTAG TTACAATTTT

121 GACTTAACTG AGACTGTGGT CTTCATGAAC GTGATTCGAC TCCTTCGTAT ACTGCGCATC

181 TTGAAG SEQ ID NO:154 INPIONCHIO exon 12 amino acid sequence

1 VAAMRKEFFS HTWLLFELGI TLVGVLDIIL IETDSISYNF DLTETVVFMN VIRLLRILRI 61 LK SEQ ID NO:155 INPIONCHIO exon 13 nucleotide sequence

1 CTTGTAACAC CAAAACTGCT GCAAATCATA GACAAAAGGA TGAGCCAGCA GATATCATTT 61 CGGTATTCTA TACTGAAAGG CTATGTCCAA GGGGAAATGG ATGTACTGAA TATAATTGAT 121 CAGATTGCAA GTTCCAAACA GACTAAACAG SEQ ID NO-.156 INPIONCHIO exon 13 amino acid sequence

1 LVTPKLLQII DKRMSQQISF RYSILKGYVQ GEMDVLNIID QIASSKQTKQ

SEQ ID NO: 157 INPIONCHIO exon 14 nucleotide sequence

1 ATATTGTTAA AGCGGGTAAT GAGGAATATG GAACATGCTA TGAAAGAGCT AG

SEQ ID NO:158 INPIONCHIO exon 14 amino acid sequence

1 ILLKRVMRNM EHAMKELDG

SEQ ID NO:159 INPIONCHIO exon 15 nucleotide sequence 1 GCTACTTAGA GTATGACCAT CCGGAAATCG CTGTCACTAT GAAAACCAAG GAGGAGATTA

61 ATGTCATGCT CAATATGGCC AGAGAAATTG TCAAGGCTTT CAGGTCCAAA GGAATTATAC 121 ACAAGGTGGA AGGCACTGAG ATTAACAAG

SEQ ID NO:160 INPIONCHIO exon 15 amino acid sequence 1 YLEYDHPEIA VTMKTKEEIN VMLNMAREIV KAFRSKGIIH KVEGTEINK

SEQ ID NO:161 INPIONCHIO exon 16 nucleotide sequence

1 TTAATCATGG CCAAAAAGAT CCAGGTGCTT GATCTGCAGT CTGTTATCCA GCCATTTAAT 61 GTTGAAGAAG CCCCGTGCAA TATCCCATGG CTTAGTGAAG ATCCTGAAGC CATAACCTTT 121 ATTCAG

SEQ ID NO: 162 INPIONCHIO exon 16 amino acid sequence

1 LIMAKKIQVL DLQSVIQPFN VEEAPCNIPW LSEDPEAITF IQ SEQ ID NO: 163 INPIONCHIO exon 17 nucleotide sequence

1 GAAAAAGCAA AAGTTGTAAC ATTTGACTGT GGAAATAACA TATTTGAAGA AGGTGATGAG 61 CCAGAAGGAA TCTATGTAAT AATTTCAGGC ATGGTTAAG

SEQ ID NO: 164 INPIONCHIO exon 17 amino acid sequence 1 EKAKVVTFDC GNNIFEEGDE PEGIYVIISG MVK

SEQ ID NO: 165 INPIONCHIO exon 18 nucleotide sequence

1 CTTAAAAGGT CAAAACCACA CCTGGAGATG GAAAGAGTAT CCGCAGAGTC AGAGATTAAA 61 ATTCATCCAC TGCCCCACAC AGAGTACCTG CTCAGCGGGG AGATAATAGG AGAGTTAAAC 121 TGTCTGACTA AAGAACGGAT GCAATATTCT GCCACCTGCA AAACTGTTGT GGAG

SEQ ID NO.-166 INPIONCHIO exon 18 amino acid sequence

1 LKRSKPHLEM ERVSAESEIK IHPLPHTEYL LSGEIIGELN CLTKERMQYS ATCKTWE SEQ ID NO:167 INPIONCHIO exon 19 nucleotide sequence

1 ACATATTTTA TTCCCATTAG CCACTTGTAT GAAGGCTTTG AAAAAAGATG TCCTAACATG 61 AAACATAAAA TGTGGCAAAA AATCGGACTT GCCATTACTG CCCAAAAGAT CCGAGAACAC 121 TTATCTTTTG AG SEQ ID NO: 168 INPIONCHIO exon 19 amino acid sequence

1 TYFIPISHLY EGFEKRCPNM KHKMWQKIGL AITAQKIREH LSFE SEQ ID NO: 169 INPIONCHIO exon 20 nucleotide sequence

1 GACTGGAACT ACAAGCTGCA GTTGAAACTC TGCAATGCCT TCATAAGAGA CATCCCCAAG

61 TCCATGAAAA CTGACATCTA TGACGAAACG GTAACCCACG TTGTCCTCAT CCATGGATCT

121 GCTGAGGACT GCCAGCTGCG AAAAATTTAT AAGGCGCCTT TCCTAATTCC TGTGACGTGC

181 CATCAG

SEQ ID NO: 170 INPIONCHIO exon 20 amino acid sequence

1 DWNYKLQLKL CNAFIRDIPK SMKTDIYDET VTHVVLIHGS AEDCQLRKIY KAPFLIPVTC 61 HQ SEQ ID NO: 171 INPIONCHIO exon 21 nucleotide sequence

1 ATACAAGGCA TGGAAGACTT CACAAAAGTG ATGATTATTC AAACTTCAAT TGCTGTAAGA

61 AAATTCAGAT GGAATGTAAG AAAGTACATC CCACCTCGAA GAATTTCGAT GAAACCAGAT

121 TCTGAAAGTG AGTTCGCGGT ACTGGGCATG ATTATAAGGA TTTGTGTTCC TTTTATAAAA

181 TAG

SEQ ID NO: 172 INPIONCHIO exon 21 amino acid sequence

1 IQGMEDFTKV MIIQTSIAVR KFRWNVRKYI PPRRISMKPD SESEFAVLGM IIRICVPFIK

SEQ ID NO: 173 INPIONCHIO nucleotide sequence 1 ATGGCCACCA TCTTTGGTGA TGATGTCAAC CACATCACTC TCATCTTCTC AGTTTTATAC

61 CTCATCTTCT ATGTTTGTGA ACTAGTTGGA ATGTCTGGAA TATTTACTCT GGCCACCATA

121 GGACTTTTTC TAAATTCTAC AAGCTTTAAA CCAGGAGTTG AAGCATTTCT GCTCGAATTC

181 TGGAACTGCC TGTCTTTTAT TGGTTTTCTT ATGGTGTTCA CTTTCATTGG ACTTCTAATC

241 CCTGCACACA CATACTTACA TATATCATTT TCTGATGTAT ATTATTCATT AAATATCTAC 301 TTCACACTGA TTGTTTTAAG ACTTTTGGTC TTTCTGCTAA TGAGCCCCAT CTTGTCTCGA

361 CTTGGTCACG GGTTCAGCTG GCGCTGGGCG TTCATCATGG TCTGGAGTGA AATGAAAGGA

421 ACACCGAACA TAAATATGGC GCTCCTGCTT GCCTACTCGG ACATTTCTCT CGGTTCTGAG

481 AGGGAAAGAT CTCAAGTAAG GAAAGCTATG TTTTCTTATT TGGTGTCAGT ATGTGTAATT

541 ACCCTGATTG TCAATAGATT TATTTTGCCA ATGGCAGTTA CTAAACTAGG TCTTCGTGAT 601 GTCACATCAA CAAAATATAA ATCGGTTTAT TATACATTCC AACACTTTCA AGAGCTAACC

661 AAATCTACAG CCATGGCACT CAAATTTGAC AAAGATCTTG CTAATGCTGA CTGGAACATG

721 GTTGACAATG CAATTATACT TCAAAATCCA TATGCAATGA ACCAAGAAGA AATAACAGAG

781 CATCAGAAGG TGAAATGTCC AGATTGCAAC AAGGAAATAG ATGAGACCCT CAACATTGAA

841 GCCATGGAGC TGACCAACAG ACGTCTCCTG TCAGCACAGA TAGCGAGCTA CCAACGACAG 901 TACAGGAATG AGGTTCTGTC CCAGAGTGCA GTGCAGGTGT TGGTAGGCGC AGCTGGAAGC

961 TTTGGTGAGA AGAAGGGAGA ATATATGAGT CCTGAGAATA TAAAGAATTT TTCAGAAAGC

1021 AAAAAACTCC TCTCCTTTCT TAGAAAATTA CTACTCAACT GGGTGTATAA TACTAAAAAA

1081 GATAAAGGGG TTCCATCAAG ACCTCATACA GTGACAGCTG CTGTGAGCTC AGTCGTGCAG

1141 CAGCTGTTAG ACCTGAAGTC CTTTTCCTAC ACTCCTCTCC CCACTGTCTC TGACCCTTCT 1201 CCCATGATGT CCCCTTGGCC TCACAAAGGA TACATGTTTC TTCATGCATG CCATAGAATA

1261 GTCTTCACAA ATGAATTTGA ATATACTGGA TACCTTGTGG TATTAATGAG CACATATCCT

1321 ATGATAATCT GTTGGATTTC CCGACTAAAA GACATCTATG ACAACGAGAT AAAGTGTGCT

1381 AACTACTATT TTCTTGCCTT CTATATTCTA GAGGCTCTAC TTAAGGTGGC AGCAATGAGG

1441 AAGGAATTTT TTTCACACAC CTGGCTCCTG TTTGAGCTGG GGATTACCTT AGTCGGCGTC 1501 CTAGATATAA TACTTATCGA AACAGACTCC ATTAGTTACA ATTTTGACTT AACTGAGACT

1561 GTGGTCTTCA TGAACGTGAT TCGACTCCTT CGTATACTGC GCATCTTGAA GCTTGTAACA

1621 CCAAAACTGC TGCAAATCAT AGACAAAAGG ATGAGCCAGC AGATATCATT TCGGTATTCT

1681 ATACTGAAAG GCTATGTCCA AGGGGAAATG GATGTACTGA ATATAATTGA TCAGATTGCA

1741 AGTTCCAAAC AGACTAAACA GATATTGTTA AAGCGGGTAA TGAGGAATAT GGAACATGCT 1801 ATGAAAGAGC TAGGCTACTT AGAGTATGAC CATCCGGAAA TCGCTGTCAC TATGAAAACC

1861 AAGGAGGAGA TTAATGTCAT GCTCAATATG GCCAGAGAAA TTGTCAAGGC TTTCAGGTCC

1921 AAAGGAATTA TACACAAGGT GGAAGGCACT GAGATTAACA AGTTAATCAT GGCCAAAAAG

1981 ATCCAGGTGC TTGATCTGCA GTCTGTTATC CAGCCATTTA ATGTTGAAGA AGCCCCGTGC 2041 AATATCCCAT GGCTTAGTGA AGATCCTGAA GCCATAACCT TTATTCAGGA AAAAGCAAAA

2101 GTTGTAACAT TTGACTGTGG AAATAACATA TTTGAAGAAG GTGATGAGCC AGAAGGAATC

2161 TATGTAATAA TTTCAGGCAT GGTTAAGCTT AAAAGGTCAA AACCACACCT GGAGATGGAA

2221 AGAGTATCCG CAGAGTCAGA GATTAAAATT CATCCACTGC CCCACACAGA GTACCTGCTC 2281 AGCGGGGAGA TAATAGGAGA GTTAAACTGT CTGACTAAAG AACGGATGCA ATATTCTGCC

2341 ACCTGCAAAA CTGTTGTGGA GACATATTTT ATTCCCATTA GCCACTTGTA TGAAGGCTTT

2401 GAAAAAAGAT GTCCTAACAT GAAACATAAA ATGTGGCAAA AAATCGGACT TGCCATTACT

2461 GCCCAAAAGA TCCGAGAACA CTTATCTTTT GAGGACTGGA ACTACAAGCT GCAGTTGAAA

2521 CTCTGCAATG CCTTCATAAG AGACATCCCC AAGTCCATGA AAACTGACAT CTATGACGAA 2581 ACGGTAACCC ACGTTGTCCT CATCCATGGA TCTGCTGAGG ACTGCCAGCT GCGAAAAATT

2641 TATAAGGCGC CTTTCCTAAT TCCTGTGACG TGCCATCAGA TACAAGGCAT GGAAGACTTC

2701 ACAAAAGTGA TGATTATTCA AACTTCAATT GCTGTAAGAA AATTCAGATG GAATGTAAGA

2761 AAGTACATCC CACCTCGAAG AATTTCGATG AAACCAGATT CTGAAAGTGA GTTCGCGGTA

2821 CTGGGCATGA TTATAAGGAT TTGTGTTCCT TTTATAAAAT AG

SEQ ID NO: 174 INPIONCHIO amino acid sequence

1 MATIFGDDVN HITLIFSVLY LIFYVCELVG MSGIFTLATI GLFLNSTSFK PGVEAFLLEF

61 WNCLSFIGFL MVFTFIGLLI PAHTYLHISF SDVYYSLNIY FTLIVLRLLV FLLMSPILSR

121 LGHGFSWRWA FIMVWSEMKG TPNINMALLL AYSDISLGSE RERSQVRKAM FSYLVSVCVI 181 TLIVNRFILP MAVTKLGLRD VTSTKYKSVY YTFQHFQELT KSTAMALKFD KDLANADWNM

241 VDNAIILQNP YAMNQEEITE HQKVKCPDCN KEIDETLNIE AMELTNRRLL SAQIASYQRQ

301 YRNEVLSQSA VQVLVGAAGS FGEKKGEYMS PENIKNFSES KKLLSFLRKL LLNWVYNTKK

361 DKGVPSRPHT VTAAVSSVVQ QLLDLKSFSY TPLPTVSDPS PMMSPWPHKG YMFLHACHRI

421 VFTNEFEYTG YLWLMSTYP MIICWISRLK DIYDNEIKCA NYYFLAFYIL EALLKVAAMR 481 KEFFSHTWLL FELGITLVGV LDIILIETDS ISYNFDLTET WFMNVIRLL RILRILKLVT

541 PKLLQIIDKR MSQQISFRYS ILKGYVQGEM DVLNIIDQIA SSKQTKQILL KRVMRNMEHA

601 MKELDGYLEY DHPEIAVTMK TKEEINVMLN MAREIVKAFR SKGIIHKVEG TEINKLIMAK

661 KIQVLDLQSV IQPFNVEEAP CNIPWLSEDP EAITFIQEKA KVVTFDCGNN IFEEGDEPEG

721 IYVIISGMVK LKRSKPHLEM ERVSAESEIK IHPLPHTEYL LSGEIIGELN CLTKERMQYS 781 ATCKTVVETY FIPISHLYEG FEKRCPNMKH KMWQKIGLAI TAQKIREHLS FEDWNYKLQL

841 KLCNAFIRDI PKSMKTDIYD ETVTHVVLIH GSAEDCQLRK IYKAPFLIPV TCHQIQGMED

901 FTKVMIIQTS IAVRKFRWNV RKYIPPRRIS MKPDSESEFA VLGMIIRICV PFIK

SEQ ID NO: 175 INPIONCH07 high quality nucleotide sequence 1 ATGCTGACTA ATATCATTCT CTGCTTTTCA ATGGTGTACA TGACTTTCTA TATTGTGGAA

61 TTTTTAGGAA TGTCAGGCAC TCTTGCCTTA GCCGCTGTAG GACTGAATTT AGATTCTTTA

121 ACTTTTAAAC CGAAGATCGA ACTTGTAATT ACTAAGTTCT TAAGAATTTT TTCATCTGTA

181 TATGAACATT TAATATATGC TTTCTTTGGC ATTGTGATTG GATGTGGAGA ACTCAGCCAC

241 TATGAATTTC ACACTATACC TTTCATATTC ATTTTATTTA CAACAGTGAA TTTGGTAAGG 301 TTGCTTACTA TTTTGTTAGT GAGCCCTATT TTGATGCATT CAAATTATGA ATATAATTGG

361 CGATGGGGAG TTGTAATCAC GTGGTCTGGA ATTAAAGGAG TTTTTAATTT ACTCTGGGCT

421 CCTGATGTTT ATAATCTCGC TGAACGAAAA GTGGAAGTAC CACAAATGTT TATACTCTAT

481 GTACAAGTAA TATCATTATT GACAATGGGA ATAAATTCAT ACGTGATGAC TCAGTCAGCC

541 AGGAAGTTAG ATTTGTGTGT TCTTTCCCTC CCAAGACAAA TGATCTTGCA AAATGCCACT 601 CAGCACATAC AGGAGATAGT ACAGAACACA ATAACTTTAT TTAAAACAGA AAAAATTTTG

661 ACAAATGTTA ACTGGACCTT AGTAGAAGAT AAAACGAGGA TCGAATACAT TCCTTTTTCC

721 CACGTTTCAC ATAATGATAT GAAGACAGAA TCCACAACAG ATGAAGCTTT AATGGAGGAA

781 GCCAGATTGC ATGTAGCTGC AATACAAATG AGTAGCTTTG AAAAACAGCG TAACAATGGA

841 ATTCTTGAAA TAGAGGCAGC CCGGATATTA ATTGGTGCAG CAAAATGCTA TTACTCCATC 901 CAAGGAAAAG GTTTAAATGT ATCAGCACTG ATATCAATAA ACTACTATTT TATGTTTTTA

961 TATGTATTAG AATCAACATT GAAGATAATA ATTTTGAAAA GGAAATATTT TCAACAATGT

1021 TGGAATACTT TGGAATTTTT TATCCTGGTT ATTGGAATCA TTGATATCTT TTGTGTATAC

1081 TTTGTGAAAT TGAGACCAGA CAACTTGGCT CTTATACAGC TTACAGTAAT AATGGGATAT

1141 TTAAGAATAA TTAGGTTTCT TCCTCTCTTC AAGATAATAG TACCAATACT GATAAGAATT 1201 GCAGATGTGC AGATCAAAAA GCGCCTCAGC TTGATGTATA GTATTACAAA AGGCTATATC

1261 AAAAGTCAAG AAGATGCCAA ACTTCTAATA AAACAAATAG CTGTCTGTGA ATCAATATAT

1321 CAGAAACTAT GTGAAATTTT GGAAACCAAC AAACAGGATG CTGTCAAAGA ATTAGTACTC

1381 ATGGAGCATG AGGGTCGTGA TGTTGTCATT GCTTTGAAGA CTAAACAGGC AATCCGGAAT

1441 GTGATTGCTA AAGCTCTAAA AAATCTCACC TTCCTTTGTT CAAGAGGCAT TATTGATAAG 1501 CATGAAGTCA TTGAGATAAA TAAGGTACTT CTTAAAAAAT TAAAAGCACT AAATAACTTT 1561 CCAAAGGCAA TCCCACCCCC AACTCCTGAC ATATACCTTC ACAACATCAT TTGGCTGGAA

1621 GGTAAAGATG TTCTCATTGA CTTCTTCAAG GAAAGAGCCA AACTTGCCTG TTTTGACTCT

1681 GGAGATACCA TTTGTAAAGG AGGTGAAATG CCACAAGGAA TCTACTTAAT TATTTCAGGA

1741 ATGGCAATTT TGCATAGTTT ATCTCCTACC TTTGGAATAG AGAGTAATCA AAGGTGTGAT 1801 AGAGGGTCCA GAGACATGTT TACAGAGTTC TGTACTACTG GGGACATAAT TGGAGAGCTA

1861 AGCTGTCTGC TTAAGCGTGA AATTGAATAT ACCGTCATCT GTGAAACTAG TTTACAGGCC 1921 TGCTTTATCT CCCTGGAGGA TTTATATGAA GGCTTTGATG CCTTCTGGCC ATCTCTGGAA 1981 TATAAAATAT GGCTAAAGCT TGCTCTCAGT ACTGCCTATC AGTATTTTGA ATCAAGTCTT 20 1 ATTGATGAGG ACTTAAGGTT TCAGAACTGT GTGATGTTCA ATCAAGCATA TGTGGAAACT 2101 TTATCAAGCT ATAGTGACAT GATTATTGAT AATATGACCA TGAAATTTGT TATCATTGTG

2161 TATGGCAGTG TAATTGATAC TAAGACAGAG GAACCATATT TTGCACCTTG CATTATACCT

2221 ACAACCTGTG AGCAGGTTCA GGGAACTTCT GATTTAAGCA AGCTGCTGAT AATCCAAGCA

2281 TCTGAGCTTA CCCAAAGAAA TAGTAACACC AATGTCATGG GAGAGATTCT AACTCCCCTA

2341 AGGTGGGCCT CTAACTCAAT TCCATTCTTT ACCTGGGTAC CCCACCACTT A

SEQ ID NO: 176 INPIONCH07 high quality amino acid sequence

1 MLTNIILCFS MVYMTFY1VE FLGMSGTLAL AAVGLNLDSL TFKPKIELVI TKFLRIFSSV

61 YEHLIYAFFG IVIGCGELSH YEFHTIPFIF ILFTTVNLVR LLTILLVSPI LMHSNYEYNW

121 RWGVVITWSG IKGVFNLLWA PDVYNLAERK VEVPQMFILY VQVISLLTMG INSYVMTQSA 181 RKLDLCVLSL PRQMILQNAT QHIQEIVQNT ITLFKTEKIL TNVNWTLVED KTRIEYIPFS

241 HVSHNDMKTE STTDEALMEE ARLHVAAIQM SSFEKQRNNG ILEIEAARIL IGAAKCYYSI

301 QGKGLNVSAL ISINYYFMFL YVLESTLKII ILKRKYFQQC WNTLEFFILV IGIIDIFCVY

361 FVKLRPDNLA LIQLTVIMGY LRIIRFLPLF KIIVPILIRI ADVQIKKRLS LMYSITKGYI

421 KSQEDAKLLI KQIAVCESIY QKLCEILETN KQDAVKELVL MEHEGRDVVI ALKTKQAIRN 481 VIAKALKNLT FLCSRGIIDK HEVIEINKVL LKKLKALNNF PKAIPPPTPD IYLHNIIWLE

541 GKDVLIDFFK ERAKLACFDS GDTICKGGEM PQGIYLIISG MAILHSLSPT FGIESNQRCD

601 RGSRDMFTEF CTTGDIIGEL SCLLKREIEY TVICETSLQA CFISLEDLYE GFDAFWPSLE

661 YKIWLKLALS TAYQYFESSL IDEDLRFQNC VMFNQAYVET LSSYSDMIID NMTMKFVIIV

721 YGSVIDTKTE EPYFAPCIIP TTCEQVQGTS DLSKLLIIQA SELTQRNSNT NVMGEILTPL 781 RWASNSIPFF TWVPHHL

SEQ ID NO: 177 INPIONCH08 high quality nucleotide sequence

1 ACACTGACGA ACGTTGTTCT CTGTTTCTCA CTGGTGTACA TGACGTTTTA CCTTGTGGAA

61 TATTTCGGAA TGTCAGGCAT TGTTGCTTTG GTCACGGTAG GCCTGAATTT GGATTCTTTA 121 AGCTTTAAAC CGAGGATGGA GTTCATCATT ACTAAGTTCT TAATAATGTG CTCATCTGTA

181 TATGAACACT TAATATATGC TTTCTTTGGC ATTGTCATTG GCTGTGGAGA AATCAAGTAT

241 TTCAAATTTC ACTCCATAGT TTTCACTGTG ACTTTATTCA TAACAGTGAA TTTTGTAAGG

301 CTGCTTACTA TCATTTTAGT GAGCCCAATT TTGATGCATT CAAGTTATGA GTATGACTGG

361 CGTTGGGGAT TCGTCATCGC ATGGTCTGGG ATCAGAGGTG TTTTCAGCTT ACTCTTGGCT 421 CCCGATATTT ACAATATTTC TCGATTTAAA TTACCAGCAC CACATATGTT TATCTTCTAT

481 ATACAAGTAC TATCGTTATT GACAACAGGA ATAAATTCAC ATATGATGCT TCGTTCAGCC

541 AAAACACTAG GTTTGTGTGC TCTCTCCCTC CCAAGACAAA TGGCTGTTCG GAATGCCATT

601 GAACACATAC AGGAGATTAT ACGGAACACA ATAACTTTAT TTAAGACAGA AAAAATTTTG

661 ACAAATGTTA ACTGGAATGT AGTAGAAGAA AAAGCAAAAA TCGAATACAA TCCTACTCAC 721 GTTCAAGTTT CCCACAGTCC AAAAGAGGAG TCCCCAACCG ATGAAGTTTT AATAGAAGAG

781 GCCAGATTGC ATGTAGCTAT AATACAAATG AGTAGCTTTG AAAAGCAGTG TAACGATGGT

841 ACCCTTGGAG TAGAGGCAGC TCGAATATTA ATTGGTGCCA CCAAAACACT GACATCCATA

901 AACTACTATT TTATGTTTTT ATATATATTA GAATCAGCAC TGAAGATACT AATTTTAAAA

961 AGGAAATATT TTCTTCAGAA TTGGAATACT TTGGACTTTT TTATCATAGT CATCGGAATC 1021 ACTGATATAC TGTGCATGTA CTTTGTCAAG CTGAGACCAG ACAGCTTGAT TCTCATCCAG

1081 TTTACGGTGG TGATAGGATA TTTAAGAGTG ATTAGGTTTC TTCCCATCTT CAAGATTATA

1141 ATACCAATAC TAATAAATAT GGCAGATGTT CAGATCAAAA AGAGCCTCAG CTTGATGTAC

1201 AGTATTACAA AAGGCTATGT CAAAAGTCAG GAAGATGCCA AGCTTTTGAT AAGGCAAATT

1261 TCTGGACGTG AATCAATCTA TCGGAAATTA TATGACATTT TAGAAAAAAA CAAACGAGAG 1321 GCTATTAGAG AACTAGGACT CATAGAGCAT GAAGGCCGTG ATGTTGTCAT AGCTCTGAAG

1381 ACGAAGCAGA CAATCCGCAA CGTGATTGCC AAAGCCCTGA AAAACCTCAC CTTTCTTTGG

1441 TCAAGAGGCA TTATTGACAA GCACGAGGGT ATTGAGATGA ACAAGGTACT TCTTACAAAA

1501 ATAAAAGCCT TGAATAACTT TCCAATGGCG ATCCCACCTC CCACCCCTGA CAAATACCTT

1561 CCCAACATTG TTTGGATGGA AAATAAGGAT GTTCTCATTG AGTTCTTCAA GGAAAGAACC 1621 AAACTCACCT ACTTTGACTA TGGGGACATC ATCTGTAGAG AAGGTGAAAT GTCTCAAGGA

1681 ATCTTCTTAA TTATCTCAGG AATGGCAAGT TTACATAGCT CATCTCCCAC CTTTGGGATA

1741 GACTCAACCC AGAGGACTGA CAGACAGTTC AAGACTATGT ATACAGAGTA CTGTACCAGT

1801 GGGGATGTAC TTGGTGAACT AAGCTGTTTG CTGAAGCGTG AAATTGAATA TACGGCCATC

1861 TGTGAAACTA CGTTGCAGGC CTTCTTCATC TCCTTGGAGG ATTTATATGA AGGTTTTGAT 1921 GTCTTCTGGC CATCTCTAGA ATATAAAATG TGGCTCAAGC TTGCTCTTAG TATTGCAAAT

1981 CAGTATTTTG AACCAAATAT TGCTGGTGAG GATTTAAAGT TTCACAAGTG TGTGTTGTAC

2041 AATCACGCAT ATGTGGAGAC TCTGTCAAGC TATAATGAGA TGACTCTTAA TCACGTGATC

2101 ATGAAACTCA TTATTCTGGT GTACGGCATT GTGATCAATA GCAAGACGGA AGAAACATTT

2161 GTGGCACCCA GCATCATCCC TAAGTCTTGT GAGCAGGTAA GAAGCATAAT TTCTAAAGAG 2221 CCCATGTGCT TTGCA

SEQ ID NO: 178 INPIONCH08 high quality amino acid sequence

1 TLTNVVLCFS LVYMTFYLVE YFGMSGIVAL VTVGLNLDSL SFKPRMEFII TKFLIMCSSV

61 YEHLIYAFFG IVIGCGEIKY FKFHSIVFTV TLFITVNFVR LLTIILVSPI LMHSSYEYDW 121 RWGFVIAWSG IRGVFSLLLA PDIYNISRFK LPAPHMFIFY IQVLSLLTTG INSHMMLRSA

181 KTLGLCALSL PRQMAVRNA1 EHIQEIIRNT ITLFKTEKIL TNVNWNVVEE KAKIEYNPTH

241 VQVSHSPKEE SPTDEVLIEE ARLHVAIIQM SSFEKQCNDG TLGVEAARIL IGATKTLTSI

301 NYYFMFLYIL ESALKILILK RKYFLQNWNT LDFFIIVIGI TDILCMYFVK LRPDSLILIQ

361 FTVVIGYLRV IRFLPIFKII IPILINMADV QIKKSLSLMY SITKGYVKSQ EDAKLLIRQI 421 SGRESIYRKL YDILEKNKRE AIRELGLIEH EGRDVVIALK TKQTIRNVIA KALKNLTFLW

481 SRGIIDKHEG IEMNKVLLTK IKALNNFPMA IPPPTPDKYL PNIVWMENKD VLIEFFKERT

541 KLTYFDYGDI ICREGEMSQG IFLIISGMAS LHSSSPTFGI DSTQRTDRQF KTMYTEYCTS

601 GDVLGELSCL LKREIEYTAI CETTLQAFFI SLEDLYEGFD VFWPSLEYKM WLKLALSIAN

661 QYFEPNIAGE DLKFHKCVLY NHAYVETLSS YNEMTLNHVI MKLIILVYGI VINSKTEETF 721 VAPSIIPKSC EQVRSIISKE PMCFA

SEQ ID NO: 179 INPIONCH09 high quality nucleotide sequence

1 GAGTTAGTTG GAATGTCAGG AATATTTACT CTGGCCATTG TGGGACTTCT TTTAAATTCT

61 ACAAGTTTTA AAGCAGCAAT TGAAGAAACA CTTCTTCTTG AATTCTGGAC TTTTCTATCA 121 CGTATTGCTT TTCTCATGGT GTTTACTTTC TTTGGACTTC TAATTCCTGC ACATACATAT

181 TTGTATATAG AATTTGTTGA TATATACTAT TCATTAAATA TCTACTTAAC ATTGATTGTT

241 TTAAGATTTC TGACCCTTCT TTTAATAAGC CCTGTTTTGT CTCGAGTTGG TCATGAGTTC

301 AGTTGGCGCT GGATATTCAT AATGGTCTGT AGTGAAATGA AGGGGATGCC TAATATAAAC 361 ATGGCCCTTC TGCTTGCCTA CTCTGATCTT TATTTTGGAT CTGACAAAGA AAAATCTCAA

421 ATATTATTTC ATGGAGTGTT AGTATGCCTA ATAACCCTTG TTGTCAATAG ATTTATTTTG

481 CCAGTGGCAG TTACTATACT AGGTCTTCGT GATGCCACAT CAACAAAATA TAAATCGGTT

541 TGTTGCACAT TTCAACACTT TCAAGAGCTA ACCAAGTCTG CAGCCTCTGC CCTTAAATTT

601 GACAAAGATC TTGCTAATGC TGATTGGAAC ATGATTGAGA AAGCAATTAC ACTTGAAAAC 661 CCATACATGT TGAACGAAGA AGAAACAACA GAACATCAGA AGGTGAAATG TCCACACTGT

721 AACAAGGAAA TAGATGAGAT CTTTAACACT GAAGCAATGG AGCTGGCCAA CAGGCGTCTC

781 TTGTCAGCAC AAATAGTACT CTACCAGAGA CAATACAGGA ATGAGATTCT GTCCCAGAGT

841 GCTGTCCAGG TGTTGGTTGG TGCAGCAGAA AGTTTTGGTG AGAAGAAGGG AAAATGTATG

901 AGTCTTGATA CAATAAAGAA TTATTCTGAA AGCCAAAAAA CAGTTACCTT TGCTAGAAAA 961 CTACTACTTA ATTGGGTGTA TAATACCAGA AAGGAAAAAG AGGGCCCATC AAAATACTTC

1021 TTTTTTCGTA TATGCCATAC AATAGTATTT ACTGAGGAAT TTGAACATGT TGGATACCTT

1081 GTGATATTAA TGAATATATT TCCCTTTATA ATCTCTTGGA TATCCCAGTT AAATGTAATC

1141 TACCACAGCG AATTAAAACA CACTAACTAC TGTTTTCTTA CACTTTATAT TCTAGAGGCA

1201 CTACTTAAGC TCATAGCACC AAAGTTGCTG CAAATAATAG ATAAAAGAAT GAGTCATCAG 1261 AAGACCTTTT GGTATGGAAT ACTAAAAGGC TATGTCCAAG GCGAAGCAGA CATAATGACC

1321 ATAATTGATC AGATTACAAG TTCTAAACAG ATTAAACAGA TGTTATTAAA GCAAGTGATA

1381 AGGAATATGG AACATGCTAT AAAAGAGCTA GGCTACTTAG AGTATGATCA CCCAGAAATT

1441 GCTGTCACTG TGAAAACAAA GGAAGAAATT AATGTTATGC TCAATATGGC TACAGAAATT

1501 CTTAAGGCTT TTGGCTTAAA AGGAATTATT AGTAAAACTG AAGGTGCTGG AATTAATAAG 1561 TTAATCATGG CCAAAAAGAA AGAGGTGCTT GATTCTCAAT CTATTATCAG GCCTCTTACT

1621 GTTGAAGAAG TTCTATATCA TATTCCGTGG CTAGATAAAA ACAAAGATTA TATAAACTTC

1681 ATTCAGCTTG AAAAATCAAA GCCAGGTTTA GGGATTGATC AAATGGTGGA GTCAAAGGAG

1741 AAAGATTTTC CGATAATTGA CACAGACTAT ATGCTCAGTG GAGAAATAAT AGGAGAGATA

1801 AACTGCTTAA CTAATGAACC TATGAAATAT TCTGCCACCT GCAAAACTGT AGTGGAGACA 1861 TGTTTTATTC CCAAAACTCA CTTGTATGAT GCTTTTGAGC AATGCTCTCC TCTCATTAAA

1921 CAAAAAATGT GGCTAAAACT TGGACTCGCT ATTACAGCCA GAAAAATCAG AGAACACTTA

1981 TCTTATGAGG ATTGGAACTA CAATATGCAA CTAAAGCTCT CTAATATTTA TGTAGTAGAT

2041 ATACCAATGA GTACCAAAAC TGATATTTAT GATGAAAATC TAATCTATGT TATCCTCATA

2101 CATGGAGCTG TAGAAGATTG TCTGTTACGA AAAACTTATA GAGCACCTTT CTTAATTCCT 2161 ATAACATGCC ATCAGATACA AAGTATTGAA GATTTCACAA AAGTAGTGAT TATTCAAACT

2221 CCGATTAACA TGAAAACATT CAGAAGGAAT ATTAGAAAGT TTGTTCCTAA ACATAAAAGT

2281 TATCTTACAC CAGGATTAAT AGGAGGATTA CATCTAATGC AGGCAATCAT CTATTACAGA

2341 TGCCGAATAA ATGATATCAA AGAGCATAGA GAAACAAAAA TCTTTTATGA TGTACGGAAA

2401 AAAACCATGC TG

SEQ ID NO: 180 INPIONCH09 high quality amino acid sequence

1 ELVGMSGIFT LAIVGLLLNS TSFKAAIEET LLLEFWTFLS RIAFLMVFTF FGLLIPAHTY

61 LYIEFVDIYY SLNIYLTLIV LRFLTLLLIS PVLSRVGHEF SWRWIFIMVC SEMKGMPNIN

121 MALLLAYSDL YFGSDKEKSQ ILFHGVLVCL ITLVVNRFIL PVAVTILGLR DATSTKYKSV 181 CCTFQHFQEL TKSAASALKF DKDLANADWN MIEKAITLEN PYMLNEEETT EHQKVKCPHC

241 NKEIDEIFNT EAMELANRRL LSAQIVLYQR QYRNEILSQS AVQVLVGAAE SFGEKKGKCM

301 SLDTIKNYSE SQKTVTFARK LLLNWVYNTR KEKEGPSKYF FFRICHTIVF TEEFEHVGYL

361 VILMNIFPFI ISWISQLNVI YHSELKHTNY CFLTLYILEA LLKLIAPKLL QIIDKRMSHQ

421 KTFWYGILKG YVQGEADIMT IIDQITSSKQ IKQMLLKQVI RNMEHAIKEL GYLEYDHPEI 481 AVTVKTKEEI NVMLNMATEI LKAFGLKGII SKTEGAGINK LIMAKKKEVL DSQSIIRPLT

541 VEEVLYHIPW LDKNKDYINF IQLEKSKPGL GIDQMVESKE KDFPIIDTDY MLSGEIIGEI

601 NCLTNEPMKY SATCKTVVET CFIPKTHLYD AFEQCSPLIK QKMWLKLGLA ITARKIREHL

661 SYEDWNYNMQ LKLSNIYVVD IPMSTKTDIY DENLIYVILI HGAVEDCLLR KTYRAPFLIP

721 ITCHQIQSIE DFTKVVIIQT PINMKTFRRN IRKFVPKHKS YLTPGLIGGL HLMQAIIYYR 781 CRINDIKEHR ETKIFYDVRK KTML

SEQ ID NO: 181 INPIONCHIO high quality nucleotide sequence

1 ATGGAAGAAA TTTCTGAAAA TTTAACTGCA TCCCACAGTA TCAAACTGAC TAATATGTGG

61 CTGGAACTTC TCAAAAGTGT GTTTCTGAGC ACTCCCCAGG ACCTCCCTGA AATCATCCTG 121 ATACTATCTT TGATCTGTAC AGTTGGAGGT GAACTAGTTG GAATGTCTGG AATATTTACT 181 CTGGCCACCA TAGGACTTTT TCTAAATTCT ACAAGCTTTA AACCAGGAGT TGAAGCATTT

241 CTGCTCGAAT TCTGGAACTG CCTGTCTTTT ATTGGTTTTC TTATGGTGTT CACTTTCATT

301 GGACTTCTAA TCCCTGCACA CACATACTTA CATATATCAT TTTCTGATGT ATATTATTCA

361 TTAAATATCT ACTTCACACT GATTGTTTTA AGACTTTTGG TCTTTCTGCT AATGAGCCCC 421 ATCTTGTCTC GACTTGGTCA CGGGTTCAGC TGGCGCTGGG CGTTCATCAT GGTCTGGAGT

481 GAAATGAAAG GAACACCGAA CATAAATATG GCGCTCCTGC TTGCCTACTC GGACATTTCT

541 CTCGGTTCTG AGAGGGAAAG ATCTCAAATA CTATTTCATG GAGTGTCAGT ATGTGTAATT

601 ACCCTGATTG TCAATAGATT TATTTTGCCA ATGGCAGTTA CTAAACTAGG TCTTCGTGAT

661 GTCACATCAA CAAAATATAA ATCGGTTTAT TATACATTCC AACACTTTCA AGAGCTAACC 721 AAATCTACAG CCATGGCACT CAAATTTGAC AAAGATCTTG CTAATGCTGA CTGGAACATG

781 GTTGACAATG CAATTATACT TCAAAATCCA TATGCAATGA ACCAAGAAGA AATAACAGAG

841 CATCAGAAGG TGAAATGTCC AGATTGCAAC AAGGAAATAG ATGAGACCCT CAACATTGAA

901 GCCATGGAGC TGACCAACAG ACGTCTCCTG TCAGCACAGA TAGCGAGCTA CCAACGACAG

961 TACAGGAATG AGGTTCTGTC CCAGAGTGCA GTGCAGGTGT TGGTAGGCGC AGCTGGAAGC 1021 TTTGGTGAGA AGAAGGGAGA ATATATGAGT CCTGAGAATA TAAAGAATTT TTCAGAAAGC

1081 AAAAAACTCC TCTCCTTTCT TAGAAAATTA CTACTCAACT GGGTGTATAA TACTAAAAAA

1141 GATAAAGGGG TTCCATCAAG ATACATGTTT CTTCATGCAT GCCATAGAAT AGTCTTCACA

1201 AATGAATTTG AATATACTGG ATACCTTGTG GTATTAATGA GCACATATCC TATGATAATC

1261 TGTTGGATTT CCCGACTAAA AGACATCTAT GACAACGAGA TAAAGTGTGC TAACTACTAT 1321 TTTCTTGCCT TCTATATTCT AGAGGCTCTA CTTAAGCTTG TAACACCAAA ACTGCTGCAA

1381 ATCATAGACA AAAGGATGAG CCAGCAGATA TCATTTCGGT ATTCTATACT GAAAGGCTAT

1441 GTCCAAGGGG AAATGGATGT ACTGAATATA ATTGATCAGA TTGCAAGTTC CAAACAGACT

1501 AAACAGATAT TGTTAAAGCG GGTAATGAGG AATATGGAAC ATGCTATGAA AGAGCTAGGC

1561 TACTTAGAGT ATGACCATCC GGAAATCGCT GTCACTATGA AAACCAAGGA GGAGATTAAT 1621 GTCATGCTCA ATATGGCCAG AGAAATTGTC AAGGCTTTCA GGTCCAAAGG AATTATACAC

1681 AAGGTGGAAG GCACTGAGAT TAACAAGTTA ATCATGGCCA AAAAGATCCA GGTGCTTGAT

1741 CTGCAGTCTG TTATCCAGCC ATTTAATGTT GAAGAAGCCC CGTGCAATAT CCCATGGCTT

1801 AGTGAAGATC CTGAAGCCAT AACCTTTATT CAGCTTAAAA GGTCAAAACC ACACCTGGAG

1861 ATGGAAAGAG TATCCGCAGA GTCAGAGATT AAAATTCATC CACTGCCCCA CACAGAGTAC 1921 CTGCTCAGCG GGGAGATAAT AGGAGAGTTA AACTGTCTGA CTAAAGAACG GATGCAATAT

1981 TCTGCCACCT GCAAAACTGT TGTGGAGACA TATTTTATTC CCATTAGCCA CTTGTATGAA

2041 GGCTTTGAAA AAAGATGTCC TAACATGAAA CATAAAATGT GGCAAAAAAT CGGACTTGCC

2101 ATTACTGCCC AAAAGATCCG AGAACACTTA TCTTTTGAGG ACTGGAACTA CAAGCTGCAG

2161 TTGAAACTCT GCAATGCCTT CATAAGAGAC ATCCCCAAGT CCATGAAAAC TGACATCTAT 2221 GACGAAACGG TAACCCACGT TGTCCTCATC CATGGATCTG CTGAGGACTG CCAGCTGCGA

2281 AAAATTTATA AGGCGCCTTT CCTAATTCCT GTGACGTGCC ATCAGATACA AGGCATGGAA

2341 GACTTCACAA AAGTGATGAT TATTCAAACT TCAATTGCTG TAAGAAAATT CAGATGGAAT

2401 GTAAGAAAGT ACATCCCACC TCGAAGAATT TCGATGAAAC CAGATTCTGA AAGATTGCAT

2461 CAGGCACCTG AGACAGGAGG AGGCTGTGAC TCAGCTTTGG TTTCATCATC TACCTGTGGC 2521 AGCTGCCCTA CACACATTGT GGATGATTAT AACAATGCCA TTGTCCTCAG CAGGATAGAG

2581 GAGTAA

SEQ ID NO: 182 INPIONCHIO high quality amino acid sequence

1 MEEISENLTA SHSIKLTNMW LELLKSVFLS TPQDLPEIIL ILSLICTVGG ELVGMSGIFT 61 LATIGLFLNS TSFKPGVEAF LLEFWNCLSF IGFLMVFTFI GLLIPAHTYL HISFSDVYYS

121 LNIYFTLIVL RLLVFLLMSP ILSRLGHGFS WRWAFIMVWS EMKGTPNINM ALLLAYSDIS

181 LGSERERSQI LFHGVSVCVI TLIVNRFILP MAVTKLGLRD VTSTKYKSVY YTFQHFQELT

241 KSTAMALKFD KDLANADWNM VDNAIILQNP YAMNQEEITE HQKVKCPDCN KEIDETLNIE

301 AMELTNRRLL SAQIASYQRQ YRNEVLSQSA VQVLVGAAGS FGEKKGEYMS PENIKNFSES 361 KKLLSFLRKL LLNWVYNTKK DKGVPSRYMF LHACHRIVFT NEFEYTGYLV VLMSTYPMII

421 CWISRLKDIY DNEIKCANYY FLAFYILEAL LKLVTPKLLQ IIDKRMSQQI SFRYSILKGY

481 VQGEMDVLNI IDQIASSKQT KQILLKRVMR NMEHAMKELG YLEYDHPEIA VTMKTKEEIN

541 VMLNMAREIV KAFRSKGIIH KVEGTEINKL IMAKKIQVLD LQSVIQPFNV EEAPCNIPWL

601 SEDPEAITFI QLKRSKPHLE MERVSAESEI KIHPLPHTEY LLSGEIIGEL NCLTKERMQY 661 SATCKTVVET YFIPISHLYE GFEKRCPNMK HKMWQKIGLA ITAQKIREHL SFEDWNYKLQ

721 LKLCNAFIRD IPKSMKTDIY DETVTHVVLI HGSAEDCQLR KIYKAPFLIP VTCHQIQGME

781 DFTKVMIIQT SIAVRKFRWN VRKYIPPRRI SMKPDSERLH QAPETGGGCD SALVSSSTCG

841 SCPTHIVDDY NNAIVLSRIE E

Claims

1. A polypeptide, which polypeptide:

(i) comprises or consists of the amino acid sequence as recited in SEQ ID NO:2, SEQ

ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22, SEQ ID

NO:24 , SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID

NO:34, SEQ JD NO:36, SEQ ID NO:38, SEQ JD NO:40 and/or SEQ JD NO:42;

(ii) is a fragment thereof having the activity of a polypeptide according to (i), or having an antigenic determinant in common with a polypeptide according to (i); or (iii) is a functional equivalent of (i) or (ii).

2. A polypeptide according to claim 1 which comprises the amino acid sequence as recited in

SEQ ID NO:42.

3. A polypeptide according to claim 2 which consists of the amino acid sequence as recited in

SEQ ID NO:42.

4. A polypeptide according to claim 1 which comprises the amino acid sequence as recited in SEQ ID NO: 176.

5. A polypeptide according to claim 4 which consists of the amino acid sequence as recited in

SEQ ID NO:176.

6. A polypeptide, which polypeptide: (i) comprises or consists of the amino acid sequence as recited in SEQ ID NO:44,

SEQ ID NO:46, SEQ ID NO:48, SEQ JD NO:50, SEQ JD NO:52, SEQ ID NO:54, SEQ JD NO:56, SEQ ID NO:58, SEQ JD NO:60, SEQ ID NO:62, SEQ JD NO:64, SEQ ID NO:66, SEQ ID NO:68, SEQ ID NO:70, SEQ JD NO:72, SEQ ID NO:74, SEQ ID NO:76, SEQ ID NO:78, SEQ ID NO:80, SEQ ID NO:82, SEQ ID NO:84 and/or SEQ LD NO:86;

(ii) is a fragment thereof having the activity of a polypeptide of (i), or having an antigenic determinant in common with a polypeptide of (i); or

(iii) is a functional equivalent of (i) or (ii).

7. A polypeptide according to claim 6 which comprises the amino acid sequence as recited in SEQ ID NO:86.

8. A polypeptide according to claim 7 which consists of the amino acid sequence as recited in SEQ ID NO:86.

9. A polypeptide according to claim 6 which comprises the amino acid sequence as recited in SEQ ID NO: 178.

10. A polypeptide according to claim 9 which consists of the amino acid sequence as recited in

SEQ ID NO: 178.

11. A polypeptide, which polypeptide:

(i) comprises or consists of the amino acid sequence as recited in SEQ ID NO:88, SEQ ID NO:90, SEQ ID NO:92, SEQ ID NO:94, SEQ ID NO:96, SEQ ID NO:98, SEQ ID

NO:100, SEQ ID NO:102, SEQ ID NO:104, SEQ ID NO:106, SEQ ID NO:108, SEQ ID NO:110, SEQ ID NO:112, SEQ ID NO:114, SEQ ID NO:116, SEQ ID NO:118, SEQ ID NO:120, SEQ ID NO:122, SEQ ID NO:124, SEQ ID NO:126, SEQ ID NO:128 and/or SEQ ID NO:130; (ii) is a fragment thereof having the activity of a polypeptide of (i), or having an antigenic determinant in common with a polypeptide of (i); or

(iii) is a functional equivalent of (i) or (ii).

12. A polypeptide according to claim 11 which comprises the amino acid sequence as recited in SEQ ID O.T30.

13. A polypeptide according to claim 12 which consists of the amino acid sequence as recited in SEQ ID NO: 130.

14. A polypeptide according to claim 11 which comprises the amino acid sequence as recited in SEQ ID NO: 180.

15. A polypeptide according to claim 14 which consists of the amino acid sequence as recited in SEQ ID NO: 180.

16. A polypeptide, which polypeptide:

(i) comprises or consists of the amino acid sequence as recited in SEQ ID NO: 132, SEQ ID NO:134, SEQ ID NO:136, SEQ ID NO:138, SEQ ID NO:140, SEQ ID NO:142, SEQ ID NO: 144, SEQ ID NO: 146, SEQ ID NO: 148, SEQ ID NO: 150, SEQ ID NO:152, SEQ ID NO:154, SEQ ID NO:156, SEQ ID NO:158 SEQ ID NO:160, SEQ ID NO:162, SEQ ID NO:164, SEQ ID NO:166, SEQ ID NO:168, SEQ ID NO:170, SEQ ID NO: 172 and/or SEQ ID NO: 174;

(«) is a fragment thereof having the activity of a polypeptide of (i), or having an antigenic determinant in common with a polypeptide of (i); or

(iii) is a functional equivalent of (i) or (ii).

17. A polypeptide according to claim 16 which comprises the amino acid sequence as recited in SEQ ID NO: 174.

18. A polypeptide according to claim 17 which consists of the amino acid sequence as recited in SEQ ID NO:174.

19. A polypeptide according to claim 16 which comprises the amino acid sequence as recited in SEQ ID NO: 182.

20. A polypeptide according to claim 19 which consists of the amino acid sequence as recited in SEQ ID NO: 182.

21. A polypeptide which is a functional equivalent according to any one of claims 1 (iii), 6 (iii), 11 (iii) or 16 (iii), characterised in that it is homologous to the amino acid sequence as recited in SEQ ID NO:2, SEQ ID NO:4, SEQ JD NO:6, SEQ ID NO:8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ JD NO:22, SEQ JD NO:24, SEQ JD NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ JD NO:34, SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:40, SEQ JD NO:42, SEQ JD NO:44, SEQ ID NO:46, SEQ ID NO:48, SEQ ID NO:50, SEQ ID NO:52, SEQ JD NO:54, SEQ ID NO:56, SEQ ID NO:58, SEQ ID NO:60, SEQ ID NO:62, SEQ ID NO:64, SEQ JD NO:66, SEQ ID NO:68, SEQ ID NO:70, SEQ ID NO:72, SEQ ID NO:74, SEQ ID NO:76, SEQ JD NO:78, SEQ ID NO:80, SEQ ID NO:82, SEQ ID NO:84, SEQ ID NO:86, SEQ LD NO:88, SEQ JD NO:90, SEQ ID NO:92, SEQ ID NO:94, SEQ JD NO:96, SEQ JD NO:98,

SEQ JD NO: 100, SEQ JD NO 102, SEQ ID NO:104, SEQ ID NO 106, SEQ ID NO 108, SEQ ID NO:110, SEQ JD NO 112, SEQ ID NO:114, SEQ ID NO 116, SEQ JD NO 118, SEQ ID NO:120, SEQ ID NO 122, SEQ ID NO:124, SEQ JD NO 126, SEQ JD NO 128, SEQ JD NO: 130, SEQ JD NO 132, SEQ JD NO:134, SEQ JD NO 136, SEQ JD NO 138, SEQ LD NO: 140, SEQ JD NO 142, SEQ ID NO:144, SEQ JD NO 146, SEQ JD NO 148, SEQ JD NO: 150, SEQ ID NO 152, SEQ JD NO: 154, SEQ JD NO 156, SEQ JD NO 158, SEQ JD NO:160, SEQ JD NO:162, SEQ JD NO:164, SEQ JD NO:166, SEQ ID NO:168, SEQ JD NO:170, SEQ ID NO:172, SEQ ID NO:174, SEQ JD NO:176, SEQ ID NO:178, SEQ ID NO:180 or SEQ JD NO:182 and has activity characteristic of a transporter/channel protein.

22. A polypeptide which is a fragment or a functional equivalent according to any one of the preceding claims, which has greater than 80% sequence identity with the amino acid sequence recited in SEQ JD NO:2, SEQ JD NO:4, SEQ JD NO:6, SEQ ID NO:8, SEQ JD NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ JD NO:22, SEQ ID NO:24, SEQ JD NO:26, SEQ JD NO:28, SEQ JD NO:30, SEQ JD NO:32, SEQ JD NO:34, SEQ JD NO:36, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:42, SEQ ID NO:44, SEQ ID NO:46, SEQ ID NO:48, SEQ ID NO:50, SEQ ID NO:52, SEQ JD NO:54, SEQ ID NO:56, SEQ JD NO:58, SEQ ID NO:60, SEQ ID NO:62, SEQ ID NO:64, SEQ JD NO:66, SEQ ID NO:68, SEQ ID NO:70, SEQ ID NO:72, SEQ ID NO:74, SEQ ID NO:76, SEQ ID NO:78, SEQ ID NO:80, SEQ ID NO:82, SEQ ID NO:84, SEQ ID NO:86, SEQ JD NO:88, SEQ JD NO:90, SEQ ID NO:92, SEQ JD NO:94, SEQ JD NO:96, SEQ ID

NO 98, SEQ JD NO:100, SEQ ID NO:102, SEQ JD NO:104, SEQ ID NO:106, SEQ ID NO 108, SEQ JD NO 110, SEQ ID NO:112, SEQ ID NO: 114, SEQ ID NO: 116, SEQ JD NO 118, SEQ ID NO 120, SEQ ID NO: 122, SEQ ID NO:124, SEQ JD NO: 126, SEQ ID NO 128, SEQ ID NO 130, SEQ ID NO: 132, SEQ ID NO: 134, SEQ ID NO: 136, SEQ ID NO 138, SEQ ID NO 140, SEQ ID NO: 142, SEQ JD NO: 144, SEQ ID NO: 146, SEQ ID NO 148, SEQ ID NO 150, SEQ ID NO: 152, SEQ ID NO: 154, SEQ ID NO: 156, SEQ ID NO 158, SEQ ID NO 160, SEQ ID NO: 162, SEQ ID NO: 164, SEQ ID NO: 166, SEQ ID NO 168, SEQ ID NO 170, SEQ ID NO: 172, SEQ ID NO: 174, SEQ ID NO: 176, SEQ ID NO 178, SEQ ID NO:180 or SEQ ID NO:182, or with an active fragment thereof, preferably greater than 85%, 90%, 95%, 98% or 99% sequence identity.

23. A polypeptide which is a functional equivalent as recited in any one of the preceding claims, which exhibits significant structural homology with a polypeptide having the amino acid sequence recited in SEQ JD NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ JD NO:10, SEQ JD NO:12, SEQ JD NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22, SEQ JD NO:24, SEQ JD NO:26, SEQ JD NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, SEQ JD NO:40, SEQ ID NO:42, SEQ ID NO:44, SEQ ID NO:46, SEQ ID NO:48, SEQ JD NO:50, SEQ JD NO:52, SEQ JD NO:54, SEQ JD NO:56, SEQ JD NO:58, SEQ JD NO:60, SEQ ID NO:62, SEQ JD NO:64, SEQ ID NO:66, SEQ ID NO:68, SEQ JD NO:70, SEQ JD NO:72, SEQ ID NO:74, SEQ ID NO:76, SEQ JD NO:78, SEQ JD NO:80, SEQ ID NO:82, SEQ JD NO:84, SEQ JD NO:86, SEQ ID NO:88, SEQ JD NO:90, SEQ JD NO:92, SEQ ID NO:94, SEQ ID NO:96, SEQ ID NO:98, SEQ ID NO:100, SEQ JD NO:102, SEQ ID NO:104, SEQ JD

NO: 106, SEQ ID NO 108, SEQ JD NO:110, SEQ ID NO: 112, SEQ ID O:114, SEQ ID NO: 116, SEQ ID NO 118, SEQ LD NO: 120, SEQ ID NO: 122, SEQ JD NO: 124, SEQ ID NO: 126, SEQ ID NO 128, SEQ JD NO: 130, SEQ ID NO: 132, SEQ JD NO: 134, SEQ ID NO:136, SEQ ID NO 138, SEQ JD NO:140, SEQ JD NO: 142, SEQ ID NO: 144, SEQ JD NO:146, SEQ ID NO 148, SEQ JD NO: 150, SEQ ID NO: 152, SEQ JD NO: 154, SEQ ID NO: 156, SEQ ID NO 158, SEQ ID NO: 160, SEQ JD NO: 162, SEQ JD NO:164, SEQ ID NO: 166, SEQ ID NO 168, SEQ ID NO: 170, SEQ JD NO: 172, SEQ JD NO:174, SEQ JD

NO:176, SEQ IDNO:178, SEQ IDNO:180 and/or SEQ JD O:182.

24. A polypeptide which is a fragment as recited in any one of the preceding claims having an antigenic determinant in common with the polypeptide of any one of claims 1 (i), 6 (i), 11 (i) or 16 (i) which consists of 7 or more (for example, 8, 10, 12, 14, 16, 18, 20 or more) amino acid residues from the amino acid sequence recited in SEQ ID NO:42, SEQ ID NO:86, SEQ ID NO:130, SEQ ID NO:174, SEQ ID NO:176, SEQ ID NO:178, SEQ ID NO-.180 or SEQ ID NO:182.

25. A purified nucleic acid molecule which encodes a polypeptide according to any one of the preceding claims.

26.A purified nucleic acid molecule according to claim 25, which comprises the nucleic acid sequence as recited in SEQ ID NO:l, SEQ ID NO:3, SEQ JD NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:ll, SEQ JD NO:13, SEQ ID NO:15, SEQ JD NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:23, SEQ JD NO:25, SEQ JD NO:27, SEQ ID NO:29, SEQ ID NO:31, SEQ ID NO:33, SEQ ID NO:35, SEQ JD NO:37, SEQ JD NO:39, SEQ ID NO:41, SEQ ID NO:43, SEQ ID NO:45, SEQ ID NO:47 SEQ ID NO:49, SEQ ID NO:51, SEQ LD NO:53, SEQ JD NO:55, SEQ ID NO:57, SEQ JD NO:59, SEQ JD NO:61, SEQ ID NO:63, SEQ ID NO:65, SEQ ID NO:67, SEQ ID NO:69, SEQ JD NO:71, SEQ ID NO:73, SEQ ID NO:75, SEQ ID NO:77, SEQ JD NO:79, SEQ JD NO:81, SEQ ID NO:83, SEQ JD NO:85, SEQ JD NO:87, SEQ LD NO:89, SEQ JD NO:91, SEQ JD NO:93, SEQ JD NO:95, SEQ JD NO:97, SEQ ID NO:99, SEQ ID NO:101, SEQ ID NO:103, SEQ JD NO:105, SEQ JD NO:107, SEQ ID NO:109, SEQ JD NO:lll, SEQ JD NO:113, SEQ JD NO:115, SEQ JD NO: 117, SEQ ID NO: 119, SEQ JD NO :121, SEQ JD NO:123, SEQ ID NO:125, SEQ ID NO: 127, SEQ ID NO: 129, SEQ JD NO :131, SEQ JD NO:133, SEQ ID NO:135, SEQ JD NO: 137, SEQ JD NO: 139, SEQ JD NO :141, SEQ ID NO:143, SEQ ID NO:145, SEQ ID NO:147, SEQ ID NO:149, SEQ ID NO :151, SEQ JD NO:153, SEQ JD NO:155, SEQ ID NO: 157, SEQ ID NO: 159, SEQ JD NO :161, SEQ ID NO:163, SEQ ID NO:165, SEQ ID NO: 167, SEQ ID NO: 169, SEQ ID NO :171, SEQ ID NO:173, SEQ JD NO.T75, SEQ ID

NO: 177, SEQ LD NO: 179 or SEQ ID NO: 181 or is a redundant equivalent or fragment thereof.

27. A purified nucleic acid molecule according to claim 26 which consists of the nucleic acid sequence as recited in SEQ ID NO:l, SEQ ID NO:3, SEQ JD NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:l l, SEQ JD NO:13, SEQ JD NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:23, SEQ ID NO:25, SEQ JD NO:27, SEQ JD NO:29, SEQ ID NO:31, SEQ ID NO:33, SEQ ID NO:35, SEQ JD NO:37, SEQ ID NO:39, SEQ ID NO:41, SEQ JD NO:43, SEQ JD NO:45, SEQ ID NO:47 SEQ JD NO:49, SEQ ID NO:51, SEQ ID NO:53, SEQ JD NO:55, SEQ LD NO:57, SEQ ID NO:59, SEQ ID NO:61, SEQ ID NO:63, SEQ ID NO:65, SEQ ID NO:67, SEQ JD NO:69, SEQ JD NO:71, SEQ JD NO:73, SEQ JD NO:75, SEQ JD NO:77, SEQ ID NO:79, SEQ JD NO:81, SEQ ID NO:83, SEQ ID NO:85, SEQ JD NO:87, SEQ ID NO:89, SEQ ID NO:91, SEQ ID NO:93, SEQ ID NO:95, SEQ ID NO:97, SEQ ID NO:99, SEQ ID NO:101, SEQ JD NO:103, SEQ ID NO:105, SEQ ID

NO: 107, SEQ JD NO 109, SEQ ID NO:lll, SEQ ID NO:113, SEQ JD NO:115, SEQ ID NO: 117, SEQ ID NO 119, SEQ ID NO.T21, SEQ ID NO:123, SEQ ID NO:125, SEQ JD NO: 127, SEQ JD NO 129, SEQ LD NO:131, SEQ ID NO.T33, SEQ ID NO:135, SEQ LD NO: 137, SEQ ID NO 139, SEQ ID NO:141, SEQ JD NO:143, SEQ JD NO.T45, SEQ ID NO: 147, SEQ JD NO 149, SEQ ID NO:151, SEQ JD NO:153, SEQ ID NO:155, SEQ ID NO: 157, SEQ JD NO 159, SEQ JD NO:161, SEQ JD NO:163, SEQ JD NO:165, SEQ JD NO:167, SEQ JD NO 169, SEQ JD NO:171, SEQ ID NO:173, SEQ ID NO:175, SEQ JD NO:177, SEQ ID NO 179 or SEQ ID NO: 181 or is a redundant equivalent or fragment thereof.

28. A purified nucleic acid molecule which hydridizes under high stringency conditions with a nucleic acid molecule according to any one of claims 25 to 27.

29. A vector comprising a nucleic acid molecule as recited in any one of claims 25 to 28.

30. A host cell transformed with a vector according to claim 29.

31. A multimeric complex comprising one or more polypeptides according to any one of claims 1 to 24.

32. A multimeric complex according to claim 31 wherein said multimeric complex is a dimer.

33. A multimeric complex according to claim 31 wherein said multimeric complex is a tetramer.

34. A multimeric complex according to any one of claims 31 to 33, having the activity of a transporter/channel protein.

35. A ligand which binds specifically to, and which preferably inhibits the activity of a polypeptide according to any one of claims 1 to 24 or a multimeric complex according to any one of claims 31 to 34.

36. A ligand according to claim 35, which is an antibody.

37. A compound that either increases or decreases the level of expression or activity of a polypeptide according to any one of claims 1 to 24 or of a multimeric complex according to any one of claims 31 to 34.

38. A compound according to claim 37 that binds to a polypeptide according to any one of claims 1 to 24 or to a multimeric complex according to any one of claims 31 to 34 without inducing any of the biological effects of the polypeptide of the transporter/channel protein family.

39. A compound according to claim 37 or 38, which is a natural or modified substrate, ligand, enzyme, receptor or structural or functional mimetic.

40. A polypeptide according to any one of claims 1 to 24, a nucleic acid molecule according to any one of claims 25 to 28, a vector according to claim 29, a multimeric complex according to any one of claims 31 to 34, a ligand according to claim 35 or claim 36, or a compound according to any one of claims 37 to 39, for use in therapy or diagnosis of a disease or disorder.

41. A polypeptide according to any one of claims 1 to 24, a nucleic acid molecule according to any one of claims 25 to 28, a vector according to claim 29, a multimeric complex according to any one of claims 31 to 34, a ligand according to claim 35 or claim 36, or a compound according to any one of claims 37 to 39, for use as a contraceptive agent.

42. A method of diagnosing a disease in a patient, comprising assessing the level of expression of a natural gene encoding a polypeptide according to any one of claims 1 to 24, or assessing the activity of a polypeptide according to any one of claims 1 to 24, or assessing the expression or activity of a multimeric complex according to any one of claims 31 to 34 in tissue from said patient and comparing said level of expression or activity to a control level, wherein a level that is different to said control level is indicative of disease.

43. A method according to claim 42 that is carried out in vitro.

44. A method according to claim 42 or claim 43, which comprises the steps of: (a) contacting a ligand according to claim 35 or claim 36 with a biological sample under conditions suitable for the formation of a complex comprising a ligand-polypeptide or a ligand- multimeric complex; and (b) detecting said formed complex.

45. A method according to claim 42 or claim 43, comprising the steps of: a) contacting a sample of tissue from the patient with a nucleic acid probe under stringent conditions that allow the formation of a hybrid complex between a nucleic acid molecule according to any one of claims 25 to 28 and the probe; b) contacting a control sample with said probe under the same conditions used in step a); and c) detecting the presence of hybrid complexes in said samples; wherein detection of levels of the hybrid complex in the patient sample that differ from levels of the hybrid complex in the control sample is indicative of a disease or disorder.

46. A method according to claim 42 or claim 43, comprising: a) contacting a sample of nucleic acid from tissue of the patient with a nucleic acid primer under stringent conditions that allow the formation of a hybrid complex between a nucleic acid molecule according to any one of claims 25 to 28 and the primer; b) contacting a control sample with said primer under the same conditions used in step a); and c) amplifying the sampled nucleic acid; and d) detecting the level of amplified nucleic acid from both patient and control samples; wherein detection of levels of the amplified nucleic acid in the patient sample that differ significantly from levels of the amplified nucleic acid in the control sample is indicative of a disease or disorder.

47. A method according to claim 42 or claim 43 comprising: a) obtaining a tissue sample from a patient being tested for a disease or disorder; b) isolating a nucleic acid molecule according to any one of claims 25 to 28 from said tissue sample; and c) diagnosing the patient for disease by detecting the presence of a mutation which is associated with disease/disorder in the nucleic acid molecule as an indication of the disease.

48. The method of claim 47, further comprising amplifying the nucleic acid molecule to form an amplified product and detecting the presence or absence of a mutation in the amplified product.

49. The method of claim 47 or claim 48, wherein the presence or absence of the mutation in the patient is detected by contacting said nucleic acid molecule with a nucleic acid probe that hybridises to said nucleic acid molecule under stringent conditions to form a hybrid double-stranded molecule, the hybrid double-stranded molecule having an unhybridised portion of the nucleic acid probe strand at any portion corresponding to a mutation associated with disease; and detecting the presence or absence of an unhybridised portion of the probe strand as an indication of the presence or absence of a disease-associated mutation.

50. A method according to any one of claims 42 to 49, wherein said disease or disorder is colitis, hypertrophy, fibrosis, heart failure, myocardial infarction, angina, obesity, hyperinsulinemia, vascular disease, renal disease, fertility disorders, infertility, testosterone deficiency, testosterone-related disorder, testicular cancer or sexual dysfunction.

51. Use of a polypeptide according to any one of claims 1 to 24 as a transporter/channel protein.

52. A pharmaceutical composition comprising a polypeptide according to any one of claims 1 to 24, a nucleic acid molecule according to any one of claims 25 to 28, a vector according to claim 29, a multimeric complex according to any one of claims 31 to 34, a ligand according to claim 35 or claim 36, or a compound according to any one of claims 37 to

39.

53. A vaccine composition comprising a polypeptide according to any one of claims 1 to 24, a multimeric complex according to any one of claims 31 to 34, or a nucleic acid molecule according to any one of claims 25 to 28.

54. A polypeptide according to any one of claims 1 to 24, a nucleic acid molecule according to any one of claims 25 to 28, a vector according to claim 29, a multimeric copmlex according to any one of claims 31 to 34, a ligand according to claim 35 or claim 36, or a compound according to any one of claims 37 to 39 or a pharmaceutical composition of claim 52, for use in the manufacture of a medicament for the treatment of a disease and disorders selected from the group consisting of colitis, hypertrophy, fibrosis, heart failure, myocardial infarction, angina, obesity, hyperinsulinemia, vascular disease, renal disease, fertility disorders, infertility, testosterone deficiency, testosterone-related disorder, testicular cancer and sexual dysfunction.

55. A method of treating a disease in a patient, comprising administering to the patient a polypeptide according to any one of claims 1 to 24, a nucleic acid molecule according to any one of claims 25 to 28, a vector according to claim 29, a multimeric complex according to any one of claims 31 to 34, a ligand according to claim 35 or claim 36, a compound according to any one of claims 37 to 39 or a pharmaceutical composition of claim 52.

56. A method according to claim 55, wherein, for diseases in which the expression of the natural gene or the activity of the polypeptide or expression or activity of the multimeric complex is lower in a diseased patient or in a patient affected with a disorder when compared to the level of expression or activity in a healthy or unaffected patient, the polypeptide, nucleic acid molecule, vector, ligand, compound or composition administered to the patient is an agonist.

57. A method according to claim 55, wherein, for diseases in which the expression of the natural gene or activity of the polypeptide or expression or activity of the multimeric complex is higher in a diseased patient or in a patient affected with a disorder when compared to the level of expression or activity in a healthy or unaffected patient, the polypeptide, nucleic acid molecule, vector, ligand, compound or composition administered to the patient is an antagonist.

58. A method of monitoring the therapeutic treatment of disease in a patient, comprising monitoring over a period of time the level of expression or activity of a polypeptide according to any one of claims 1 to 24, or the level of expression of a nucleic acid molecule according to any one of claims 25 to 28, or the level of expression or activity of a multimeric complex according to any one of claims 31 to 34 in tissue from said patient, wherein altering said level of expression or activity over the period of time towards a control level is indicative of regression of said disease.

59. A method for the identification of a compound that is effective in the treatment and/or diagnosis of a disease/disorder, comprising contacting a polypeptide according to any one of claims 1 to 24, or a nucleic acid molecule according to any one of claims 25 to 28, or a multimeric complex according to any one of claims 31 to 34 with one or more compounds suspected of possessing binding affinity for said polypeptide, nucleic acid molecule or multimeric complex, and selecting a compound that binds specifically to said polypeptide, nucleic acid molecule or multimeric complex.

60. A kit useful for diagnosing disease comprising a first container containing a nucleic acid probe that hybridises under stringent conditions with a nucleic acid molecule according to any one of claims 25 to 28; a second container containing primers useful for amplifying said nucleic acid molecule; and instructions for using the probe and primers for facilitating the diagnosis of disease.

61. The kit of claim 60, further comprising a third container holding an agent for digesting unhybridised RNA.

62. A kit comprising an array of nucleic acid molecules, at least one of which is a nucleic acid molecule according to any one of claims 25 to 28.

63. A kit comprising one or more antibodies that bind to a polypeptide as recited in any one of claims 1 to 24 or to a multimeric complex as recited in any one of claims 31 to 34, and a reagent useful for the detection of a binding reaction between said antibody and said polypeptide/multimeric complex.

64. A transgenic or knockout non-human animal that has been transformed to express higher, lower or absent levels of a polypeptide according to any one of claims 1 to 24.

65. A method for screening for a compound effective to treat a disease/disorder, by contacting a non-human transgenic animal according to claim 64 with a candidate compound and determining the effect of the compound on the disease/disorder of the animal.