AU747846B2 - Human potassium channel genes - Google Patents

Description

WO 99/43696 PCT/US99/03826 HUMAN POTASSIUM CHANNEL GENES

INTRODUCTION

Background Ion channels are multi-subunit, membrane bound proteins critical for maintenance of cellular homeostasis in nearly all cell types. Channels are involved in a myriad of processes including modulation of action potentials, regulation of cardiac myocyte excitability, heart rate, vascular tone, neuronal signaling, activation and proliferation of T-cells, and insulin secretion from pancreatic islet cells. In humans, ion channels comprise extended gene families with hundreds, or perhaps thousands, of both closely related and highly divergent family members. The majority of known channels regulate the passage of sodium chloride calcium and potassium ions across the cellular membrane.

Given their importance in maintaining normal cellular physiology, it is not surprising that ion channels have been shown to play a role in heritable human disease. Indeed, ion channel defects are involved in predisposition to epilepsy, cardiac arrhythmia (long QT syndrome), hypertension (Bartter's syndrome), cystic fibrosis, (defects in the CFTR chloride channel), several skeletal muscle disorders (hyperkalemic periodic paralysis, paramyotonia congenita, episodic ataxia) and congenital neural deafness (Jervell-Lange-Nielson syndrome), amongst others.

The potassium channel gene family is believed to be the largest and most diverse ion channel family. K' channels have critical roles in multiple cell types andpathways, and are the focus of significant investigation. Four human conditions, episodic ataxia with myokymia, long QT syndrome, epilepsy and Bartter's syndrome have been shown to be caused by defective K' ion channels.

As the K channel family is very diverse, and given that these proteins are critical components of virtually all cells, it is likely that abnormal K' channels will be involved in the etiology of additional renal, cardiovascular and central nervous system disorders of interest to the medical and pharmaceutical community.

The K channel superfamily can be broadly classified into groups, based upon the number of transmembrane domain (TMD) segments in the mature WO 99/43Mi PCT/US99/03826 protein. The minK (IsK) gene contains a single TMD, and although not a channel iby itself, ninK associates with different K' channel subunits, such as KvLQT1 and HERG imanodify the activity of these channels. The inward rectifying K+ channels (GIRK, lK, CIR, ROMK) contain 2 TMD domains and a highly conserved pore domain. Twik-1 is a member of the newly emerging 4TMD K' channel subset.

Twik-like channels (leak channels) are involved in maintaining the steady-state K potentiat across membranes and therefore the resting potential of the cell near the equilibrium potential for potassium (Duprat et al. (1997) EMBO J 16(17):5464- 5471). These proteins are particularly intriguing targets for therapeutic regulation.

The 61TMD, or Shaker-like channels, presently comprise the largest subset of known iK channels. The slopoke (slo) related channels, or Ca" regulated channes apparently have either 10 TMD, or 6 TMD with 4 additional hydrophobic domains.

Four transmembrane domain, tandem pore domain K+ channels (4T/2P channels) represent a new family of potassium selective ion channels involved in the control of background membrane conductances. In mammals, five channels fitting the 4T/2P architecture have been described: TWIK, TREK, TASK-1, TASK- 2 and TRAAK. The 4T/2P channels all have distinct characteristics, but are all thought to be involved in maintaining the steady-state K' potentials across membranes and therefore the resting potential of the cell near the equilibrium potential for potassium (Duprat et al. (1997) EMBO J 16(17):5464-5471). These proteins are particularly intriguing targets for therapeutic regulation. Within this group, TWIK-1, TREK-1 and TASK-1 and TASK-2 are widely distributed in many different tissues, while TRAAK is present exclusively in brain, spinal cord and retina. The 4T/2P channels have different physiologic properties; TREK-1 channels, are outwardly rectifying (Fink et al. (1996) EMBO J 15(24):6854-62), while TWIK-1 channels, are inwardly rectifying (Lesage et al. (1996) EMBO J 15(5):1004-11. TASK channels are regulated by changes in PH while TRAAK channels are stimulated by arachidonic acid (Reyes et al. (1998) JBC 273(47):30863-30869).

The degree of sequence homology between different K' channel genes is substantial. At the amino acid level, there is about 40% similarity between WO 99/43696 PCTIUS99/03826 different human genes, with distinct regions having higher homology, specifically the pore domain. It has been estimated that the K+ channel gene family contains approximately 102-103 individual genes. Despite the large number of potential genes, an analysis of public sequence databases and the scientific literature demonstrates that only a small number, approximately 20-30, have been identified. This analysis suggests that many of these important genes remain to be identified.

Potassium channels are involved in multiple different processes and are important regulators of homeostasis in nearly all cell types. Their relevance to basic cellular physiology and role in many human diseases suggests that pharmacological agents could be designed to specific channel subtypes and these compounds then applied to a large market (Bulman, D.E. (1997) Hum Mol Genet 6:1679-1685; Ackerman, M.J. and Clapham D.E. (1997) NEJM 336:1575- 1586, Curran, M.E. (1998) Current Opinion in Biotechnology 9:565-572). The variety of therapeutic agents that modulate K+ channel activity reflects the diversity of physiological roles and importance of K+ channels in cellular function.

A difficulty encountered in therapeutic use of therapeutic agents that modify K+ channel activity is that the presently available compounds tend to be non-specific and elicit both positive and negative responses, thereby reducing clinical efficacy.

To facilitate development of specific compounds it is desirable to have further characterize novel K+ channels for use in in vitro and in vivo assays.

Relevant Literature A large body of literature exists in the general area of potassium channels.

A review of the literature may be found in the series of books, "The Ion Channel Factsbook", volumes 1-4, by Edward C. Conley and William J. Brammar, Academic Press. An overview is provided of: extracellular ligand-gated ion channels (ISBN: 0121844501), intracellular ligand-gated channels (ISBN: 012184451X), Inward rectifier and intercellular channels (ISBN: 0121844528), and voltage gated channels (ISBN: 0121844536). Hille, B. (1992) "Ionic Channels of Excitable Membranes", 2 nd Ed. Sunderland MA:Sinauer Associates, also reviews potassium channels.

WO 99/43696 PCT/US99/03826 Jan and Jan (1997) Annu. Rev. Neurosci. 20:91-123 review cloned potassium channels from eukaryotes and prokaryotes. Ackerman and Clapham (1997) N. Enql. J. Med. 336:1575-1586 discuss the basic science of ion channels in connection with clinical disease. Bulman (1997) Hum. Mol. Genet. 6:1679- 1685 describe some phenotypic variation in ion channel disorders.

Stephan et al. (1994) Neurology 44:1915-1920 describe a pedigree segregating a myotonia with muscular hypertrophy and hyperirritability as an autosomal dominant trait (rippling muscle disease, Ricker et al. (1989) Arch.

Neurol. 46405-408). Electromyography demonstrated that mechanical stimulation provoked electrically silent contractions. The responsible gene was localized to the distal end of the long arm of chromosome 1, in a 12-cM region near D1S235.

Type II pseudohypoaldosteronism is the designation used for a syndrome of chronic mineralocorticoid-resistant hyperkalemia with hypertension. The primary abnormality in type II PHA is thought to be a specific defect of the renal secretory mechanism for potassium, which limits the kaliuretic response to, but not the sodium and chloride reabsorptive effect of, mineralocorticoid. By analysis of linkage in families with autosomal dominant transmission, Mansfield et al.

(1997) Nature Genet. 16:202-205 demonstrated locus heterogeneity of the trait, with linkage of the PHA2 gene to 1q31-q42 and 17pl 1-q21.

Sequences of four transmembrane, two pore potassium channels have been previously described. Reyes et al. (1998) J Biol Chem 273(47):30863- 30869 discloses a pH sensitive channel. As with the related TASK-1 and TRAAK channels, the outward rectification is lost at high external K+ concentration. The TRAAK channel is described by Fink et al. (1998) EMBO J 17(12):3297-308.

A

cardiac two-pore channel is described in Kim et al. (1998) Circ Res 82(4):513-8.

An open rectifier potassium channel with two pore domains in tandem and having a postsynaptic density protein binding sequence at the C terminal was cloned by Leonoudakis et a. (1998) J Neurosci 18(3):868-77.

The electrophysiological properties of Task channels are of interest, (Duprat et al. (1997) EMBO J 16:5464-71). TASK currents are K+-selective, instantaneous and non-inactivating. They show an outward rectification when external is low, which is not observed for high [K+]out, suggesting a lack of intrinsic voltage sensitivity. The absence of activation and inactivation kinetics as well as voltage independence are characteristic of conductances referred to as leak or background conductances. TASK is very sensitive to variations of extracellular pH in a narrow physiological range, a property probably essential for its physiological function, and suggests that small pH variations may serve a communication role in the nervous system.

Summary of the Invention Isolated nucleotide compositions and sequences are provided for K+Hnov genes.

The K+Hnov nucleic acid compositions find use in identifying homologous or related genes; in producing compositions that modulate the expression or function of its encoded io proteins; for gene therapy; mapping functional regions of the proteins; and in studying associated physiological pathways. In addition, modulation of the gene activity in vivo is used for prophylactic and therapeutic purposes, such as treatment of potassium channel defects, identification of cell type based on expression, and the like.

Accordingly, a first aspect of the present invention provides an isolated nucleic acid encoding a mammalian K+Hnov protein.

A second aspect of the present invention provides an expression cassette comprising a transcriptional initiation region functional in an expression host, a nucleic acid according to the first aspect of the present invention described above, under the transcriptional regulation of said transcription initiation region, and a transcriptional go 20 termination region functional in said expression host.

A third aspect of the present invention provides a cell comprising an expression I: cassette of the second aspect of the present invention described above, as part of an extrachromosomal element or integrated into the genome of a host cell as a result of introduction of said expression cassette into said host cell, and the cellular progeny of said .i 25 host cell.

A fourth aspect of the present invention provides a method for producing is mammalian K+Hnov protein, said method comprising: growing a cell according to claim 9, whereby said mammalian K+Hnov protein is Sexpressed; and 30 isolating said K+Hnov protein free of other proteins.

A fifth aspect of the present invention provides a mammalian K+Hnov protein produced by the method of the fourth aspect of the invention described above.

[I:\1ADAYLIB\1iba]4750.doc:sak A sixth aspect of the present invention provides a purified polypeptide composition comprising at least 50 weight of the protein present as a K+Hnov protein or a fragment thereof.

A seventh aspect of the present invention provides an isolated monoclonal antibody binding specifically to a K+Hnov protein.

Description of the Specific Embodiments Nucleic acid compositions encoding K+Hnov polypeptides are provided. They are used in identifying homologous or related genes; in producing compositions that modulate the expression or function of the encoded proteins; for gene therapy; mapping 0o functional regions of the proteins; and in studying associated physiological pathways.

The K+Hnov gene produces are members of the potassium channel gene family, and have high degrees of homology to known potassium channels. The encoded polypeptides may be alpha subunits, which form the functional channel, or accessory subunits that act to modulate the channel activity.

Characterisation of K+ Hnov The sequence data predict that the provided K+Hnov genes encode potassium channels. Table 1 summarises the DNA sequences, corresponding SEQ ID Nos, chromosomal locations, and polymorphisms. The provided *e o« [I:\DAYLIB\liba]4750.doc:sak WO 99/43696 PCT/US99/03826 sequences may encode a predicted K*channel, e.g. voltage gated, inward rectifier, etc.; or a modulatory subunit.

Electrophysiologic characterization of ion channels is an important part of understanding channel function. Full length ion channel cDNAs may be combined with proper vectors to form expression constructs of each individual channel. Functional analyses of expressed channels can be performed in heterologous systems, or by expression in mammalian cell lines. For expression analyses in heterologous systems such as Xenopus oocytes, synthetic mRNA is made through in vitro transcription of each channel construct. mRNA is then injected, singly or in combination with interacting channel subunit mRNAs, into prepared oocytes and the cells allowed to express the channel for several days.

Oocytes expressing the channel of interest are then analyzed by whole cell voltage clamp and patch clamp techniques.

To determine the properties of each channel when expressed in mammalian cells expression vectors specific to this type of analyses may be constructed and the resultant construct used to transform the target cells (for example human embryonic kidney (HEK) cells). Both stable and transiently expressing lines may be studied using whole cell voltage clamp and patch clamp techniques. Data obtained from EP studies includes, but is not limited to: current profiles elicited by depolarization and hyperpolarization, current-voltage (I-V) relationships, voltage dependence of activation, biophysical kinetics of channel activation, deactivation, and inactivation, reversal potential, ion selectivity, gating properties and sensitivity to channel antagonists and agonists.

Heterologous or mammalian cell lines expressing the novel channels can be used to characterize small molecules and drugs which interact with the channel. The same experiments can be used to assay for novel compounds which interact with the expressed channels.

In many cases the functional ion channel formed by K+Hnov polypeptides will be heteromultimers. Heteromultimers are known to form between different voltage gated, outward rectifying potassium channel a subunits, generally comprising four subunits, and frequently associated with auxiliary, p subunits.

Typically such a subunits share a six-transmembrane domain structure (S1-S6), WO 99/43696 PCT/US99/03826 with one highly positively charged domain (S4) and a pore region situated between S5 and S6. Examples of such subunits are K+Hnov4, K+Hnov9, and K+Hnov12. Channels are also formed by mutimerization of subunits of the two transmembrane and one pore architecture. It is predicted that two subunits of K+Hnov49 or K+Hnov59 will be required to form a functional channel.

Heteromultimers of greatest interest are those that form between subunits expressed in the same tissues, and are a combination of subunits from the same species. In addition, the formation of multimers between the subject polypeptides and subunits that form functional channels are of particular interest. The resulting channel may have decreased or increased conductance relative to a homomultimer, and may be altered in response to beta subunits or other modulatory molecules.

Known voltage gated K+ channel a subunits include Kv1.1-1.8 (Gutman et al. (1993) Sem. Neurosci. 5:101-106); Kv2.1-2.2; Kv3.1-3.4; Kv4.1-4.3; Kv5.1; Kv6.1; Kv7.1; Kv8.1; Kv9.1-9.2. The subunits capable of forming ion inducing channels include all of those in the Kvl through Kv4; and Kv7 families. The Kv5.1, Kv6.1, Kv8.1 and Kv9.1-9.2 subunits may be electrically silent, but functional in modifying the properties in heteromultimers.

TABLE I Name cDNA SEQ Protein SEQ Polymorphisms Chromosome Channel Type Position K+Hnovl SEQ ID NO: 1 SEQ ID NO:2 Alternative poly(A) tail: 1236, 2q37 ATP-sensitive inward rectifying 2395 K+Hnov4 SEQ ID NO:3 SEQ ID NO:4 A312C unknown Voltage gated K+ channel T335C A377G T344C A401 G 1 GG (AlaIThr) K+Hnov6 SEQ ID NO:5 SEQ ID NO:6 2p23 Delayed rectifying K+ channel K+Hnov9 SEQ ID NO:7 SEQ ID NO:8 Alternative poly(A) tail: 2304 8q23 Voltage gated K+ channel K+H-nov12 SEQ ID NO:9 SEQ ID NO: 10 C321T (Pro/Leu) Xp2l Voltage gated K+ channel A375G (GluiGly) C407T (Leu/Phe) SEQ ID NO:1I SEQ ID N0:12 Alternative poly(A) tail: 1427 13q14 modulatory subunit A689G (Gly/Arg) K+Hnov27 SEQ ID NO: 13 SEQ ID NO: 14 T365A (lle/Asn) 18q12 modulatory subunit K-.Hnov2 SEQ ID NO:15 SEQ ID NO:16 N/A N/A 4 transmembrane domain, 2 pore K+ channel K+Hnov 11 SEQ ID NOV1 SEQ ID NO:18 N/A N/A Humnan orftholog of murine ge6e, 6 tranismemfbrane dorninas. voltage delayed reetbfi K+ cihiel K+Hnov 14 SEQ ID NO: 19 SEQ ID NO:2O C3166T Q2q14 4 tranriffembrfjie dewfii, voltage gated K+ channel K+Hnov28 SEQ ID NO:21-24 SEQ ID NO:25 4 alternative 5' splices 3q29 Modulatory subunit K+Hnov42 SEQ ID NO:26 SEQ ID NO:27 G1162A; T1460A; T2496A BqIl Homology to K+ channel protein of C. elegans K+Hnov44 SEQ ID NO:28-29 SEQ ID NO:30 N/A 22p13 beta-subunit.

K+Hnov49 SEQ ID NO:80 SEQ ID NO:81 (ATCT), repeats in the 3' 1q41 4T/2P channel; linked to the UTR sequence, starting at disease loci for rippling muscle position 2186 disease 1 (RMD1), and type 11 pseudohypoaldosteronism K+Hnov59 SEQ ID NO:82 SEQ ID NO:83 N/A chr19 4T/2P channel WO 99/43696 PCT/US99/03826 K+HNOV NUCLEIC ACID COMPOSITIONS As used herein, the term "K+Hnov" is generically used to refer to any one of the provided genetic sequences listed in Table 1. Where a specific K+Hnov sequence is intended, the numerical designation, e.g. K49 or K59, will be added.

Nucleic acids encoding K+Hnov potassium channels may be cDNA or genomic DNA or a fragment thereof. The term "K+Hnov gene" shall be intended to mean the open reading frame encoding any of the provided K+Hnov polypeptides, introns, as well as adjacent 5' and 3' non-coding nucleotide sequences involved in the regulation of expression, up to about 20 kb beyond the coding region, but possibly further in either direction. The gene may be introduced into an appropriate vector for extrachromosomal maintenance or for integration into a host genome.

The term "cDNA" as used herein is intended to include all nucleic acids that share the arrangement of sequence elements found in native mature mRNA species, where sequence elements are exons and 3' and 5' non-coding regions.

Normally mRNA species have contiguous exons, with the intervening introns, when present, removed by nuclear RNA splicing, to create a continuous open reading frame encoding a K+Hnov protein.

A genomic sequence of interest comprises the nucleic acid present between the initiation codon and the stop codon, as defined in the listed sequences, including all of the introns that are normally present in a native chromosome. It may further include the 3' and 5' untranslated regions found in the mature mRNA. It may further include specific transcriptional and translational regulatory sequences, such as promoters, enhancers, etc., including about 1 kb, but possibly more, of flanking genomic DNA at either the 5' or 3' end of the transcribed region. The genomic DNA may be isolated as a fragment of 100 kbp or smaller; and substantially free of flanking chromosomal sequence. The genomic DNA flanking the coding region, either 3' or or internal regulatory sequences as sometimes found in introns, contains sequences required for proper tissue and stage specific expression.

WO 99/43696 PCT/US99/03826 The sequence of the 5' flanking region may be utilized for promoter elements, including enhancer binding sites, that provide for developmental regulation in tissues where K+Hnov genes are expressed. The tissue specific expression is useful for determining the pattern of expression, and for providing promoters that mimic the native pattern of expression. Naturally occurring polymorphisms in the promoter regions are useful for determining natural variations in expression, particularly those that may be associated with disease.

Alternatively, mutations may be introduced into the promoter regions to determine the effect of altering expression in experimentally defined systems.

Methods for the identification of specific DNA motifs involved in the binding of transcriptional factors are known in the art, e.g. sequence similarity to known binding motifs, gel retardation studies, etc. For examples, see Blackwell et al.

(1995) Mol Med 1: 194-205; Mortlock et al. (1996) Genome Res. 6: 327-33; and Joulin and Richard-Foy (1995) Eur J Biochem 232: 620-626.

The regulatory sequences may be used to identify cis acting sequences required for transcriptional or translational regulation of K+Hnov expression, especially in different tissues or stages of development, and to identify cis acting sequences and trans acting factors that regulate or mediate K+Hnov expression.

Such transcription or translational control regions may be operably linked to a K+Hnov gene in order to promote expression of wild type or altered K+Hnov or other proteins of interest in cultured cells, or in embryonic, fetal or adult tissues, and for gene therapy.

The nucleic acid compositions of the subject invention may encode all or a part of the subject polypeptides. Double or single stranded fragments may be obtained of the DNA sequence by chemically synthesizing oligonucleotides in accordance with conventional methods, by restriction enzyme digestion, by PCR amplification, etc. For the most part, DNA fragments will be of at least 15 nt, usually at least 18 nt or 25 nt, and may be at least about 50 nt. Such small DNA fragments are useful as primers for PCR, hybridization screening probes, etc.

Larger DNA fragments, i.e. greater than 100 nt are useful for production of the encoded polypeptide. For use in amplification reactions, such as PCR, a pair of WO 99/43696 PCT/US99/03826 primers will be used. The exact composition of the primer sequences is not critical to the invention, but for most applications the primers will hybridize to the subject sequence under stringent conditions, as known in the art. It is preferable to choose a pair of primers that will generate an amplification product of at least about 50 nt, preferably at least about 100 nt. Algorithms for the selection of primer sequences are generally known, and are available in commercial software packages. Amplification primers hybridize to complementary strands of DNA, and will prime towards each other.

The K+Hnov genes are isolated and obtained in substantial purity, generally as other than an intact chromosome. Usually, the DNA will be obtained substantially free of other nucleic acid sequences that do not include a K+Hnov sequence or fragment thereof, generally being at least about 50%, usually at least about 90% pure and are typically "recombinant", i.e. flanked by one or more nucleotides with which it is not normally associated on a naturally occurring chromosome.

The DNA may also be used to identify expression of the gene in a biological specimen. The manner in which one probes cells for the presence of particular nucleotide sequences, as genomic DNA or RNA, is well established in the literature and does not require elaboration here. DNA or mRNA is isolated from a cell sample. The mRNA may be amplified by RT-PCR, using reverse transcriptase to form a complementary DNA strand, followed by polymerase chain reaction amplification using primers specific for the subject DNA sequences.

Alternatively, the mRNA sample is separated by gel electrophoresis, transferred to a suitable support, e.g. nitrocellulose, nylon, etc., and then probed with a fragment of the subject DNA as a probe. Other techniques, such as oligonucleotide ligation assays, in situ hybridizations, and hybridization to DNA probes arrayed on a solid chip may also find use. Detection of mRNA hybridizing to the subject sequence is indicative of K+Hnov gene expression in the sample.

The sequence of a K+Hnov gene, including flanking promoter regions and coding regions, may be mutated in various ways known in the art to generate targeted changes in promoter strength, sequence of the encoded protein, etc.

WO 99/43696 PCT/US99/03826 The DNA sequence or protein product of such a mutation will usually be substantially similar to the sequences provided herein, i.e. will differ by at least one nucleotide or amino acid, respectively, and may differ by at least two but not more than about ten nucleotides or amino acids. The sequence changes may be substitutions, insertions or deletions. Deletions may further include larger changes, such as deletions of a domain or exon. Other modifications of interest include epitope tagging, e.g. with the FLAG system, HA, etc. For studies of subcellular localization, fusion proteins with green fluorescent proteins (GFP) may be used.

Techniques for in vitro mutagenesis of cloned genes are known. Examples of protocols for site specific mutagenesis may be found in Gustin et al., Biotechniques 14:22 (1993); Barany, Gene 37:111-23 (1985); Colicelli et al., Mol Gen Genet 199:537-9 (1985); and Prentki et al., Gene 29:303-13 (1984).

Methods for site specific mutagenesis can be found in Sambrook et al., Molecular Cloning: A Laboratory Manual, CSH Press 1989, pp. 15.3-15.108; Weiner et al., Gene 126:35-41 (1993); Sayers et al., Biotechniques 13:592-6 (1992); Jones and Winistorfer, Biotechniques 12:528-30 (1992); Barton et al., Nucleic Acids Res 18:7349-55 (1990); Marotti and Tomich, Gene Anal Tech 6:67-70 (1989); and Zhu, Anal Biochem 177:120-4 (1989). Such mutated genes may be used to study structure-function relationships of K+Hnov, or to alter properties of the protein that affect its function or regulation.

Homologs and orthologs of K+Hnov genes are identified by any of a number of methods. A fragment of the provided cDNA may be used as a hybridization probe against a cDNA library from the target organism of interest, where low stringency conditions are used. The probe may be a large fragment, or one or more short degenerate primers. Nucleic acids having sequence similarity are detected by hybridization under low stringency conditions, for example, at 0 C and 6XSSC (0.9 M sodium chloride/0.09 M sodium citrate) and remain bound when subjected to washing at 55 0 C in 1XSSC (0.15 M sodium chloride/0.015 M sodium citrate). Sequence identity may be determined by hybridization under stringent conditions, for example, at 50 0 C or higher and WO 99/43696 PCTIUS99/03826 0.1XSSC (15 mM sodium chloride/01.5 mM sodium citrate). Nucleic acids having a region of substantial identity to the provided K+Hnov sequences, e.g. allelic variants, genetically altered versions of the gene, etc., bind to the provided K+Hnov sequences under stringent hybridization conditions. By using probes, particularly labeled probes of DNA sequences, one can isolate homologous or related genes. The source of homologous genes may be any species, e.g.

primate species, particularly human; rodents, such as rats and mice, canines, felines, bovines, ovines, equines, yeast, nematodes, etc.

Between mammalian species, e.g. human and mouse, homologs have substantial sequence similarity, i.e. at least 75% sequence identity between nucleotide sequences, in some cases 80 or 90% sequence identity, and may be as high as 95% sequence identity between closely related species. Sequence similarity is calculated based on a reference sequence, which may be a subset of a larger sequence, such as a conserved motif, coding region, flanking region, etc.

A reference sequence will usually be at least about 18 nt long, more usually at least about 30 nt long, and may extend to the complete sequence that is being compared. Algorithms for sequence analysis are known in the art, such as BLAST, described in Altschul et al. (1990), J. Mol. Biol. 215:403-10. In general, variants of the invention have a sequence identity greater than at least about 65%, preferably at least about 75%, more preferably at least about 85%, and may be greater than at least about 90% or more as determined by the Smith- Waterman homology search algorithm as implemented in MPSRCH program (Oxford Molecular). Exemplary search parameters for use with the MPSRCH program in order to identify sequences of a desired sequence identity are as follows: gap open penalty: 12; and gap extension penalty: 1.

K+HNov POLYPEPTIDES The subject nucleic acid sequences may be employed for producing all or portions of K+Hnov polypeptides. For expression, an expression cassette may be employed. The expression vector will provide a transcriptional and translational initiation region, which may be inducible or constitutive, where the coding region WO 99/43696 PCT/US99/03826 is operably linked under the transcriptional control of the transcriptional initiation region, and a transcriptional and translational termination region. These control regions may be native to a K+Hnov gene, or may be derived from exogenous sources.

The peptide may be expressed in prokaryotes or eukaryotes in accordance with conventional ways, depending upon the purpose for expression. For large scale production of the protein, a unicellular organism, such as E. coli, B. subtilis, S. cerevisiae, insect cells in combination with baculovirus vectors, or cells of a higher organism such as vertebrates, particularly mammals, e.g. COS 7 cells, may be used as the expression host cells. In some situations, it is desirable to express the K+Hnov gene in eukaryotic cells, where the K+Hnov protein will benefit from native folding and post-translational modifications. Small peptides can also be synthesized in the laboratory. Peptides that are subsets of the complete K+Hnov sequence may be used to identify and investigate parts of the protein important for function, or to raise antibodies directed against these regions.

Fragments of interest include the transmembrane and pore domains, the signal sequences, regions of interaction between subunits, etc. Such domains will usually include at least about 20 amino acids of the provided sequence, more usually at least about 50 amino acids, and may include 100 amino acids or more, up to the complete domain. Binding contacts may be comprised of noncontiguous sequences, which are brought into proximity by the tertiary structure of the protein. The sequence of such fragments may be modified through manipulation of the coding sequence, as described above. Truncations may be performed at the carboxy or amino terminus of the fragment, e.g. to determine the minimum sequence required for biological activity.

With the availability of the protein or fragments thereof in large amounts, by employing an expression host, the protein may be isolated and purified in accordance with conventional ways. A lysate may be prepared of the expression host and the lysate purified using HPLC, exclusion chromatography, gel electrophoresis, affinity chromatography, or other purification technique. The WO 99/43"i51 PCT/US99/03826 purified potein will generally be at least about 80% pure, preferably at least about pm and may be up to and including 100% pure. Pure is intended to mean free ofediter proteins, as well as cellular debris.

~Wte expressed K+Hnov polypeptides are useful for the production of antibodis, where short fragments provide for antibodies specific for the particular polypepite, and larger fragments or the entire protein allow for the production of antibodies over the surface of the polypeptide. Antibodies may be raised to the wild-tye or variant forms of K+Hnov. Antibodies may be raised to isolated ,peptides corresponding to specific domains, e.g. the pore domain and the transmemanrane domain, or to the native protein.

antibodies are prepared in accordance with conventional ways, where the expresse polypeptide or protein is used as an immunogen, by itself or conjugated to known immunogenic carriers, e.g. KLH, pre-S HBsAg, other viral or eukarylc proteins, or the like. Various adjuvants may be employed, with a series df iections, as appropriate. For monoclonal antibodies, after one or more booster injections, the spleen is isolated, the lymphocytes immortalized by cell fusion, and then screened for high affinity antibody binding. The immortalized cells, i.e. hybridomas, producing the desired antibodies may then be expanded.

For further description, see Monoclonal Antibodies: A Laboratory Manual, Harlow and Lane eds., Cold Spring Harbor Laboratories, Cold Spring Harbor, New York, 1988. If desired, the mRNA encoding the heavy and light chains may be isolated and mutagenized by cloning in E. coil, and the heavy and light chains mixed to further enhance the affinity of the antibody. Alternatives to in vivo immunization as a method of raising antibodies include binding to phage "display" libraries, usually in conjunction with in vitro affinity maturation.

K+HNov GENOTYPING The subject nucleic acid and/or polypeptide compositions may be used to genotyping and other analysis for the presence of polymorphisms in the sequence, or variation in the expression of the subject genes. Genotyping may be performed to determine whether a particular polymorphisms is associated with WO 99/43696 PCT/US99/03826 a disease state or genetic predisposition to a disease state, particularly diseases associated with defects in excitatory properties of cells, e.g. cardiac, muscle, renal and neural cells. Disease of interest include rippling muscle disease, and type II psuedohypoaldosteronism.

Clinical disorders associated with K+ channel defects include long-QT syndrome; a congenital disorder affecting 1 in 10,000-15,000. Affected individuals have a prolonged QT interval in the electrocardiogram due to a delayed repolarization of the ventricle. Genetic linkage analyses identified two loci for long QT syndrome, LQT1, in 11p15.5 and LQT2, in 7q35-36. Positional cloning techniques identified the novel K+ channel KvLQT1 on chromosome 11 while candidate gene analysis identified causative mutations in the HERG K+ channel for LQT2.

The weaver mouse exhibits several abnormal neurological symptoms, including severe ataxia, loss of granule cell neurons in the cerebellum and dopaminergic cells in the substantia nigra, as well as seizures and male infertility.

A G-protein-coupled K+ channel having a mutation in the conserved pore domain has been determined to cause the disease. The pancreatic-islet 1i-cell ATPsensitive K+ channel (KATP) is composed of two subunits, the sulfonylurea receptor (SUR) and the inward rectifier K+ channel Kir6.2. Mutations in both SUR and Kir6.2 have been identified in patients with persistent hyperinsulinemic hypoglycemia of infancy, which is caused by unregulated secretion of insulin.

Genotyping may also be performed for pharmacogenetic analysis to assess the association between an individual's genotype and that individual's ability to react to a therapeutic agent. Differences in target sensitivity can lead to toxicity or therapeutic failure. Relationships between polymorphisms in channel expression or specificity can be used to optimize therapeutic dose administration.

Genetic polymorphisms are identified in the K+Hnov gene (examples are listed in table e.g. the repeat variation in the 3' UTR of K49. Nucleic acids comprising the polymorphic sequences are used to screen patients for altered reactivity and adverse side effects in response to drugs that act on K+ channels.

WO 99/43696 PCT/US99/03826 K+Hnov genotyping is performed by DNA or RNA sequence and/or hybridization analysis of any convenient sample from a patient, e.g. biopsy material, blood sample, scrapings from cheek, etc. A nucleic acid sample from an individual is analyzed for the presence of polymorphisms in K+Hnov, particularly those that affect the activity, responsiveness or expression of K+Hnov. Specific sequences of interest include any polymorphism that leads to changes in basal expression in one or more tissues, to changes in the modulation of K+Hnov expression, or alterations in K+Hnov specificity and/or activity.

The effect of a polymorphism in K+Hnov gene sequence on the response to a particular agent may be determined by in vitro or in vivo assays. Such assays may include monitoring during clinical trials, testing on genetically defined cell lines, etc. The response of an individual to the agent can then be predicted by determining the K+Hnov genotype with respect to the polymorphism. Where there is a differential distribution of a polymorphism by racial background, guidelines for drug administration can be generally tailored to a particular ethnic group.

Biochemical studies may be performed to determine whether a sequence polymorphism in a K+Hnov coding region or control regions is associated with disease, for example the -association of K+Hnov 9 with idiopathic generalized epilepsy. Disease associated polymorphisms may include deletion or truncation of the gene, mutations that alter expression level, that affect the electrical activity of the channel, etc.

A number of methods are available for analyzing nucleic acids for the presence of a specific sequence. Where large amounts of DNA are available, genomic DNA is used directly. Alternatively, the region of interest is cloned into a suitable vector and grown in sufficient quantity for analysis. The nucleic acid may be amplified by conventional techniques, such as the polymerase chain reaction (PCR), to provide sufficient amounts for analysis. The use of the polymerase chain reaction is described in Saiki et al. (1985) Science 239:487, and a review of current techniques may be found in Sambrook et al. Molecular Cloning: A Laboratory Manual, CSH Press 1989, pp.14.2-14.33. Amplification may be used WO 99/43696 PCT/US99/03826 to determine whether a polymorphism is present, by using a primer that is specific for the polymorphism. Alternatively, various methods are known in the art that utilize oligonucleotide ligation as a means of detecting polymorphisms, for examples see Riley et al. (1990) N.A.R. 18:2887-2890; and Delahunty et al.

(1996) Am. J. Hum. Genet.58:1239-1246.

A detectable label may be included in an amplification reaction. Suitable labels include fluorochromes, e.g. fluorescein isothiocyanate (FITC), rhodamine, Texas Red, phycoerythrin, allophycocyanin, 6-carboxyfluorescein (6-FAM), 2',7'-dimethoxy-4',5'- dichloro-6-carboxyfluorescein (JOE), 6-carboxy-X-rhodamine (ROX), 6-carboxy-2',4',7',4,7- hexachlorofluorescein (HEX), or N,N,N',N'-tetramethyl-6- carboxyrhodamine (TAMRA), radioactive labels, e.g. 32P, 35S, 3H; etc. The label may be a two stage system, where the amplified DNA is conjugated to biotin, haptens, etc. having a high affinity binding partner, e.g. avidin, specific antibodies, etc., where the binding partner is conjugated to a detectable label. The label may be conjugated to one or both of the primers. Alternatively, the pool of nucleotides used in the amplification is labeled, so as to incorporate the label into the amplification product.

The sample nucleic acid, e.g. amplified or cloned fragment, is analyzed by one of a number of methods known in the art. The nucleic acid may be sequenced by dideoxy or other methods. Hybridization with the variant sequence may also be used to determine its presence, by Southern blots, dot blots, etc.

The hybridization pattern of a control and variant sequence to an array of oligonucleotide probes immobilised on a solid support, as described in U.S.

5,445,934, or in W095/35505, may also be used as a means of detecting the presence of variant sequences. Single strand conformational polymorphism (SSCP) analysis, denaturing gradient gel electrophoresis (DGGE), mismatch cleavage detection, and heteroduplex analysis in gel matrices are used to detect conformational changes created by DNA sequence variation as alterations in electrophoretic mobility. Alternatively, where a polymorphism creates or destroys a recognition site for a restriction endonuclease (restriction fragment length polymorphism, RFLP), the sample is digested with that endonuclease, and the WO 99/43696 PCT/US99/03826 products size fractionated to determine whether the fragment was digested.

Fractionation is performed by gel or capillary electrophoresis, particularly acrylamide or agarose gels.

In one embodiment of the invention, an array of oligonucleotides are provided, where discrete positions on the array are complementary to one or more of the provided sequences, e.g. oligonucleotides of at least 12 nt, frequently nt, or larger, and including the sequence flanking a polymorphic position in a K*Hnov sequence; coding sequences for different K Hnov channels, panels of ion channels comprising one or more of the provided K channels; etc. Such an array may comprise a series of oligonucleotides, each of which can specifically hybridize to a different polymorphism. For examples of arrays, see Hacia et al.

(1996) Nature Genetics 14:441-447; Lockhart et al. (1996) Nature Biotechnol.

14:1675-1680; and De Risi etal. (1996) Nature Genetics 14:457-460.

Screening for polymorphisms in K+Hnov may be based on the functional or antigenic characteristics of the protein. Protein truncation assays are useful in detecting deletions that may affect the biological activity of the protein. Various immunoassays designed to detect polymorphisms in K+Hnov proteins may be used in screening. Where many diverse genetic mutations lead to a particular disease phenotype, functional protein assays have proven to be effective screening tools. The activity of the encoded K+Hnov protein as a potassium channel may be determined by comparison with the wild-type protein.

Antibodies specific for a K+Hnov may be used in staining or in immunoassays. Samples, as used herein, include biological fluids such as semen, blood, cerebrospinal fluid, tears, saliva, lymph, dialysis fluid and the like; organ or tissue culture derived fluids; and fluids extracted from physiological tissues. Also included in the term are derivatives and fractions of such fluids.

The cells may be dissociated, in the case of solid tissues, or tissue sections may be analyzed. Alternatively a lysate of the cells may be prepared.

Diagnosis may be performed by a number of methods to determine the absence or presence or altered amounts of normal or abnormal K+Hnov polypeptides in patient cells. For example, detection may utilize staining of cells WO 99/43696 PCT/US99/03826 or histological sections, performed in accordance with conventional methods.

The antibodies of interest are added to the cell sample, and incubated for a period of time sufficient to allow binding to the epitope, usually at least about 10 minutes.

The antibody may be labeled with radioisotopes, enzymes, fluorescers, chemiluminescers, or other labels for direct detection. Alternatively, a second stage antibody or reagent is used to amplify the signal. Such reagents are well known in the art. For example, the primary antibody may be conjugated to biotin, with horseradish peroxidase-conjugated avidin added as a second stage reagent.

Alternatively, the secondary antibody conjugated to a flourescent compound, e.g.

flourescein, rhodamine, Texas red, etc. Final detection uses a substrate that undergoes a color change in the presence of the peroxidase. The absence or presence of antibody binding may be determined by various methods, including flow cytometry of dissociated cells, microscopy, radiography, scintillation counting, etc.

MODULATION OF GENE EXPRESSION The K+Hnov genes, gene fragments, or the encoded protein or protein fragments are useful in gene therapy to treat disorders associated with K+Hnov defects. Expression vectors may be used to introduce the K+Hnov gene into a cell. Such vectors generally have convenient restriction sites located near the promoter sequence to provide for the insertion of nucleic acid sequences.

Transcription cassettes may be prepared comprising a transcription initiation region, the target gene or fragment thereof, and a transcriptional termination region. The transcription cassettes may be introduced into a variety of vectors, e.g. plasmid; retrovirus, e.g. lentivirus; adenovirus; and the like, where the vectors are able to transiently or stably be maintained in the cells, usually for a period of at least about one day, more usually for a period of at least about several days to several weeks.

The gene or K+Hnov protein may be introduced into tissues or host cells by any number of routes, including viral infection, microinjection, or fusion of vesicles. Jet injection may also be used for intramuscular administration, as WO 99/43696 PCT/US99/03826 described by Furth et al. (1992) Anal Biochem 205:365-368. The DNA may be coated onto gold microparticles, and delivered intradermally by a particle bombardment device, or "gene gun" as described in the literature (see, for example, Tang et al. (1992) Nature 356:152-154), where gold microprojectiles are coated with the K+Hnov or DNA, then bombarded into skin cells.

Antisense molecules can be used to down-regulate expression of K+Hnov in cells. The anti-sense reagent may be antisense oligonucleotides (ODN), particularly synthetic ODN having chemical modifications from native nucleic acids, or nucleic acid constructs that express such anti-sense molecules as RNA.

The antisense sequence is complementary to the mRNA of the targeted gene, and inhibits expression of the targeted gene products. Antisense molecules inhibit gene expression through various mechanisms, e.g. by reducing the amount of mRNA available for translation, through activation of RNAse H, or steric hindrance. One or a combination of antisense molecules may be administered, where a combination may comprise multiple different sequences.

Antisense molecules may be produced by expression of all or a part of the target gene sequence in an appropriate vector, where the transcriptional initiation is oriented such that an antisense strand is produced as an RNA molecule.

Alternatively, the antisense molecule is a synthetic oligonucleotide. Antisense oligonucleotides will generally be at least about 7, usually at least about 12, more usually at least about 20 nucleotides in length, and not more than about 500, usually not more than about 50, more usually not more than about 35 nucleotides in length, where the length is governed by efficiency of inhibition, specificity, including absence of cross-reactivity, and the like. It has been found that short oligonucleotides, of from 7 to 8 bases in length, can be strong and selective inhibitors of gene expression (see Wagner et al. (1996) Nature Biotechnology 14:840-844).

A specific region or regions of the endogenous sense strand mRNA sequence is chosen to be complemented by the antisense sequence. Selection of a specific sequence for the oligonucleotide may use an empirical method, where several candidate sequences are assayed for inhibition of expression of WO 99/431~b PCTIUS99/03826 ,the targEt gene in an in vitro or animal model. A combination of sequences may also be used, where several regions of the mRNA sequence are selected for antisese complementation.

Atisense oligonucleotides may be chemically synthesized by methods known iim the art (see Wagner et al. (1993) supra. and Milligan et al., supra.) Preferrem oligonucleotides are chemically modified from the native phosphaoiester structure, in order to increase their intracellular stability and binding afinity. A number of such modifications have been described in the literature, which alter the chemistry of the backbone, sugars or heterocyclic bases.

rAmong useful changes in the backbone chemistry are phosphorothioates; phospharodithioates, where both of the non-bridging oxygens are substituted with sulfur; .phosphoroamidites; alkyl phosphotriesters and boranophosphates. Achiral phosphate derivatives include 3'-O'-5'-S-phosphorothioate, phosphorothioate, 3'-CH2-5'-O-phosphonate and Peptide nucleic acids replace the entire ribose phosphodiester backbone with a peptide linkage. Sugar modifications are also used to enhance stability and affinity. The ao-anomer of deoxyribose may be used, where the base is inverted with respect to the natural p-anomer. The 2'-OH of the ribose sugar may be altered to form 2'-O-methyl or 2'-O-allyl sugars, which provides resistance to degradation without comprising affinity. Modification of the heterocyclic bases must maintain proper base pairing. Some useful substitutions include deoxyuridine for deoxythymidine; 5-methyl-2'-deoxycytidine and 5-bromo-2'deoxycytidine for deoxycytidine. 5- propynyl-2'-deoxyuridine and 5-propynyl-2'deoxycytidine have been shown to increase affinity and biological activity when substituted for deoxythymidine and deoxycytidine, respectively.

As an alternative to anti-sense inhibitors, catalytic nucleic acid compounds, e.g. ribozymes, anti-sense conjugates, etc. may be used to inhibit gene expression. Ribozymes may be synthesized in vitro and administered to the patient, or may be encoded on an expression vector, from which the ribozyme is synthesized in the targeted cell (for example, see International patent application WO 99/43696 PCT/US99/03826 WO 9523225, and Beigelman et al. (1995) Nucl. Acids Res 23:4434-42).

Examples of oligonucleotides with catalytic activity are described in WO 9506764.

Conjugates of anti-sense ODN with a metal complex, e.g. terpyridylCu(ll), capable of mediating mRNA hydrolysis are described in Bashkin et al. (1995) App Biochem Biotechnol 54:43-56.

GENETICALLY ALTERED CELL OR ANIMAL MODELS FOR K+HNOV FUNCTION The subject nucleic acids can be used to generate transgenic animals or site specific gene modifications in cell lines. Transgenic animals may be made through homologous recombination, where the normal K+Hnov locus is altered.

Alternatively, a nucleic acid construct is randomly integrated into the genome.

Vectors for stable integration include plasmids, retroviruses and other animal viruses, YACs, and the like.

The modified cells or animals are useful in the study of K+Hnov function and regulation. For example, a series of small deletions and/or substitutions may be made in the K+Hnov gene to determine the role of different transmembrane domains in forming multimeric structures, ion channels, etc. Of interest are the use of K+Hnov to construct transgenic animal models for epilepsy and other neurological defects, where expression of K+Hnov is specifically reduced or absent. Specific constructs of interest include anti-sense K+Hnov, which will block K+Hnov expression, expression of dominant negative K+Hnov mutations, etc. One may also provide for expression of the K+Hnov gene or variants thereof in cells or tissues where it is not normally expressed or at abnormal times of development.

DNA constructs for homologous recombination will comprise at least a portion of the K+Hnov gene with the desired genetic modification, and will include regions of homology to the target locus. DNA constructs for random integration need not include regions of homology to mediate recombination. Conveniently, markers for positive and negative selection are included. Methods for generating cells having targeted gene modifications through homologous recombination are WO 99/43696 PCT/US99/03826 known in the art. For various techniques for transfecting mammalian cells, see Keown et al. (1990) Methods in Enzvmology 185:527-537.

For embryonic stem (ES) cells, an ES cell line may be employed, or embryonic cells may be obtained freshly from a host, e.g. mouse, rat, guinea pig, etc. Such cells are grown on an appropriate fibroblast-feeder layer or grown in the presence of leukemia inhibiting factor (LIF). When ES or embryonic cells have been transformed, they may be used to produce transgenic animals. After transformation, the cells are plated onto a feeder layer in an appropriate medium.

Cells containing the construct may be detected by employing a selective medium.

After sufficient time for colonies to grow, they are picked and analyzed for the occurrence of homologous recombination or integration of the construct. Those colonies that are positive may then be used for embryo manipulation and blastocyst injection. Blastocysts are obtained from 4 to 6 week old superovulated females. The ES cells are trypsinized, and the modified cells are injected into the blastocoel of the blastocyst. After injection, the blastocysts are returned to each uterine horn of pseudopregnant females. Females are then allowed to go to term and the resulting offspring screened for the construct. By providing for a different phenotype of the blastocyst and the genetically modified cells, chimeric progeny can be readily detected.

The chimeric animals are screened for the presence of the modified gene and males and females having the modification are mated to produce homozygous progeny. If the gene alterations cause lethality at some point in development, tissues or organs can be maintained as allogeneic or congenic grafts or transplants, or in in vitro culture. The transgenic animals may be any non-human mammal, such as laboratory animals, domestic animals, etc. The transgenic animals may be used in functional studies, drug screening, etc., e.g. to determine the effect of a candidate drug on Ras or related gene activation, oncogenesis, etc.

WO 99/43696 PCT/US99/03826 TESTING OF K+HNOV FUNCTION and RESPONSES Potassium channels such as K+Hnov polypeptides are involved in multiple biologically important processes. Pharmacological agents designed to affect only specific channel subtypes are of particular interest. Presently available compounds tend to be non-specific and elicit both positive and negative responses, thereby reducing clinical efficacy.

The subject polypeptides may be used in in vitro and in vivo models to test the specificity of novel compounds, and of analogs and derivatives of compounds known to act on potassium channels. Numerous pharmacological agents have profound affects on K+ channel activity. As examples, Sotalol (BETAPACE) is a class III antiarrhythmic drug that prolongs cardiac action potentials by inhibiting delayed rectifier K+ channels. Sulfonylurea drugs, such as Glipizide (GLUCOTROL) and Tolazamide (TOLAMIDE) function as antidiabetic drugs by blocking ATP-sensitive K+ channels present in pancreatic islet cells, thereby regulating insulin secretion. Diazoxide (HYPERSTAT IV) is an antihypertensive drug that activates ATP-sensitive K+ channels, resulting in the relaxation of vascular smooth muscle. There are several other examples of drugs that have antidiabetic, antihypertensive, or antiarrhythmic activities. A number of drugs that activate K+ channels that have been proposed as coronary vasodilators for the treatment of both vasospastic and chronic stable angina.

The availability of multiple K+ channel subunits allows in vitro reconstruction of functional channels, which may comprise different alpha and beta subunits. The individual components may be modified by sequence deletion, substitution, etc. to determine the functional role of specific domains.

Drug screening may be performed using an in vitro model, a genetically altered cell or animal, or purified K+Hnov protein, either as monomers, homomultimers or hetermultimers. One can identify ligands or substrates that bind to, modulate or mimic the action of K+Hnov. Drug screening identifies agents that provide a replacement for K+Hnov function in abnormal cells. Of particular interest are screening assays for agents that have a low toxicity for human cells. A wide variety of assays may be used for this purpose, including WO 99/43696 PCT/US99/03826 monitoring cellular excitation and conductance, labeled in vitro protein-protein binding assays, electrophoretic mobility shift assays, immunoassays for protein binding, and the like. The purified protein may also be used for determination of three-dimensional crystal structure, which can be used for modeling intermolecular interactions.

The term "agent" as used herein describes any molecule, e.g. protein or pharmaceutical, with the capability of altering or mimicking the physiological function of K+Hnov polypeptide. Generally a plurality of assay mixtures are run in parallel with different agent concentrations to obtain a differential response to the various concentrations. Typically, one of these concentrations serves as a negative control, i.e. at zero concentration or below the level of detection.

Candidate agents encompass numerous chemical classes, though typically they are organic molecules, preferably small organic compounds having a molecular weight of more than 50 and less than about 2,500 daltons. Candidate agents comprise functional groups necessary for structural interaction with proteins, particularly hydrogen bonding, and typically include at least an amine, c-rbonyl, hydroxyl or carboxyl group, preferably at least two of the functional chemical groups. The candidate agents often comprise cyclical carbon or heterocyclic structures and/or aromatic or polyaromatic structures substituted with one or more of the above functional groups. Candidate agents are also found among biomolecules including peptides, saccharides, fatty acids, steroids, purines, pyrimidines, derivatives, structural analogs or combinations thereof.

Candidate agents are obtained from a wide variety of sources including libraries of synthetic or natural compounds. For example, numerous means are available for random and directed synthesis of a wide variety of organic compounds and biomolecules, including expression of randomized oligonucleotides and oligopeptides. Alternatively, libraries of natural compounds in the form of bacterial, fungal, plant and animal extracts are available or readily produced. Additionally, natural or synthetically produced libraries and compounds are readily modified through conventional chemical, physical and biochemical means, and may be used to produce combinatorial libraries. Known WO 99/43696 PCTIUS99/03826 pharmacological agents may be subjected to directed or random chemical modifications, such as acylation, alkylation, esterification, amidification, etc. to produce structural analogs.

Where the screening assay is a binding assay, one or more of the molecules may be joined to a label, where the label can directly or indirectly provide a detectable signal. Various labels include radioisotopes, fluorescers, chemiluminescers, enzymes, specific binding molecules, particles, e.g. magnetic particles, and the like. Specific. binding molecules include pairs, such as biotin and streptavidin, digoxin and antidigoxin etc. For the specific binding members, the complementary member would normally be labeled with a molecule that provides for detection, in accordance with known procedures.

A variety of other reagents may be included in the screening assay. These include reagents like salts, neutral proteins, e.g. albumin, detergents, etc that are used to facilitate optimal protein-protein binding and/or reduce non-specific or background interactions. Reagents that improve the efficiency of the assay, such as protease inhibitors, nuclease inhibitors, anti-microbial agents, etc_ may be used. The mixture of components are added in any order that provides for the requisite binding. Incubations are performed at any suitable temperature, typically between 4 and 400C. Incubation periods are selected for optimum activity, but may also be optimized to facilitate rapid high-throughput screening.

Typically between 0.1 and 1 hours will be sufficient.

The compounds having the desired pharmacological activity may be administered in a physiologically acceptable carrier to a host in a variety of ways, orally, topically, parenterally e.g. subcutaneously, intraperitoneally, by viral infection, intravascularly, etc. Depending upon the manner of introduction, the compounds may be formulated in a variety of ways. The concentration of therapeutically active compound in the formulation may vary from about 0.1-100wt.%. The pharmaceutical compositions can be prepared in various forms, such as granules, tablets, pills, suppositories, capsules, suspensions, salves, lotions and the like. Pharmaceutical grade organic or inorganic carriers and/or diluents suitable for oral and topical use can be used to make up WO 99/43696 PCT/US99/03826 compositions containing the therapeutically-active compounds. Diluents known to the art include aqueous media, vegetable and animal oils and fats. Stabilizing agents, wetting and emulsifying agents, salts for varying the osmotic pressure or buffers for securing an adequate pH value, and skin penetration enhancers can be used as auxiliary agents.

It is to be understood that this invention is not limited to the particular methodology, protocols, cell lines, animal species or genera, and reagents described, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims.

As used herein the singular forms "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a cell" includes a plurality of such cells and reference to "the cell" includes reference to one or more cells and equivalents thereof known to those skilled in the art, and so forth. All technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention belongs unless clearly indicated otherwise.

It must be noted that as used herein and in the appended claims, the singular forms "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a complex" includes a plurality of such complexes and reference to "the formulation" includes reference to one or more formulations and equivalents thereof known to those skilled in the art, and so forth.

All publications mentioned herein are incorporated herein by reference for the purpose of describing and disclosing, for example, the methods and methodologies that are described in the publications which might be used in connection with the presently described invention. The publications discussed above and throughout the text are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an WO99/436% PCTIUS99/03826 admissnthat the inventors are not entitled to antedate such disclosure by virtue ,of priorinvention.

EXPERIMENTAL

i e following examples are put forth so as to provide those of ordinary skill in the aftuith a complete disclosure and description of how to make and use the subject~iention, and are not intended to limit the scope of what is regarded as the invertbon. Efforts have been made to ensure accuracy with respect to the numbers used amounts, temperature, concentrations, etc.) but some 1o experin-mal errors and deviations should be allowed for. Unless otherwise indicate,, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees centigrade; and pressure is at or near atmospteis-.

Methods Two different types of sequence searches were performed. The first centered on the most highly conserved region of the K+ channel family, the pore domain. The pore is composed of 15-17 amino acids and can be divided into subfamiies based on the number of transmembrane segments present in the channel. Eleven variant peptide sequences corresponding to the pore domain were used in TBLASTN searches against the EST division of Genbank.

Significant matches were identified, and classified into 2 categories: identical to known human K+ channels and related to known K+ channels. The pore sequences are shown in Table 2.

TABLE 2 SEQ ID NO Genbank 49 L02751 TGGTGGGCTGTGGTGACCATGACMACTGTGGGCTATGGGGACATG M60451 TGGTGGGCAGTGGTCACCATGACCACTGTGGGCTACGGGGACATG 51 L02752 TGGTGGGCAGTCGTCTCCATGACMACTGTAGGCTATGGAGACATG 52 M5551 5 TGGTGGGCAGTGGTAACCATGACMACAGTGGGUTACGGCGATATG 53 ZI 1585 TGGTGGGCTGTGGTCACCATGACGACCCTGGGCTATGGAGACATG 54 U40990 TGGTGGGGGGTGGTCACAGTCACCACCATCGGCTATGGGGAcMAG 126643 TGGTGGGCAGTGGTCACCATGACCACGGTTGGCTATGGGGACATG 56 M96747 TGGTGGGCCGTGGTCACCATGACGACCCTGGGCTArGGAGACATG 57* M4676 TGGTGGGCTGTGGTCACCATGACGACACTGGGCTACGGAGACATG 58 M5551 4 TGGTGGGCTGTGGTGACCATGACAACTGTGGGCTATGGGGACATG 59 X63582 TTCCTGTrCTCCATTGAGACCGWACMCCATTGGGTATGGCUrCCG S78884 TTMATCTCMTAGAGACAGAACCACCATTGGTTATGGCTACCG 61 U2241 3 TTCCTCTTCTCCATTGAGACCCAGACMACCATAGGCTATGGTTTCAG 62 U240SO TTCCTGTTCTCGGTGGAGACGCAGACGACCATCGGCTATGGGTTICCG 63 U521 55 TTCCTCTTCTCCCTTGAATCCCWACCACCATGGCTATGGCTTCCG 64 D87291 lTTCTC1TTCCCTGGAATCCCAGACACCATTGGCTATGGAGTCCG D50S82 TTCCTTTTCTCCATTGAGGTCCAAGTGACTATGGCmTGGGGGGCG 66 D5031 5 1TTCTCTCTCCATTGAAGTTCAAG-rACCATTGGG-1TGGAGGGAG 67 U04270 GCGCTCTACrTCACCTTCAGCAGCCTCACCAGTGTGGGCTCGGCMAC WO 99/43696 PCT/US99/03826 The unique pore peptides sequences are shown in Table 3 TABLE 3 68 WWAWSMTTVGYGDM 69 WWAVVTMTTLGYGDM

WWGVVTVTTIGYGDK

71 WWAVVTMTTVGYGDM 72 FLFSIEVQVTIGFGG 73 FLFSLESQTTIGYGV 74 FLFSIETETTIGYGY

FLFSIETQTTIGYGF

76 FLFSVETQTTIGYGF 77 FLFSLESQTTIGYGF 78 FLFSIETETTIGYGF 79 ALYFTFSSLTSVGFGN The second set of experiments was based on a complex, reiterative process.

Annotated protein and DNA sequences were obtained from GenBank for all known K+ channels from all species. The TBLASTN and BLASTN programs were used to identify homologous ESTs, which were then analyzed using the BLASTX and BLASTN algorithms to identify ESTs which were related to K+ channels yet not identical to any known human K+ channel gene.

Novel human K+ channels were defined as those that had clear homology to known K+ channels from any species and were not present as identities or near identities to any human-derived sequences in any division of Genbank.

Isolation of full length cDNA sequence. EST clones were picked from the IMAGE consortium cDNA library and end-sequenced with vector primers. Gap closure was achieved either by primer walking or transposon sequencing. GeneTrapper (Life WO 99/43696 PCT/US99/03826 Technologies) was used to isolate larger cDNA clones according to the provided protocol. RACE was used to extend the sequences as necessary using standard protocols.

Sequences were assembled in Sequencher (Gene Codes). The presence of open reading frames was assessed as well as potential start codons. Potential polymorphisms were detected as sequence variants between multiple independent clones. Sequence homologies were detected using the BLAST algorithms.

The completed gene sequences and predicted amino acid sequences are provided as SEQ ID NO:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21-24, 26 and 28-29.

Polymorphisms, chromosome locations and family assignments are shown in Table 1.

ESTs that had top human hits with >95% identity over 100 amino acids were discarded. This was based upon the inventors' experience that these sequences were usually identical to the starting probe sequences, with the differences due to sequence error. The remaining BLASTN and BLASTX outputs for each EST were examined manually, ESTs were removed from the analysis if the inventors determined that the variation from the known related probe sequence was a result of poor database sequence. Poor database sequence was usually identified as a number of 'N' nucleotides in the database sequence for a BLASTN search and as a base deletion or insertion in the database sequence, resulting in a peptide frameshift, for a BLASTX output. ESTs for which the highest scoring match was to non-related sequences were also discarded at this stage. The EST sequences that correspond to each clone are shown in Table 4.

Table 4 Genbank K+Hnov clone ID Trace IMAGE Plate Read 5'13' Accession# Coordinates N39619 K+Hnov2 277113 yy51h05.sl 611p10 3' N46767 K+Hnov2 277113 yy51h05.rl 611p10 R19352 K+Hnovl 33144 yg24f12.rl 155o24 R44628 K+Hnovl 1 33144 yg24f12.sl 155024 3' WO 99/43696 WO 9943696PCTIUS99/03826 R35526 K+Hnovl4 37299 yg64e08.rI 165015 R73353 K+Hnovl4 157854 yIl0eO4.rl 251 g07 AA397616 K+Hnovl4 728558 zt79c08.rl 1 787j 15 AA286692 K+Hnov28 700757 zs48h03.ri 1715d6 AA1 50494 K+Hnov42 491748 zI08e07. sI 11 70o1 3 3' AA1 56697 K+Hnov42 491748 zl08e07.rl 1 170o03 AA191752 K+Hnov42 626699 zp82d06.rl 1 52211 2 AA216446 K+Hnov42 626699 zp82d06.sl 152211 2 3' AA430591 K+Hnov42 773611 zw5l fl0. rl 1904o20 AA236930 K+Hnov44 683888 zsOl1aO. sl1 1671e9 3 AA236968 K+Hnov44 683888 zs0l aOS.rl 1671e9 EXAMPLE 2: CHROMOSOMAL LocALIZArION Two primers were designed in the 3'-untranslated regions of each gene sequence to amplify a product across the Stanford G3 radiation hybrid map, or the Whitehead G84 panel. The PCR data were submitted for automatic two-point analysis.

Mapping data were correlated with cytoband information and comparisons with the OMIM human gene map data base were made. The following primers were made: K+Hnovl on G134 (SEQ ID NO:31) F: 5' TATCCACATCAATGGACAAAGC 3' (SEQ ID NO:32) R: 5' TGCATAACTGGCTGGGTGTA 3' Results: 1.71 cR from 025331, Cytogenetic location of 2q37 K+Hnov2 on G3 F: 5'GTCAGGTGACCGAGTTCA 3' R: 5' GCTCCATCTCCAGATTCTTC 3' Results: 0.0 cR from SHGC-1 320, Cytogenetic location of 11 q1 2 K4-Hnov6 on G84 (SEQ ID NO:33) F: 5' TGACATCACTGGATGAACTTGA 3' (SEQ ID NO:34) R: 5' TGCCTGCMAAGTrTGAACAT 3' Results: 5.23 cR from WI-5509, Cytogenetic location of 2p23 K+Hnov9 on G134 (SEQ ID NO:35) F: 5' TGACATCACTGGATGAACTTGA 3' (SEQ ID NO:36) R: 5 TGCCTGCAAAGT1TGAACAT 3' WO 99/43696 WO 9943696PCTIUS99/03826 Results: 1.21 cR from AFM200VC7, Cytogenetic location of 8q23 K+Hnovl 1 on GB4 (SEQ ID NO:37) F: 5' ACCTGGTGGTATGGAAGCAr 3' (SEQ ID NO:38) Rm 5 TTTCTCCTGGCCTCTACCC 3' Results: 2.43 cR from WI-6756, Cytogenetic location of 8q23 K'Hnovl2 on G3 (SEQ 10 NO:39) F: 5' TCCCTCTTGGGTGACCTTC 3' (SEQ ID NO:40) R: 5' ATCTrGTCAGCCACCAGCT 3' Results: 7.45 cR from SHGC-32925, Cytogenetic location of Xp2l K.'Hnovl4 on GB34 (SEQ ID NO:41) F: 5'AGGTGTGCTGCCATCTGCTGUTCG3.

(SEQ ID NO:42) R: Results: 7.69 cR from WJ-7107, Cytogenetic location of 12q 14 K+Hnov28 on GB4 (SEQ ID NO:43) F: 5' AAGCAGAGTACTCATGATGCC 3' (SEQ ID NO:44) R: 5' TCTGGTAGACAGTACAGTGG 3' Results: 35.38 cR from Wl-9695, Cytogenetic location of 3q29 K+Hnov42 on G3 (SEQ ID NO:45) F: 5' CAUTTGGCTGGTCCAAGATG 3' (SEQ ID NO:46) R: 5' AGTCATTGGTAGGGAGGTAC 3' Results: 7.45 cR from SHGC-32925, Cytogenetic location of Xp2l K+Hnov44 on G3 (SEQ ID NO:47) F: 5' CATGCTTCTACAGTCCAGCC 3' (SEQ ID NO:48) R: 5' GGTCCTCAG1TGCAGAAATC 3' Results: 7.45 cR from SHGC-32925, Cytogenetic location of Xp21 Map positions for K+Hnovl 5 and K+Hnov27 were obtained from public databases.

K+Hnov2 and K+Hnov4 have not been mapped.

EXAMPLE 3: EXPRESSION ANALYSIS RT-PCR was utilized to characterize the expression pattern of the novel ion channels. This approach used RNA from 30 different tissues to generate first strand cONA. Total RNA was purchased (Clontech, Invitrogen) and used to synthesize first strand cDNA using M-MLV reverse transcriptase and the supplied buffer (Gibco-BRL).

The 20 pI reaction contained 5 pg total RNA, 100 ng of random primers, 10 MM OTT.

WO 99/43696 PCT/US99/03826 mM each dNTP, and an RNAse inhibitor (Gibco-BRL). Identical reactions were set up without reverse transcriptase to control for DNA contamination in the RNA samples.

The synthesis reaction proceeded for 1 hour at 37°C followed by 10 minutes at These cDNAs, along with control cDNA synthesis reactions without reverse transcriptase, were diluted 1:5 and 2 pl of each sample were arrayed into 96-well trays, dried, and resuspended in PCR buffer prior to PCR amplification. The cDNAs were tested with primers with defined expression patterns to verify the presence of amplifiable cDNA from each tissue. Gene-specific primers were used to amplify the cDNAs in 20 pl PCR reactions with standard conditions, 2.5 mM MgCI2, Taq Gold, and an appropriate annealing temperature.

This approach provides for relatively high-throughput analysis of gene expression in a large set of tissues in a cost-efficient manner and provides qualitative analysis of gene expression only. Modifications can be employed, such as the use of internal control primers, limited cycling parameters, and dilution series to convert this to a quantitative experiment.

Table 3 IntnnovcI K*Hnov4 I1 ItHno-++ +iii +I +l u 17 1 1 4 i- -1 j1 IL1L Z4) r 1 1 1 1 Itnnov I I K*Hnovll K*Hnovl2 K*Hnovl4 4Hnov IS 4 4 4 K*Hnovl# 4 4 4 K~KZIII3 4 4 4 4 4 4' 4 4 4 4 9 K.Hnov42 K*Hnov44 4 4 4 4 indicates expression in the tissue, a 0- indicates no expression, and blank square indicates no data for that sample.

WO 99/43696 PCT/US99/03826 K+Hnov49 on Whitehead GB4 RH mapping panel: Primer 1 (SEQ ID NO:5): 5' CATAGCCATAGGTGAGGACT 3' Primer 2: (SEQ ID N:6) 5' GAGAGGAAAACAGTCTGGGC 3' Results: Cytogenetic location 1q41, 4.6cR from framework marker D1S217 K+Hnov59 on Whitehead GB4 RH mapping panel Primer 1 (SEQ ID NO:7): 5' GGACATCGAACTAAGACCTG 3' Primer 2 (SEQ ID NO:8): 5' TCCCATGCCATTCAGATCTG 3' Results: Cytogenetic location 19q13.2, 8.34cr from framework marker D19S425 EXPRESSION ANALYSIS OF K+HNOV49 A probe was created from a fragment corresponding to nucleotides 50 to 1284 of SEQ ID NO:83 (K+Hnov49) and purified DNA fragment was labeled with 32 P]dCTP (Amersham) by the random primer method. Adult human Multiple Tissue Northern (MTMTM) Blots (Clontech) were hybridized with the 3 2 P]-labeled fragment in ExpressHybTM solution (Clontech) for four hours, washed to a final stringency of 0.1xSSC, 0.1% SDS at 65°C and subjected to autoradiography for 24 hours.

Analysis revealed that K+Hnov49 is expressed as an approximately 4.2kb mRNA. Expression levels of K+Hnov49 are high in brain and liver and low in kidney tissues. No mRNA was detectable on these Northern blots for heart, skeletal muscle, colon, thymus, spleen, small intestine, placenta, lung or peripheral blood leukocytes indicating either a very low level of expression or that it is not expressed in these tissues. Expression analysis was also carried out by RT-PCR across an extended series of tissues. The results of these analyses are shown in Table 4. Primer pairs used for amplification of K+Hnov49 and 59 are the same as those used for RH mapping as indicated above.

Adipose Adrenal Gland Bladder 0 Brain Cerebellum Cervix I I Colon Esophagus I Fetal Brain Fetal Liver Heart He La Cell Kidney Liver Lung Mammary Gland -i *Pancreas 0) **Placenta CTD P'rostate Re ctumn Salivary Gland Skeletal Muscle 6 Skin Small Intestine Spleen Stomach le sti1s Thymus *Trachea +*Uterus

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Editorial Note File No 27809/99 The following sequence listing is numbered 1 to followed by page number WO 99/43696 WO 9943696PCTIUS99/03826 SEQUENCE LISTING <110> Miller, Andrew Curran, Mark Buckler, Alan ':120> Novel Human Potassium Channels <130> <150> 60/076,687 ':151> 1998-02-25 <150> 60/095,836 ':151> 1998-08-07 <150> 60/116,448 <151> 1999-01-19 <160> 87 <170> FastSEQ for Windows Version <210> 1 <211> 2932 ':212> DNA <213> H. sapiens <220> <221> CDS <222> (103) (1180) <223> K+Hnovl <400> 1 attaaaatta tctgatcaaa aaggcagact ctgtaaattt taaaggctga cccagcaaaa gaactgagaa atacagcctg aat Asn gtc Val ggt, Gly tgg Trp ct Leu cta Leu ct Leu.

tgg Trp tct Ser gt Val caa Gln 15 atg Met atc Ile tct Ser gct Ala ccttaagacc taccttggca ag atg gac agc agt Met Asp Ser Ser 1 aga tac cgg agg atg Arg Tyr Arg Arg Met gat ggc gct caa aga Asp Gly Ala Gln Arg cta atg gac atg cgc Leu Met Asp Met Arg ttt gtt gic cac tgg Phe Val Val His Trp gag atg aat ggt gat Glu Met Asn Gly Asp 114 162 210 258 306 354 WO 99/43696 WO 9943696PCTIUS99/03826 ctg Leu aag Lys caa Gin agt Ser gag Giu aat Asn 165 atg Met agc Ser gaa Giu atc Ile cac His 245 aat Asn ggc Gly ate Ile ggt Giy ttt gaa Glu tat Tyr etc Leu gca Ala get Ala 150 cga Arg gat Asp cct Pro aat Asn agt Ser 230 tcc Ser ect Pro act Thr atg Met gaa Giu 310 cca cta gat cat Leu Asp His ate ace agt Ile Thr Ser 105 aca att ggt Thr Ile Gly 120 ate gee tta Ile Ala Leu 135 ttt ate aca Phe Ile Thr get ttt tea Ala Phe Ser ggc aaa ect Gly Lys Pro 185 eta ace agt Leu Thr Ser 200 gge aaa etc Gly Lys Leu 215 tet gac gaa Ser Asp Glu att aca eca Ile Thr Pro tet eac tt-t Ser His Phe 265 gga gaa ata Gly Giu Ile 280 tta cat cac Leu His His 295 tat caa ate Tyr Gin Ile act ect etg gat gee eca ect gaa aae eac act ate Asp Ala Pro Pro Giu Asn His Thr Ile tte Phe tat Tyr ett Leu ggt Gly att Ile 170 aat Asn gte Vai tac Tyr tgt Cys tea Ser 250 gaa Giu tgc Cys tgt Cys aag Lys gtt a ca Thr ggt Gly gee Ala get Ala 155 ege Arg ett Leu egg Arg cag Gin eca Pro 235 agt Ser tta Leu eaa Gin ttt Phe atg Met 315 tet get Ala ace Thr ata Ile 140 ttt Phe ttt Phe ate Ile gte Val ace Thr 220 tte Phe cet Pro gtt Val agg Arg gca Ala 300 gag Giu aaa gca Ala atg Met 125 eaa Gin gtg Val act Thr ttc Phe tea Ser 205 agt Ser tte Phe ctg Leu gta Val agg Arg 285 tet Ser aat Asn age tte Phe 110 ttC Phe atg Met 9gg Al a gae Asp eaa Gin 190 get Ala gtg Val1 ate Ile get Ala ttc Phe 270 aca.

Thr etg Leu ttt Phe eca 2 tee Ser ccc Pro etc Leu aag Lys aca Thr 175 gtg Val gta Val gat Asp ttt Phe act Thr 255 ett Leu tc Ser ttg Leu gac Asp aa c tte Phe agt Ser eta Leu att Ile 160 gea Ala gee Ala etc Leu tte Phe eca Pro 240 etg Leu tea Ser tac Tyr ace Thr aag Lys 320 agg tec Ser ggt Giy ggc Gly 145 gee Ala gta Val1 aae Asn tat Tyr eac His 225 eta Leu etc Leu gca Ala eta Leu cga Arg 305 act Thr act etg Leu gac Asp 130 etc Leu egg Arg gta Val ace Thr eag Gin 210 ctt Leu aeg Thr cag Gin atg Met ceg Pro 290 ggt Gly gte Val gac tgt Cys gag Giu 115 tgt Cys atg Met eca Pro get Ala ega Arg 195 gaa Giu gat Asp tac Tyr cat His cag Gin 275 tet Ser tee Ser cct Pro ctg gte Vai 100 aca Thr e ca Pro eta Leu aaa Lys eac His 180 cet Pro aga Arg gge Gly tat Tyr gaa Giu 260 gag Glu gaa Glu aaa Lys gaa Giu gat 402 450 498 546 594 642 690 738 786 834 882 930 978 1026 1074 1122 WO 99/43M WO 994~I~PCTIUS99/03826 Phe P=D Thr Pro Leu Val Ser Lys Ser Pro Asri Arg Thr Asp Leu Asp '325 330 335 340 at-c czx atc aat gga caa agc att gac aat ttt cag at~c tct gaa aca -Ile le Asn Giy Gin Ser Ile Asp Asn Phe Gin Ile Ser Giu Thr 345 350 355 gga cz aca g aataagadtt atccattttt taatgtatta aatacaccca Gly Leu Thr 1170 1220 gccagttg tatag..cttc a ta cam*rtc gtaacitmac tatgaa aaat caa ctagbct ga tttd I'tC agtatzaamt gtacagat gtggtat~t tcaaaqtg gtatgatttCa tatttgc aaatc.a~ag cctgtttca aggaggttIqg ttaagqaat caaaacaaaa tctgaaatt gtgat~qacct gtgtgaagag gaaaataaag cacagaaact gtagaaatca agaattctta attgaagact cagctacttt tacatcacgg tggaaacata ttgacagaca gtaatgaagg ttaatctctc gggtggaatg aagacaacaa ccttaatttt tacataaacc t tgtggcaga gcattgcaag attcatctaa tttgatcata tttatagata tagataaagc acttcaaata actagatgaa tgttttttat catttgcatg accaaaaaag cccttattca aggcaggaa t cagggctcag aagaactctg taattattgt gaccaacaga tttctataat taaaaaaaaa ttctttactg taatcatgcc acactctaca cttatacaga caaaatggac attttcatct acgacttcac agatcattca taacaactaa taaaagcatt aggtgatcag gagacgcaaa atgacttcta taaaacatca taaagcttta aaaagataat gttttttcta ctctattatt tttatctatg attttcattt tcaccctatc ggtttctgtg catctcttga cagcaagtca gagtggtcta gaacttttgc ttttcccaac aaattaacaa aaaaaaaaaa tatctcatgt tatgcctaca ttacaaagtt aatgttgctg agtgaagttt gcaaattgaa tatacttagt tttggttctt gaacaaaaat tgaacatgac ataagctcca attttatttt gcaacctaag tgatggctc t cttagatata taggcaacaa taaacacaaa tctttctaaa ctaaaatgag caataaaaaa aggtttcaaa ggaaaaa tga aataaatact catttttcta agactgataa tgt ttgaaaa c caagac tat gattcaccta aa tttctttttt t aagaatggc tgttacctgc gtgaatttat aacacaactg gcaacagttt gaatatcctt tatactatga taacgagaaa acccgaacac gcccaaatgg aaaactgtcc taaaaacatt aattcataaa acttgagtga agcattttca atcagtgttt tctaatagtc ccctttccct aagagaaact cagatttgtg aagattaacc agctgagtaa ctatttgacc tagcagaaga tcttagacat tgtaacacat acctttgaaa caatgctaat tgagctaaca tgaaatcaat aagaatgtgg aactctaaga agtttcaaac taagagctgg aac ttgagta aacaacaaag atacatatat aacctgtggg tccataataa cccctcctat tacaaaaata gtagggaaaa aactcaaatt attcaccagt tataaaaatt tatgtccagt gtccttaaaa gctgttcttt ttccccactg aggcaagcag aaaaggaaaa atatcaagaa tcattcttaa aaagacagca ataaagtagt 1280 1340 1400 1460 1520 1580 1640 1700 1760 1820 1880 1940 2000 2060 2120 2180 2240 2300 2360 2420 2480 2540 2600 2660 2720 2780 2840 2900 2932 <210> 2 <211> 359 <212> PRT <213> H. sapiens <400> Met Asp Ser 2 Ser Asn Cys Lys Val Ile 1 Tyr Pro Leu Leu Ser Thr Leu Arg Arg Met Val Thr Lys Asp Gly Leu Ser Gin Arg Gin Met Asp Gly Ile Leu Ala Ser Phe Gly Ala Gin Arg Gly Leu Ala Met Asp Met Arg Trp Arg Trp Val Vai His Trp Leu Val Phe 70 Tyr Met Arg Asp Ala Met Leu Val Ala Val Leu Met Asn Gly Asp Leu Giu Leu Asp His Trp Tyr Val Leu Ala Pro Pro Giu Thr Ala Ala Phe Ala Asn His Ser Phe Thr Ile Cys Val Lys Tyr Ile Thr Ser WO 99/43696 WO 9943696PCT/US99/03826 Ser Leu Giu Thr Gin Leu Thr Ile Giy Tyr Gly Thr Met Phe Pro Ser Gly Giy 145 Ala Val Asn Tyr His 225 Leu Leu Al a Leu Arg 305 Thr Thr Ile 115 Cys Met Pro Ala Arg 195 Giu Asp Tyr His Gin 275 Ser Ser Pro Leu Giu 355 Pro Leu Lys His 180 Pro Arg Gly Tyr Giu 260 Glu Glu Lys Giu Asp 340 Thr Ser Giu Asn 165 Met Ser Glu Ile His 245 Asn Gly Ile Gly Phe 325 Ile Gly 120 Al a Ala 150 Arg Asp Pro Asn Ser 230 Ser Pro Thr Met Giu 310 Pro His Leu Ile 135 Phe Al a Gly Leu Gly 215 Ser Ile Ser Gly Leu 295 Tyr Thr Ile Thr Ala Ile Phe Lys Thr 200 Lys Asp Thr His Giu 280 His Gin Pro Asn Leu Thr Ser Pro 185 Ser Leu Glu Pro Phe 265 Ile His Ile Leu Gly 345 Al a Ala Arg Leu Arg Gin Pro 235 Ser Leu Gin Phe Met 315 Ser Ser 125 Gin Met Val Ala Thr Asp Phe Gin 190 Ser Ala 205 Ser Val Phe Ile Leu Ala Val Phe 270 krg Thr 285 Ser Leu ksn Phe Ser Pro ksp Asn 350 Leu Lys Thr 175 Val Val Asp Phe Thr 255 Leu Ser Leu Asp Asn 335 Phe Leu Ile 160 Ala Ala Leu Phe Pro 240 Leu Ser Tyr Thr Lys 320 Arg Gin <210> 3 <211> 1927 <212> DNA <213> H. sapiens <220> <221> CDS <222> (105) (1908) <223> K+Hnov4 <400> 3 ggagccccgc agcgcttctt atgatcagct cggtgtgtgt agtcggggaa caagcctccg tccaaaacat gtctgaagga gag gcg tcg gag aag atc atc atc aac gtg ggc Glu Ala Ser Giu Lys Ile Ile Ile Asn Val Gly 10 15 acc tac cgc agc acc ctg cgc acc cta ccg gga Thr Tyr Arg Ser Thr Leu Arg Thr Leu Pro Gly 30 ctg gcc gac ccc gac ggc ggg ggc cgg ccc gag Leu Ala Asp Pro Asp Gly Gly Gly Arg Pro Glu 45 Ctcctcctac cgcgggcgca ggag atg gcc aag ggc Met Ala Lys Gly 1 ggc acg cga cat gag Gly Thr Arg His Glu acc cgc ctc gcc tgg Thr Arg Leu Ala Trp acc gat ggc ggc ggt Thr Asp Gly Gly Gly 164 212 260 WO 99/43696 WO 9943696PCTIUS99/03826 gtg ggt Val Gly gac agg Asp Arg ggc aag Gly Lys gag ctg Glu Leu tgg atg Trp Met ttc gag Phe Glu ctg gcg Leu Ala 2.50 ccc gac Pro Asp 165 gcc ctc Ala Leu ttt gct Phe Ala gaa aca Giu Thr atc aat Ile Asn 230 gcc ttg Ala Leu 245 ttt tta Phe Leu aat ctc Asn Leu agc agc ggc Ser Ser Gly cac ccg ggc His Pro Gly ctg cac tgc Leu His Cys gcc ttc tgg Ala Phe Trp 105 acc tac cgg Thr Tyr Arg 120 acc ccc gac Thr Pro Asp 135 gcc aag agg Ala Lys Arg ggc aaa tct Gly Lys Ser ttc gaa gac Phe Glu Asp 185 tct tta ttc Ser Leu Phe 200 cat gaa gct His Glu Ala 215 ggc aca agt Gly Thr Ser acg tat gta Thr Tyr Val gtc cgt att Val Arg Ile 265 ttg aat atc Leu Asn Ile 280 agc agc ggc ggc ggg Ser Ser Gly Gly Gly tgc gag ttc ttc ttc Cys Giu Phe Phe Phe gtc Val

CCC

Pro 90 ggc Gly cag Gin ctc Leu c tg Leu ggc Gly 170 ccc Pro ttc Phe ttC Phe gtt Val gaa Giu 250 gtt Val att Ile ttc Phe 75 gca Al a at c Ile Ca c His att Ile Gly 155 cgc Arg tac Tyr atc Ile aat Asn gtt Val 235 gga Gly ttt Phe gac Asp gcc Ala gac Asp gac Asp cgc Arg ggc Gly 140 atc Ile tgg Trp tcg Ser ctg Leu att Ile 220 cta Leu gtg Val tca Ser ttt Phe tac Tyr gtg Val gag Glu gac Asp 125 ggc Gly gag Glu agg Arg tcc Ser gtt Val 205 gtt Val cag Gin tgt Cys' ccc Pro gtg Val 285 gtg Val tgC Cys acc Thr 1.10 Al a gac Asp gac Asp agg Arg aga Arg 190 tca Ser aaa Lys tat Tyr gtg Val1 Asn 270 gcC Ala ctc Leu ggg Gly 95 gac Asp gag Glu ccc Pro gcg Ala ctg Leu 175 gcc Ala at t Ile aac Asn gaa Glu gtg Val 255 aaa Lys atc Ile aac Asn ccg Pro gtg Val gag Glu ggc Gly gcg Ala 160 cag Gin gcc Ala aca Thr aag Lys att Ile 240 tgg Trp ctt Leu cta Leu tac Tyr ctc Leu gag Glu gcg Al a gac Asp 145 9gg Gly ccc Pro agg Arg act Thr aca Thr 225 gaa Glu ttt Phe gaa Giu cct.

Pro tac Tyr ttc Phe ccc Pro ctg Leu 130 gac Asp ctc Leu cgc Arg ttt Phe ttt Phe 210 gaa Glu acg Thr act Thr ttc Phe ttc Phe cgc Arg gag Giu tgc Cys 115 gac Asp gag Glu ggg Gly atg Met att Ile 195 tgc Cys cca Pro gat Asp ttt.

Phe atc Ile 275 tac Tyr acc Thr gag Glu 100 tgc Cys atc Ile gac Asp ggc Gly tgg_ Trp 2.80 gct Al a ctg Leu gtc Val cct Pro gaa Glu 260 aaa Lys tta Leu 356 404 452 500 548 596 644 692 740 788 836 884 932 980 290 gag gtg gga ctc agt ggg ctg tca tcc gtgtaagtggct 12 qct. gct aaa gat gtg ctt 1028 WO 99/43696 WO 9943696PCTIUS99/03826 Giu Val ggc ttc Gly Phe 310 ctc aco Leu Thr 325 gct agt Ala Ser gtt ttg Val Leu oaa cct Gin Pro coo att Pro Ile 390 ggg gat Gly Asp 405 tgt got Cys Ala gto aat Vai Asn ctt cca Leu Pro tca cct Ser Pro 470 cag agt Gin Ser 485 aga tca Arg Ser toa ccc Ser Pro aao aga Asn Arg Gly 295 ctc Leu ogc Arg act Thr ata Ile aac Asn 375 ggg Gly atg Met ctg Leu aat Asn agg Arg 455 act Thr gac Asp gtg Val c oa Pro aga Arg Leu agg Arg cat His aat Asn ttt Phe 360 gac Asp ttc Phe tac Tyr got Al a ttt Phe 440 aaa Lys ttt Phe aoa Thr tta Leu gaa Glu 520 ggg Gly Ser gtg Val ttt Phe gaa Glu 345 got Al a ct Pro tgg Trp 000 Pro gga Gly 425 gga Gly aga Arg tgo Cys tgt Cys tca Ser 505 agg Arg gaa Glu Gly gta Val gta Val 330 ttt Phe ac Thr toa Ser tgg Trp oaa Gin 410 gtg Val1 atg Met aag Lys aag Lys otg Leu 490 ggt Gly oto Leu aoa Thr Leu agg Arg 315 ggt Gly ttg Leu atg Met got Ala got Ala 395 aca Thr otg Leu tao Tyr aag Lys aca Thr 475 ggo Gly gao Asp c Pro tgt Cys Ser 300 ttt Phe otg Leu otg Leu ato Ile agt Ser 380 gta Vai tgg Trp aca Thr tao Tyr cac His 460 gaa Giu aaa Lys gao Asp ato Ile tto Phe Ser Lys gtg agg Val Arg agg gtg Arg Val otg ata Leu Ilie 350 tao tat Tyr Tyr 365 gag cao GJlu His gtg aco Val Thr toa ggo Ser Gly ata goo Ile Ala 430 too ttg Ser Leu 445 ato cot.

Ile Pro tta aat Leu Asn gao aat Asp Asn agt aoa Ser Thr 510 aga ogo Arg Arg 525 Ota Otg Leu Leu 6 Al a ato Ilie Ott.

Leu 335 at t Ile gco Ala aoa Thr atg Met atg Met 415 atg Met goa Al a cct Pro atg Met oga Arg 495 gga Gly tot.

Ser aog Thr Ala Lys Asp 305 Otg aga att Leu Arg Ile 320 gga oat act Gly His Thr ttc otg got Phe Leu Ala gag aga gtg Giu Arg Val 370 cag ttc aaa Gin Phe Lys 385 aot aoo otg Thr Thr Leu 400 otg gtg gga Leu Val Gly cca gtg Oct Pro Val Pro atg goa aag Met Ala Lys 450 got cot oag Ala Pro Gin 465 goc tgo aat Ala Cys Asn 480 ott otg gaa Leu Leu Glu agt gag cog Ser Giu Pro agt aoo aga Ser Thr Arg 530 aoa ggt gat Thr Gly Asp Val Leu ttc aag Phe Lys ott oga Leu Arg 340 ota gga Leu Gly 355 gga got Gly Ala aao att Asn Ile ggt tat Gly Tyr gc otg Ala Leu 420 gtc att Val Ile 435 oag aaa Gin Lys goa ago Ala Ser agt aoa Ser Thr oat aao His Asn 500 ooa ota Pro Leu 515 gao aaa Asp Lys tao aog Tyr Thr 1076 1124 1172 1220 1268 1316 1364 1412 1460 1508 1556 1604 1652 1700 1748 WO 99/43696 WO 9943696PCTIUS99/03826 tgt gct Cys Ala 550 tta aac Leu Asn 535 tct Ser aac Asn 540 545 gat gga ggg atc agg aaa gga tat gaa aaa tcc Cga agc Asp Gly Gly Ile Arg Lys Gly Tyr Giu Lys Ser Arg Ser 555 560 ata gcg ggc ttg gca ggc aat gct ctg agg ctc tct cca Ile Ala Gly Leu Ala Gly Asn Ala Leu Arg Leu Ser Pro 570 575 580 ccc tac aac tct cct tgt cct ctg agg cgc tct cga tct Pro Tyr Asn Ser Pro Cys Pro Leu Arg Arg Ser Arg Ser 585 590 595 tct atc t tgtaaaccaa accctcgtg Ser Ile 600 1796 1844 1892 1927 aca tca Thr Ser ccc atc cca Pro Ile Pro <210> 4 <211> 6' <212> P) <213> H <400> 4 Met Ala Lys G: 1 Thr Arg His G~ Arg Leu Ala T~ Asp Gly Gly G Glu Phe Phe P1 Tyr Tyr Arg Ti Leu Phe Glu G~ 1( Giu Pro Cys C~ 115 Ala Leu Asp I: 130 Asp Asp Giu A~ 145 Giy Leu Gly G Pro Arg Met T~ if Arg Phe Ile A] 195 Thr Phe Cys LE 210 Thr Giu Pro Vz 225 Giu Thr Asp P2 Phe Thr Phe GJ 26 Giu Phe Ile L3 275 01 .sapiens ly lu 0 Ly ir lu

(S

Le Ly -p 30 La Is Ala Tyr Ala Gly Arg 70 Lys Leu Met Giu Ala 150 Asp Leu Ala Thr Asn 230 Leu Leu Leu Glu Ser Pro Ser Pro His Phe Tyr 120 Pro Lys Lys Glu Leu 200 Giu Thr Tyr Arg Asn 280 Lys Thr 25 Asp Gly Gly Cys Trp 105 Arg Asp Arg Ser Asp 185 Phe Ala Ser Val Ile 265 Ile Ile 10 Leu Gly Ser Val Pro Gly Gin Leu Leu Gly 170 Pro Phe Phe Val Giu 250 Val Ile Ile Arg Gly Ser Phe 75 Ala Ile His Ile Gly 155 Arg Tyr Ile Asn Val 235 Gly Phe Val Pro Pro Gly Val Cys Thr 110 Ala Asp Asp Arg Arg 190 Ser Lys Tyr Val Asn Gly Gly Giu Gly Leu Gly Asp Glu Pro Ala Leu 175 Ala Ile Asn Giu Val 255 Lys Gly Thr Thr Cys Asn Pro Val Giu Gly Ala 160 Gin Ala Thr Lys Ile 240 Trp, Leu 270 Ala Ile Leu Asp Phe Val 285 WO 99/43696 WO 9943696PCTIUS99/03826 Pro Phe Tyr Leu Glu Val Gly Leu Ser Gly Leu Ser Ser Lys Ala Ala Lys 305.

Arg His Leu Arg Phe 385 Thr Val Val Al a Pro 465 Cys Leu Giu Thr Gly 545 Lys Arg Arg Val Phe Leu Leu 355 Gly Asn Gly Ala Val 435 Gin Ala Ser His Pro 515 Asp Tyr Arg Ser Arg 595 Leu Lys Arg 340 Gly Ala Ile Tyr Leu 420 Ile Lys Ser Thr Asn 500 Leu Lys Thr Ser Pro 580 Ser Gly Leu 325 Ala Val Gin Pro Gly 405 Cys Val Leu Ser Gin 485 Arg Ser Asn Cys Leu 565 Val Pro 295 Leu Arg Arg His Thr Asn Ile Phe 360 Asn Asp 375 Gly Phe Met Tyr Leu Ala Asn Phe 440 Arg Lys 455 Thr Phe Asp Thr Val Leu Pro Giu 520 Arg Gly 535 Ser Asp Asn Ile Ser Pro Pro Ser 600 300 Val Phe Giu 345 Ala Pro Trp Pro Giy 425 Gly Arg Cys Cys Ser 505 Arg Giu Gly Ala Tyr 585 Ile Arg 315 Gly Leu Met Al a Al a 395 Thr Leu Tyr Lys Thr 475 Giy Asp Pro Cys Ile 555 Leu Ser Phe Leu Leu Ile Ser 380 Val Trp Thr Tyr His 460 Glu Lys Asp Ile Phe 540 Arg Ala Pro Val Arg Leu Tyr 365 Giu Vai Ser Ile Ser 445 Ile Leu Asp Ser Arg 525 Leu Lys Gly Cys Arg Val1 Ile 350 Tyr His Thr Gly Al a 430 Leu Pro Asn Asn Thr 510 Arg Leu Gly Asn Pro 590 Ile Leu 335 Ile Ala Thr Met Met 415 Met Al a Pro Met Arg 495 Gly Ser Thr Tyr Al a 575 Leu Leu 320 Gly Phe Glu Gin Thr 400 Leu Pro Met Ala Ala 480 Leu Ser Ser Thr Glu 560 Leu Arg <210> <211> 2293 <212> DNA <213> H. sapiens <220> <221> CDS <222> (330) (1800) <223> K-iHnov6 <400> gggaagagcg aacccagggc ccttgctctc gtgcagcgct gcgccctggg tggggacggc gtgaggcttg cagcgcaggt gagagtgatt ttccagtgat tgctttggcc tgtacaacca gagaacagga ttcttccctt Ctttttggcc accaaatgcc tatgtgcacc acacattcca gtgtgctgag aagggcagag cttcttggat gatgatggac gtcccaccgg gcaggatgaa ggcagagcgt gtggcatctc cacctcaagg gtgcagcctg atcttcctct tctcccttgC cagccagcac tctgccttct gtatccacc atg gtg ttt ggt gag ttt ttc cat Met Val Phe Gly Glu Phe Phe His 1. WO 99/43696 cgc cct gga Arg Pro Gly PCT/US99/03826 caa gac gag gaa ctt gtc aac ctg aat gtg ggg ggc ttt Gin Asp Giu Giu Leu Val Asn Leu Asn Val Gly Gly Phe aag Lys ctg Leu tgt Cys ccc Pro cat His tac Tyr 105 tac Tyr agc Ser gag Giu aag Lys aag Lys 185 gcc Ala gtg Val ttc Phe aaa cag Gin ggg Gly gat Asp tcc Ser gtc Val tgg Trp, cag Gin cat His aaa.

Lys aaa.

Lys 170 ctt Leu atg Met gat Asp acc Thr ttc tct Ser aag Lys gat Asp ttg Leu atg Met ggc Gly gaa.

Giu gat Asp gag Giu 155 atc Ile atc Ile tgc Cys gat Asp ggg Gly 235 tgg gtt Val ctg Leu tac Tyr ttc Phe gag Giu atc Ile cgc Arg gtg Val 140 ctg Leu tg Trp gct Ala gtt Val ccg Pro 220 gag Glu aaa gac Asp ctt Leu agt Ser aga Arg gag Giu aa c Asn aag Lys 125 agt.

Ser gag Giu att Ile atc Ile cac His 205 gtg Val ctt Leu aac caa Gin 30 act Thr gtg Val tat Tyr ctg Leu gag Giu 110 gag Glu acc Thr aag Lys aga Arg tcc Ser 190 agc Ser ctg Leu gcc Ala cct agc S er tgc Cys gcc Ala gtt Val tgc Cys 95 ctc Leu gaa Glu gac Asp ttt Phe atg Met 175 tcc Ser atg Met gaa, Giu gtc Val ctg acc Thr cat His ga t Asp ttg Leu 80 gta.

Val ttc Phe aac Asn tcc Ser gac Asp 160 gag Glu ttg Leu tcg Ser gga Gly cgg Arg 240 aac ctc Leu tct S er aag Lys 65 aat Asn ttc Phe att Ile cac His tcg Ser 145 aca Thr aat Asn agc Ser gag Giu gtg Val 225 ctg Leu atc ctg Leu gaa Giu 50 gaa Glu ttt Phe tca Ser gat Asp gag Glu 130 ttt Phe ctg Leu cca Pro gtg Val ttc Phe 210 gag Glu gct Ala att 9 cgg Arg 35 gag Glu tac Tyr tat Tyr ttc Phe tct Ser 115 aag Lys gaa Glu cga Arg gcg Ala gtg Val 195 cag Gin atc Ile gcc Ala gac ttt Phe gcc Ala tac Tyr tac Tyr tgc Cys 100 tgc Cys gac Asp gag Giu ttt Phe tac Tyr 180 ctg Leu aat Asn gcg Ala gct Ala ttt cct cac Pro His att ctg Ile Leu ttt gat Phe Asp acg ggg Thr Gly cag gag Gin Glu tgc agc Cys Ser tgg gac Trp Asp tcg tct Ser Ser 150 ggt cag Gly Gin 165 tgc ctg Cys Leu gcc tcc Ala Ser gag gat Glu Asp tgc att Cys Ile 230 cct. tgt Pro Cys 245 gtc tct acc aga Thr Arg gag ctg Giu Leu cgg aat Arg Asn aag ctg Lys Leu atc gag Ile Giu aat cgc Asn Arg 120 cag aaa Gin Lys 135 ctg ttt Leu Phe ctc cgg Leu Arg tcc gct Ser Ala atc gtg Ile Val 200 gga gaa.

Gly Giu 215 gcc tgg Ala Trp, caa. aag Gin Lys att att 401 449 497 545 593 641 689 737 785 833 881 929 977 1025 1073 1121 WO 99/4MW CIS9/32 PCTfUS99/03826 Lys ccc Pro 265 gat Asp att 11ie cta iLeu ctc Leu Val 345 ,tgg Trp cac His tgt Cys

CCC

Phe agt Ser 425 agg Arg tct Ser at Phe Trp tctat P.-he Tyr ,ad gag 'IAp Gilu cga Pirn Arg gst gcc Giw. Ala 315 tL= ctc Ph?- Leu 3M3 ga~ aaa Glui ]Lys tqT egg Tilm Trp Pmo Yal1 9-9c atc Giy Ile 395 tCC aag Ser Lys 410 gag gat Glu Asp gat ata Asp Ile gta ggc Val Gly gaa gac Lys Asn Pro Leu Asn Ile Ile Asp Phe Val Ser Ile 255 260 gcc Ala aac Asn at Ile 300 aca Thr tcC Ser gat Asp gcc Ala ac c Thr 380 ttg Leu tac Tyr gca Ala tat Tyr at Ile 460 aat acg Thr atg Met 285 cta Leu ctg Leu gtg Val gac Asp acc Thr 365 ttg Leu gtg Val tac Tyr cca Pro gca Ala 445 geg Vai gag ttg Leu 270 ggc Gly aag Lys aga Arg ggc Gly cac His 350 atc Ile gcg Ala gtg Val cag Gin gag Giu 430 cag Gin gtg Val gac gct Ala aag Lys cCC Leu cac His at Ile 335 aca Thr agc Ser gga Gly gcc Ala aag Lys 415 aag Lys cgg Arg agc Ser at gta Val gtg Val gcc Ala agc Ser 320 cc Ser tC Ser atg Met aag Lys ctC Leu 400 caa Gin tgt Cys atg Met gat Asp tgt Cys 480 gac Asp gtc Val cgg Arg 305 tac Tyr at Ile agc Ser aca Thr ctc Leu 385 ccc Pro aag Lys cat His cac His ccC Pro 465 aac acc Thr cag Gin 290 cac His cat His tcC Phe ctC Leu act Thr 370 atc Ile atc Ile gac Asp gag Giu gcc Ala 450 gac Asp acc aag Lys 275 atc Ile Ccg Ser gaa Giu tcC Ser acc Thr 355 gtg Val gcc Al a acc Thr at Ile cta Leu 435 tC Phe tC Ser acc gag Giu cta Leu gta.

Val1 gtt Val1 gtg Vali 340 agc Ser ggC Gly agc Ser atc Ile gat Asp 420

CCC

Pro at Ile aca Thr tcc gaa Giu Arg gga Gly ggg Gly 325 cCC Leu atc Ile tat Tyr aca Thr atc Ile 405 gtg Val Cac Tyr acc Thr gat Asp Ctg gag Giu cCC Leu cCC Leu 310 ctt Leu atc Ile ccc Pro gga Gly tgc Cys 390 tc Phe gac Asp

CCC

Phe agt Ser gcC Aia 470 gag agt Ser atg Met 295 Cgg Arg ctg Leu tac Tyr atc Ile gac Asp 375 atc Ile aac Asn cag Gin aac Asn ctC Leu 455 Cca Ser aat Ile gag Giu 280 agg Arg cCC Ser cCC Leu Ccc Ser Cgc Cys 360 acc Thr atc Ile aag Lys tgc Cys at Ile 440 tcC Ser agc Ser tgc 1169 1217 1265 1313 1361 i4 09 1457 1505 1553 1601 1649 1697 1745 1793 1850 Ile Giu Asp Asn Giu Asp Ile 475 aca gca Thr Ala a aatgagcggg ggtgtttgtg Asn Thr Thr Ser Leu Giu Asn Cys 485 cctgtctc ttatcctttc ccaacattag WO 99/43696 WO 9943696PCTIUS99/03826 gttaacacag cctttcagcc tttCtctgtg gtgatagagt gcatcattct aatcaaaggt atgtaaatcc cagaaaaaaa ctttataaac atagttggac aggtcaatta ttggaatata gtgtttgtca gcagctgact atgctcatgt aaaaaaaaaa ctcagtgggt tcgttaaaat catttaattc tcagggtgta attcattgct gaattctgaa atgatagaat tgtctttatt aatgccttgt tctgaaattt attttttaca agagagagtt agataaatgg tattgggtgg ggtttgtggc tacagcttat tttactcaca ttgagctaac tttaaattac tgacaagtag gagacgacat gcatgtaaga tccacaaaat gagacaatgc tctaaacatg gaaactagga gcctaataaa Cttcctaatt aaa 1910 1970 2030 2090 2150 2210 2270 2293 <210> 6 <211> 4: <212> P1 <213> H <400> 6 Met Val Phe G 1 Val Asn Leu A~ Leu Leu Arg P1 Ser Giu Giu A: Lys Giu Tyr T' Asn Phe Tyr T~ Phe Ser Phe C' 1c Ile Asp Ser C 115 His Giu Lys A~ 130 Ser Phe Glu G 145 Thr Leu Arg P1 Asn Pro Ala T) if Ser Vai Vai Lf 195 Giu Phe Gin Ac 210 Val Giu Ile A] 225 Leu Ala Ala Al Ile Ile Asp Pf 26 Asp Thr Lys G1 275 Val Gin Ile LE 290 Arg His Ser Va 305 Tyr His Glu Va Ile Phe Ser Ve

RT

.sapiens sn 0 he la (s

(S

00

(S

5i Li ie Glu 5 Val Pro Ile Phe Thr Gin Cys Trp Ser Gly 165 Cys Ala Glu Cys Pro 245 Vai Giu Arg Gly Gly 325 Leu Phe Gly His Leu Asp 70 Gly Giu Ser Asp Ser 150 Gin Leu Ser Asp Ile 230 Cys Ser Giu Leu Leu 310 Leu Ile Phe His Arg Pro Gly Gin Asp Glu Glu Leu 10 Giy Phe Lys Gin Ser Val Asp Gin Ser Thr 25 Thr Arg Leu Gly Lys Leu Leu Thr Cys His 40 Giu Leu Cys Asp Asp Tyr Ser Vai Ala Asp 55 Arg Asn Pro Ser Leu Phe Arg Tyr Val Leu 75 Lys Leu His Vai Met Giu Giu Leu Cys Val 90 Ile Glu Tyr Trp Gly Ile Asn Giu Leu Phe 105 110 Asn Arg Tyr Gin Giu Arg Lys Giu Giu Asn 120 125 Gin Lys Ser His Asp Val Ser Thr Asp Ser 135 140 Leu Phe Giu Lys Giu Leu Giu Lys Phe Asp 155 160 Leu Arg Lys Lys Ile Trp Ile Arg Met Glu 170 175 Ser Ala Lys Leu Ile Ala Ile Ser Ser Leu 185 190 Ile Val Ala Met Cys Vai His Ser Met Ser 200 205 Gly Giu Val Asp Asp Pro Val Leu Giu Gly 215 220 Ala Trp Phe Thr Gly Giu Leu Ala Val Arg 235 240 Gin Lys Lys Phe Trp Lys Asn Pro Leu Asn 250 255 Ile Ile Pro Phe Tyr Ala Thr Leu Aia Val 265 270 Ser Giu Asp Ile Glu Asn Met Gly Lys Vai 280 285 Met Arg Ile Phe Arg Ile Leu Lys Leu Ala 295 300 Arg Ser Leu Giy Ala Thr Leu Arg His Ser 315 320 Leu Leu Leu Phe Leu Ser Val Gly Ile Ser 330 335 Tyr Ser Val Giu Lys Asp Asp His Thr Ser 350 WO 99/43696 WO 9943696PCTIUS99/03826 Ser Leu Thr 355 Thr Thr Val Ser Ile Pro Ile Trp Trp Trp Ala Ile Ser Met Ala Gly Lys Gly Tyr Gly His Pro Val 370 Leu Ile Ala Ser Thr 385 Pro Cys 390 Phe Ile Cys Gly Val Val Ala Ile Thr Ile Ile Asn Lys Phe Tyr Tyr Gin Lys Gin 415 Lys Asp Ile His Glu Leu Asp Vai Asp 420 Pro Tyr Phe Ile Thr Ser Gin Cys Asn Ile 440 Leu Ser Asp Ala Pro Asp Ile Tyr Giu Lys Cys 430 Gin Arg Met Val Ser Asp 435 Phe His Ala 450 Pro Asp Ser Val Gly 455 Ser Ile 460 Asn Ser Thr Asp Ser Ile Giu Giu Asp Ile 465 Asn Thr Thr Ser Leu 485 Asn Cys Thr Ala 490 <210> 7 <211> 3080 <212> DNA <213> <220> <221> <222> <223> H. sapiens

CDS

(480) (1977) K+Hnov9 <400> 7 gtctctcctc tccacccacc gcgaagttgg cagggactgt gctccctgtc cggcaggagg tcgggagccc aagcttccgg ttcctcctcc aagtagcgag gaggcggggt gtcgggcttg tcctctttct aggaaggcgc ggggaatccc cgtgtcccca tccgccccac tcattcaatc gacaacgttt gacct cacc t gccacttgtg acagcgggtg ggccgccacc actttgtggc atctccctcc tgtacacctc gggaagggcc gatcctctct cgctgcttcc gagagggtgc aggggccgtg gccctcaggc ttcctccctt ctgggctggg agggcgaccg cttagcgcga gcgcactccc gccaaggaga ccaccgccct cgcggcgact ccccaacccc aatcgcaatt gcagtgtgca cccttcctct ggctccctag ggtaacc cc t cgcgggacca gggttagag 120 180 240 300 360 420 479 527 575 atg cct tcc agc ggc aga gcg ctg ctg Met Pro Ser Ser Gly Arg Ala Leu Leu 1 5 tcc ctg acc tcc ctg gac tct agt gtc Ser Leu Thr Ser Leu Asp Ser Ser Val 25 tcg ccg ctg gac agc ggc Ser Pro Leu Asp Ser Gly ttc tgc agc gag Phe Cys Ser Giu ggt gaa ggg Gly Glu Gly gag ccc ttg Giu Pro Leu gcg ctc ggg gac tgc ttc acg gtc aac gtg ggc ggc agc Ala Leu Gly Asp Cys Phe Thr Vai Asn Val Gly Gly Ser cgc ttc Arg Phe gtg ctc tcg cag Val Leu Ser Gin gcg ctg tcc tgc Ala Leu Ser Cys ccg cac acg cgc Pro His Thr Arg ggc aag ctg gc Gly Lys Leu Ala gtg gtg gct tcc Val Val Ala Ser cgc cgc ccc ggg Arg Arg Pro Gly ctg gcc gcc gtg ccc agc cct ctg gag Leu Ala Ala Val Pro Ser Pro Leu Giu tgc gac gat gcc aac ccc Cys Asp Asp Ala Asn Pro WO 99/43696 WO 9943696PCTIUS99/03826 gtg gac aac Val Asp Asn gag Giu tac ttc ttc gac cgc agc tog cag Tyr Phe Phe Asp Arg Ser Ser Gin ttc cga tat Phe Arg Tyr 100 gtc Val tgc Cys ct 0 Leu 145 ctg Leu caa Gin cgc Arg gcc Ala att Ile 225 ctg Leu ttt Phe aag Lys act Thr gag Giu 305 ctg Leu gcg Aila 130 agc Ser agt Ser cat His cag Gin cgt Arg 210 aa 0 Asn ctg Leu gtc Vai gtg Vai ctt Leu 290 aac Asn ca c His 115 ctc Leu atc Ile gaa Glu gag Giu aag Lys 195 atc Ile atg Met gaa Giu ct C Leu cca Pro 275 ctg Leu gtg Val tac Tyr t cc Ser gat Asp act Thr agt Ser 180 ote Leu ttt Phe gcc Ala atc Ile cgc Arg 260 aac Asn gta Val ggg Gly tac Tyr ttc Phe tco Ser tta Leu 165 gaa Giu tgg Trp ggc Gly ctg Leu otg Leu 245 tto Phe at c Ile gag Giu ogc Arg cgc Arg etg Leu tgc Cys 150 gac Asp cag Gin aat Asn gt c Vai atg Met 230 gag Giu ctg Leu ata Ile agc Ser att Ile 310 acc ggc Thr Giy 120 cag gag Gin Giu 135 tgc agg Cys Arg ttc aag Phe Lys gac ttc Asp Phe atc ctg Ile Leu 200 atc too Ile Ser 215 tca got Ser Ala tat gtg Tyr Val tgt gtg Cys Val gao oto Asp Leu 280 ota agt Leu Ser 295 gte oag Val Gin 105 cgc Arg atc Ile gac Asp aag Lys too Ser 185 gag Giu att Ile gag Giu tgc Cys egg Arg 265 ctt Leu ggg Giy gtg Val ctg cat Leu His cag tao Gin Tyr aga tao Arg Tyr 155 gac aoa Asp Thr 170 caa gga.

Gin Gly aaa cot Lys Pro atc ttc Ile Phe tta ago Leu Ser 235 att. agc Ile Ser 250 gao agg Asp Arg goc atc Ala Ile ago cag Ser Gin ttg agg Leu Arg 315 gto atg Val Met 125 tgg ggc Trp Gly 140 tte aga Phe Arg gaa gac Glu Asp cot. tgt Pro Cys gga tet Gly Ser 205 gtg gtg Val Vai 220 tgg otg Trp Leu tgg ttc Trp Phe tgt cgc Cys Arg ttg ccc Leu Pro 285 acc acg Thr Thr 300 ctg etc Leu Leu gag Glu ate Ile agg Arg cag Gin coo Pro 190 t Co Ser gtg Val gac Asp ace Thr tte Phe 270 t to Phe cag Gin agg Arg cag Gin gat Asp aaa Lys gaa Giu 175 act Thr aca Thr tee Ser otg Leu ggg Gly 255 ota Leu tac Tyr gag Giu get Ala etg Leu gag Glu gag Glu 160 agt Ser gtt Val gct Ala ate Ile cag Gin 240 gag Glu aga Arg ate Ile ctg Leu ctg Leu 320 815 863 911 959 1007 1055 1103 1151 1199 1247 1295 1343 1391 1439 ego atg eta aag otg Arg Met Leu Lys Leu 325 aga eat tco aca. gga tta cgc tco ett Arg His Ser Thr Gly Leu Arg Ser Leu 330 335 1487 WO 99/43696 WO 9943696PCTIUS99/03826 atg aca atc met Thr Ile cta tec gtg Leu Ser Val 355 acc Thr 340 cag tgt tac gaa Gin Cys Tyr Glu gaa Giu 345 gte ggc eta. ctg Vai Giy Leu Leu ctc eta ttt Leu Leu Phe 350 ttt get gag Phe Aia Glu 1535 1583 gga ate tct ata Gly Ile Ser Ile tca act gta gaa.

Ser Thr Vai Giu caa age Gin Ser 370 att cct gac aca Ile Pro Asp Thr ttc aca agt gte ect tgt gca tgg tgg Phe Thr Ser Val Pro Cys Aia Trp Trp, 380 tgg gee ace ace tet Trp Ala Thr Thr Ser 385 gac ace ace aca ggc Asp Thr Thr Thr Giy 405 atg Met 390 act act gtg gga.

Thr Thr Val Gly tat Tyr 395 ggg gac att aga Gly Asp Ile Arg 1631 1679 1727 aaa ate gtg gee Lys Ile Vai Aia atg tgt ata tta Met Cys Ile Leu teg gga Ser Gly 415 att ctt gte Ile Leu Val get tgc tac Ala Cys Tyr 435 gee ttg cet att Ala Leu Pro Ile att att. aac gat Ile Ilie Asn Asp cgc ttc tct Arg Phe Ser 430 aga cag cgt Arg Gin Arg 1775 1823 ttc ace ttg aaa Phe Thr Leu Lys aag gaa gca get Lys Glu Ala Ala gaa gee Giu Ala 450 eta aag aag ctt Leu Lys Lys Leu aag aat ata gee Lys Asn Ile Ala act Thr 460 gac tca tat ate Asp Ser Tyr Ile agt Ser 465 gtt aae ttg aga Val Asn Leu Arg gte tat gee egg Val Tyr Ala Arg ate atg gag atg Ile Met Glu Met ctg Leu 480 1871 1919 1967 ega ctg aaa ggc Arg Leu Lys Gly gaa aga gea agt Giu Arg Ala Ser act Thr 490 agg age age ggg Arg Ser Ser Gly gga gat Gly Asp 495 gat tte tgg Asp Phe Trp t tttgaattaa ttttcaattt atttacaaaa getatgtaca 2017 attaaetaaa gagtactgct acatcaceta aaeacaacca tgttattgca tttgeaeeae aaatatttaa ttactccgtt eeeatatttg eaaatgaaet tagattgcag actgagtgta tggtetttaa atgtaaaagt tttcataaat ttgttaacaa aaactttgca atgataaagc catettaatt taaeaactge aatacaactg ataeatacaa taatttttta gaaeatattg ctetatcagt atgggcagag gatetctgta tacatgagte gtatgtggag atgtetettt gaggtagtga gggaaatata aaaaatacta ggeattttga agtgatgtgg aatttttgct aeagtgttet ggccaatata aaaagttaaa aaaatggaag aacaaetttg taaagctatt attatatc teecattatt taeacaaaga eataaaaeag atggatgtat aeateetaaa tgttaaatga.

tggaeagett catteatcat atttetgtat gatatattge gacaeatttg aaeatgtttg gattttatgt gtaaactgca etatttaaag gaatataata tatcttcttt, aetataagag ettcaacaat catatttctt.

tgttcacatt tttctaeact catcaetgga tctgattgtt aacaacacaa tctgatgatg ttcatctaet agtgtccaaa aattgtcaaa ateactaaea tagcccagag atattatcca cttagcttta ttcatgtaaa gtgggaatec tgcacatctt agtattteat atggetttaa ggaattacta tgaacttgaa ggggtaaata tteetagaca agtctettca agaatatttc atagccaatt tataaaataa ttagaagttt aaagataagt agtacataaa caagagaaaa eeactggtca caaaactgct eattetecca gaatatcaga aataatgaat aataatctta gatettttac gcaaatgttc ttgtattata 2077 2137 2197 2257 2317 2377 2437 2497 2557 2617 2677 2737 2797 2857 2917 2977 3037 WO 99/43696 WO 9943696PCTIUS99/03826 taattaaagc caaaacctct aaagctaaaa aaaaaaaaaa aaa <210> 8 3080 <211> <212> <213> 499

PRT

H. sapiens <400> 8 Met Ser Glu Arg Leu Leu Val Val Cys Leu 145 Leu Gin Arg Ala Ile 225 Leu Phe Lys Thr Giu 305 Arg Met Leu Gin Trp 385 Asp Pro Leu Pro Phe Gly Ala Asp Leu Ala 130 Ser Ser His Gin Arg 210 Asn Leu Val Val Leu 290 Asn Met Thr Ser Ser 370 Ala Thr Ser Thr Leu Val Lys Ala Asn His 115 Leu Ile Giu Giu Lys 195 Ile Met Giu Leu Pro 275 Leu Val Leu Ile Val 355 Ile Thr Thr Ser Ser Al a Leu Leu Val Giu 100 Tyr Ser Asp Thr Ser 180 Leu Phe Al a Ile Arg 260 Asn Val Gly Lys Thr 340 Gly Pro Thr Thr Gly Leu Leu Ser Ala Pro Tyr Tyr Phe Ser Leu 165 Glu Trp Gly Leu Leu 245 Phe Ile Giu Arg Leu 325 Gin Ile Asp Ser Gly 405 Arg Asp Gly Gin Val 70 Ser Phe Arg Leu Cys 150 Asp Gin Asn Val Met 230 Giu Leu Ile Ser Ile 310 Gly Cys Ser Thr Met 390 Lys Ala Leu Leu Asp Ser Pro Leu Asp Ser Gly 10 Ser Asp Gin 55 Val Pro Phe Thr Gin 135 Cys Phe Asp Ile Ile 215 Ser Tyr Cys Asp Leu 295 Val Arg Tyr Ile Thr 375 Thr Ile Ser Cys Ala Vai Leu Asp Gly 120 Giu Arg Lys Phe Leu 200 Ser Ala Val Val Leu 280 Ser Gin His Giu Phe 360 Phe Thr Val Val 25 Phe Leu Al a Giu Arg 105 Arg Ile Asp Lys Ser 185 Giu Ile Glu Cys Arg 265 Leu Gly Vai Ser Glu 345 Ser Thr Val Ala Phe Cys Thr Vai Ser Cys Ser Tyr 75 Leu Cys 90 Ser Ser Leu His Gin Tyr Arg Tyr 155 Asp Thr 170 Gin Gly Lys Pro Ile Phe Leu Ser 235 Ile Ser 250 Asp Arg Aia Ile Ser Gin Leu Arg 315 Thr Giy 330 Val Gly Thr Vai Ser Vai Giy Tyr 395 Phe Met 410 Ser Asn Phe Arg Asp Gin Vai Trp 140 Phe Giu Pro Giy Val 220 Trp, Trp, Cys Leu Thr 300 Leu Leu Leu Glu Pro 380 Gly Cys Gly Giu Gly Giy His Thr Pro Gly Ala Asn Phe Arg 110 Giu Gin Ile Asp Arg Lys Gin Giu 175 Pro Thr 190 Ser Thr Val Ser Asp Leu Thr Gly 255 Phe Leu 270 Phe Tyr Gin Glu Arg Aia Ser Leu 335 Leu Leu 350 Phe Ala Ala Trp Ile Arg Leu Ser Gly Ser Arg Ala Pro Tyr Leu Glu Glu 160 Ser Val Ala Ile Gin 240 Giu Arg Ile Leu Leu 320 Gly Phe Glu Trp, Pro 400 Gly Ile Leu Val Leu Ala Leu Pro Ile Ala Ile Ile Asn Asp Arg Phe Ser WO 99/43696 WO 9943696PCT/US99/03826 Ala Cys Tyr 435 Giu Ala Leu 420 Phe Thr Leu Lys Lys Lys Leu Thr Leu 440 Lys Giu Ala Ala 430 Arg Gin Arg Ser Tyr Ile Asn Ile Ala 450 Ser Val 455 Val Thr 460 Ile Asn Leu Arg 465 Arg Asp 470 Glu Tyr Ala Arg Ser 475 Arg Met Giu Met Leu 480 Asp Leu Lys Giy Arg 485 Arg Ala Ser Ser Ser Gly Gly 495 Asp Phe Trp <210> 9 <2i1> 3424 <212> DNA <213> H. sapiens <220> <221> CDS <222> (257) (2195) <223> K+Hnovl2 <400: Ctcttctcca aggttctgta cttggcctct.

cccaccatcc ct tggggagt.

cgg gca gcz Arg Ala AlF tgtccccaag gcccttctca gtccctcaga acattgccca ggcccctcct aatgtccccc agactccttc ccatctcttt agttcttcct cctggttcct ctagacaccc ccagtttcct. tgtttgggtg gctcaaggtg tctccaagcc tggagacagc cacattctcc taaacgccac cctcactaag tctccctggg ggcacg atg gcg gca ggc ctg gcc acg tgg ctg cct ttt gct Met Ala Ala Gly Leu Ala Thr Trp Leu Pro Phe Ala 120 180 240 292 340 gca gtg ggc Ala Val Gly tgg ctg Trp Leu ccc ccg gcc cag caa ccc ctg ccc Pro Pro Ala Gin Gin Pro Leu Pro ccg gca Pro Ala ccg ggg gtg aag Pro Gly Val Lys gca Ala 35 tct, cga gga gat grg gtt ctg gtg gtg Ser Arg Gly Asp Xaa Val Leu Val Val gtg agc gga cgg Val Ser Gly Arg ttt gag act tgg Phe Giu Thr Trp, aat acg ctg gac Asn Thr Leu Asp tac cca gac acc Tyr Pro Asp Thr ctg ggc agc tcg Leu Gly Ser Ser gag Glu aag gaa ttc ttc Lys Giu Phe Phe tac gat Tyr Asp gct gac tca Ala Asp Ser cat gtg ctg His Val Leu gag tac ttc ttc Glu Tyr Phe Phe cgc gac cct gac Arg Asp Pro Asp atg ttc cgc Met Phe Arg cca cgg cag Pro Arg Gin aac ttc tac cga.

Asn Phe Tyr Arg acg Thr 100 ggg cgg ctg cat Gly Arg Leu His gag tgc Giu Cys 110 atc cag gcc ttc Ile Gin Ala Phe gac Asp 115 gaa. gag ctg gct ttc tac ggc ctg gtt Giu Glu Leu Ala Phe Tyr Gly Leu Val ccc gag cta gtc ggt gac tgc tgc ctt. gaa gag tat cgg gac cga, aag Pro Glu Leu Val Gly Asp Cys Cys Leu Glu Glu Tyr Arg Asp Arg Lys WO 99/43W6 PCTIUS99/03826 125 130 135 140 ,aag ;gpg ast goc gag cgc ctg gca gag gat gag gag goa gag cag gcc 724 Lys GlifuA~n Ala Glu Arg Leu Ala Giu Asp Glu Giu Ala Giu Gin Ala 145 150 155 ggg gac %q cca gcc ctg coa gca ggc agc tcc ctg cgg cag oggoctc 772 Gly 'Asp GaLy Pro Ala Leu Pro Ala Gly Ser Ser Leu Arg Gin Arg Leu 160 165 170 tgg cgg Tc ttc gag aat cca cac acg ago acc gca gcc cto gtt ttc 820 Trp Arg Raa Phe Giu Asn Pro His Thr Ser Thr Ala Ala Leu Val Phe 2175 180 185 ,tac tat qtg acc ggc ttc ttc atc gcc gtg tcg gtc atc gcc aat gtg 868 Tyr Tyr VA~i Thr Gly Phe Phe Ile Ala Val Ser Vai Ile Ala Asn Val 190 195 200 *gtg gag c-wc atc cca tgc cgc ggc tot gca. cgc agg tcc tca agg gag 916 Val -Glu Thr Ile Pro Cys Arg Giy Ser Ala Arg Arg Ser Ser Arg Giu 205 210 215 220 cag -ccc tgt ggc gaa cgo ttc cca cag gcc ttt ttc tgc atg gac aca 964 'Gin 'Pro C.ys Gly Giu Arg Phe Pro Gin Ala Phe Phe Cys Met Asp Thr 225 230 235 gcc tgt Sta ctc ata ttc aca ggt gaa tac otc ctg ogg ctg ttt gcc 1012 Ala Cys Val Leu Ile Phe Thr Gly Giu Tyr Leu Leu Arg Leu Phe Ala 240 245 250 gc cc agc cgt tgc cgc ttc ctg cgg agt gtc atg agc ctc atc gac 1060 Ala Pro Ser Arg Cys Arg Phe Leu Arg Ser Val Met Ser Leu Ile Asp 255 260 265 gtg gtg gcc atc ctg ccc tac tac att ggg ott ttg gtg coo aag aac 1108 Val Val Ala Ile Leu Pro Tyr Tyr Ile Gly Leu Leu Val Pro Lys Asn 270 275 280 gao gat gtc tct ggc gcc ttt gtc acc ctg ogt gtg ttc cgg gtg ttt 1156 Asp Asp Val Ser Gly Ala Phe Val Thr Leu Arg Val Phe Arg Val Phe 285 290 295 300 cgc atc ttc aag ttc tcc agg cac tca cag ggc ttg agg att ctg ggc 1204 Arg Ile Phe Lys Phe Ser Arg His Ser Gin Gly Leu Arg Ile Leu Giy 305 310 315 tao aca etc aag ago tgt goo tot gag otg ggo ttt oto oto ttt too 1252 Tyr Thr Leu Lys Ser Cys Ala Ser Giu Leu Gly Phe Leu Leu Phe Ser 320 325 330 ota. aoo atg goc atc ato ato ttt goo act gtc atg ttt tat got gag 1300 Leu Thr Met Ala Ile Ile Ile Phe Ala Thr Val Met Phe Tyr Ala Giu 335 340 345 aag ggo aca aao aag aoo aao ttt aca ago ato cot gog goo ttc tgg 1348 Lys Gly Thr Asn Lys Thr Asn Phe Thr Ser Ile Pro Ala Ala Phe Trp 350 355 360 tat aoo att gtc aco atg aoc aog ott ggc tac gga gao atg gtg ccc 1396 Tyr Thr Ile Vai Thr Met Thr Thr Leu Gly Tyr Gly Asp Met Vai Pro 365 370 375 380 WO 99/43696 WO 9943696PCT/US99/03826 agc acc att gct ggc Ser Thr Ile Ala Gly 385 aag att ttc Lys Ile Phe ggg Gly atc tgc tca ctc agt Ile Cys Ser Leu Ser 395 390 gtc Val cgc Arg aag Lys gcc Al a 445 ggc Gly caa Gin ttc Phe ggt Gly ccc Pro 525 gcc Ala cag Gin agc Ser tgc Cys cct Pro ttg Leu atc Ile gtg Val 430 ttc Phe gag Giu cat His aca Thr ggc Gly 510 gga Gly at c Ile gag Glu cgc Arg gac Asp 590 gcc Ala gtc Val1 tac Tyr 415 cgc Arg ctg Leu gaa Glu cac His gat Asp 495 cgc Arg agc Ser cgc Arg ctg Leu tcc Ser 575 agc Ser aac Asn att Ile 400 ca c His ttg Leu cag Gin cag Gin ca c His 480 gag Glu acc Thr ctg Leu ctt Leu gac Asp 560 agc Ser cgg Arg acc Thr gcc Al a cag Gin gca Ala tac Tyr gct Ala 465 ttg Leu ct c Leu agc Ser ctg Leu gcc Ala 545 atg Met ctc Leu gac Asp cca Pro ctg Leu aac Asn agg Arg aag Lys 450 ctt Leu ctg Leu acc Thr cgt Arg tct Ser 530 aac Asn ctg Leu aat Asn ttc Phe gat Asp cca Pro 405 gct Ala ttg Leu ggg Gly agg Arg cta Leu 485 gaa Glu tct Ser tgc Cys gcc Ala ctg Leu 565

CCC

Pro gcc Ala caa Gin gtc Val gac Asp gca Ala ggC Gly aac Asn 470 gag Giu gcc Ala gtg Val cct Pro tca Ser 550 cgc Arg cat His att Ile cct Pro att Ile aag Lys aag Lys ctt Leu 455 cgt Arg aag Lys ctg Leu tct Ser cgc Arg 535 gt c Val agg Arg gac Asp atc Ile tcC Ser gtg Val cgc Arg agt Ser 440 gag Glu tct Ser aca Thr gga.

Gly tcC Ser 520 agg Arg agc Ser agc Ser agc Ser agc Ser 600 tcC Ser aac ttt Asn Phe 410 gca cag Ala Gin acc acc Thr Thr agc ggc Ser Gly ttt gaa Phe Glu 475 tgc cat Cys His 490 gtc tcg Val Ser cca gtg Pro Val aag cgc Lys Arg ggc agc Gly Ser 555 gcc cct Ala Pro 570 gac ctg Asp Leu Oct acc Pro Thr ggc ggc Gly Gly ggc Gly agc Ser cag Gin aat Asn agt Ser 460 cag Gln gag Glu ccg Pro gga Gly cgc Arg 540 atq Met cag Gin aac Asn cct Pro ggt Gly 620 1444 1492 1540 1588 1636 1684 1732 1780 1828 1876 1924 1972 2020 2068 2116 WO 99/43696 WO 9943696PCTIUS99/03826 ggc agg gcc ggc agc acc ctc agg aac tcc agc ctg ggt acc cct tgc Gly Arg Ala Gly Ser Thr Leu Arg Asn Ser Ser Leu Gly Thr Pro Cys 625 630 635 ctc ttc ccc gag act gtc aag atc tca tcc C tgtgaggggt aggcctgctg Leu Phe Pro Glu Thr Val Lys Ile Ser Ser attcagaggg gagaggggca tcatgaaatg agacat ttt t cctagcacac ggctctcaga ttgagatttc cctcacctct agattctgaa gccatcccca acaaattcta ctgggccccc gaccagtttg tcctcctctc tgagataaga ccatgttctt tttgggagtt tcacatattc atctggcatc aaagatgtag aaaaaaaaa tcctcttcat ggcttgggca gtccacatag cctggtggga tgggactggc tgaaggcaaa ctcctccctc gatctggcct gcttggaatg ggccttgcct ccatcccctt agcaaactct ctgcagcatt ttctcctctg gcctggcaac gggcaacagt ataggagaca ctttcttctc atctcaggtt tttccatcag ttttgggaac ccccttctgc tggggaagta gctgaagcac cccactctcc gctttgatcc tggctgggat ctacgagagg caaacacagg gaggggtcag ccctggctgc agcaatagca tacatctgcc gtttgcgtcc cagcaagagc ccagaagcat ggaggaactt cctcttgggt ccctgtcccc tcaataaaac tcctttccaa, cccccccact gccaggaaat tgggcttcca cagctggact gacatctgag atggagcttt tcctcatctc ct tcatgggc gctgcctctc tggaaatgga.

gctgctgccg ctaatcagag ttcctgggtt tgggctgtat caggggctcc ctcctcctcc gaccttccaa agcactgtcc ctgagaggag agccatattt gagaactatg gagaaacttc caggcccctg cctgcatgct ctctagccta ggaggttcag catctggccc tgtggcctct ccaacacaca ccccgcaacc tgt cattatg gggccacctc gggctggagt ttggagatca ggcctgggat tcctccccta aactctgctc ccatggagct agatgaggaa t tgggaggca caatggagtt ctcccacccc gcctccttgc cctccccttg agaaggagag agaagagaac aacaattccc gcagcgacct ctcagatagc ctgtcctctg caaagcctct taactcctcc ctggactggc tgggctgatt gtttctgaac caattccttt tcaggctgaa ggtggctgac aaaaaaaaaa 2164 2215 2275 2335 2395 2455 2515 2575 2635 2695 2755 2815 2875 2935 2995 3055 3115 3175 3235 3295 3355 3415 3424 <210> <211> <212> <213> <220> <221> <222> <223> 646

PRT

H. sapiens

VARIANT

(646) Xaa Any Amino Acid Met 1 Val <400> Ala Ala Gly Leu Ala Thr Trp Leu Pro 10 Phe Ala Arg Ala Ala Ala Gly Trp Leu Pro Ala Gin Gln 25 Gly Asp Xaa Val Pro Leu Pro Pro Val Lys Ala Arg Arg Phe Ser Arg Leu Val Val Ala Pro Gly Val Ser Gly Pro Asp Thr Glu Thr Trp Thr Leu Asp Leu Leu Gly Ser Ser Glu Phe Phe Glu Ala Asp Ser Tyr Phe Phe Asp Pro Asp Met Pro Arg His Val Leu Asn Phe Tyr Arg Ala Phe Asp 115 Gly Asp Cys Thr Gly Arg Leu His 100 Glu Glu Leu Ala Phe 120 Cys Leu Giu Glu Tyr Arg Gin Glu Gly Leu Val Cys Ile Gln 110 Glu Leu Val Glu Asn Ala Arg Asp Arg Lys 130 Glu Arg 145 Leu Ala Giu Asp Glu 150 Glu Ala Glu Gly Asp Gly Pro 160 WO 99/43696 WO 9943696PCTIUS99/03826 Ala Leu Pro Ala Gly Ser Ser Leu Arg Gin Arg Leu Trp Arg Ala Phe 170 Giu Gly Pro Glu 22S Ile Cys Leu Gly Phe 305 Ser Ile Lys Thr Gly 385 Ala Gin Ala Tyr Ala 465 Leu Leu Ser Leu Ala.

545 Met Leu Asp Pro Ser 625 Asn Phe Cys 210 Arg Phe Arg Pro Ala 290 Ser Cys Ile Thr Met 370 Lys Leu Asn Arg Lys 450 Leu Leu Thr Arg Ser 530 A.sn Leu Asn Phe Asp 610 rhr Pro Phe 195 Arg Phe Thr Phe Tyr 275 Phe Arg Ala Ile Asn 355 Thr Ile Pro Gin Ile 435 Gin Cys His Phe Ser 515 Ser Ser Ala Ala Val 595 Giu Leu His 180 Ile Gly Pro Gly Leu 260 Tyr Vai His Ser Phe 340 Phe Thr Phe Val Arg 420 Arg Asn Val Cys Ser 500 Thr Cys Thr Gly Lays 580 Alia Ser Arg Thr Al a Ser Gin Giu 245 Arg Ile Thr Ser Glu 325 Ala Thr Leu Gly Pro 405 Ala Leu Giy Arg Leu 485 Glu Ser Cys Ala Leu 565 Pro Ala Gin Asn Ser Val Ala Al a 230 Tyr Ser Giy Leu Gin 310 Leu Thr Ser Gly Ser 390 Val Asp Ala Gly Asn 470 Giu Ala Val Pro Ser 550 Arg His Ile Pro Ser 630 Thr Ser Arg 215 Phe Leu Val Leu Arg 295 Gly Gly Val Ile Tyr 375 Ile Ile Lys Lys Leu 455 Arg Lys Leu Ser Arg 535 Val Arg Asp Ile Ser 615 Ser Ala Val 200 Arg Phe Leu Met Leu 280 Val Leu Phe Met Pro 360 Gly Cys Val Arg Ser 440 Giu Ser Thr Gly Ser 520 Arg Ser Ser Ser Ser 600 Ser Leu Ala 185 Ile Ser Cys Arg Ser 265 Vai Phe Arg Leu Phe 345 Ala Asp Ser Ser Arg 425 Gly Asp Ala Thr Al a 505 Gin Ala Arg His Leu 585 Ile Pro Gly Leu Ala Ser Met Leu 250 Leu Pro Arg Ile Leu 330 Tyr Ala Met Leu Asn 410 Ala Thr Ser Phe Cys 490 Val Pro Lys Gly Ala 570 Asp Pro Gly Thr *Val Asn Arg Asp 235 Phe Ile Lys Val1 Leu 315 Phe Al a Phe Vai Ser 395 Phe Gin Thr Gly Gi u 475 His Ser Val Arg Ser 555 Pro Leu Thr Gly Pro 635 Phe Val Giu 220 Thr Ala Asp Asn Phe 300 Gly Ser Giu Trp Pro 380 Gly Ser Gin Asn Ser 460 Gin Giu Pro Gly Arg 540 Met Gin Asn Pro Gly 620 Cys Tyr Val 205 Gin Ala Ala Val Asp 285 Arg Tyr Leu Lys Tyr 365 Ser Val Arg Lys Ala 445 Gly Gin Phe Giy Pro 525 Ala Gin Ser Cys Pro 605 Gly Leu Tyr 190 Giu Pro Cys Pro Vai 270 Asp Ile Thr Thr Gly 350 Thr Thr Leu Ile Val 430 Phe Giu His Thr Gly 510 Gly Ile Giu Arg Asp 590 Ala Arg Phe 175 Val Thr Cys Val Ser 255 Al a Val Phe Leu Met 335 Thr Ile Ile Val Tyr 415 Arg Leu Glu His Asp 495 Arg Ser Arg Leu Ser 575 Ser A~sn Al a Pro Thr Sle Gly Leu 240 Arg Ile Ser Lys Lys 320 Al a Asn Val Ala Ile 400 His Leu Gin Gin His 480 Glu Thr Leu Leu Asp 560 Ser Arg Thr Gly Giu 640 Thr Val Lys Ile Ser Ser WO 99/43696 WO 9943696PCTIUS99/03826 <210> <211> <212> <213> <220> <221> <222> <223> 645 1862

DNA

H. sapiens

CDS

(383) (1157) K+Hnovl <400> 11 cagctgaatg tggaggcctt actactgacc aacatttcag tgactcttaa ttacatcaca cttttcaaga agcagaaagc gagctgacag cgcaggcgat taaaggcgtg cttgtgtggt gctgaaatag catcttcaaa taagagaact gctgatcctc cctgtgtcga tcctgcatac gctgccagcg agtgtctctt aa atg gag Met Giu tccagctcct gtaaaaaccc agaccagagg cagacctcga agttactctc cttactctcc cactctctgg gaaaagactg aagaaataat ataggctgat acgccaccta ctgcaaaacc tttccattcc atcaccaggc tggggctgaa tttaaaaaat ctcaaagcca agaagaacaa cgt aaa ata aac aga aga gaa aaa Arg Lys Ile Asn Arg Arg Glu Lys gaa aag gag tat gaa ggg aaa cac aac Giu Lys Giu Tyr Giu Gly Lys His Asn agc Ser 20 ctg gaa. gat act Leu Glu Asp Thr gat caa Asp Gin 460 gga aag aac Gly Lys Asn aaa tcc aca ctg Lys Ser Thr Leu acc ctc aac gtt Thr Leu Asn Val ggt gga tat Gly Gly Tyr gac act ttc Asp Thr Phe tta tac Leu Tyr ctt gaa Leu Glu act caa aaa caa Thr Gin Lys Gin ctg acc aag tac Leu Thr Lys Tyr ggt ata gta aat Gly Ile Val Asn aaa atc ctc tgc Lys Ile Leu Cys ttt gat gct gat Phe Asp Ala Asp 556 604 652 700 ggt Gly cat tat ttc ata His Tyr Phe Ile agg gat ggt ctc Arg Asp Gly Leu ttc agg cat gtc Phe Arg His Val aac ttc cta cga Asn Phe Leu Arg gga gaa ctt cta Gly Glu Leu Leu ttg Leu 100 ccc gaa ggg ttt Pro Giu Gly Phe cga gaa Arg Glu 105 aat caa ctt Asn Gin Leu gca gag gaa Ala Giu Giu 125 gca caa gaa gca Ala Gin Giu Ala gaa Glu 115 ttc ttt cag ctc Phe Phe Gin Leu aag gga. ctg Lys Gly Leu 120 gtg aaa tcc agg Val Lys Ser Arg gag aaa gaa cag cta aca ccc aga Giu Lys Giu Gin Leu Thr Pro Arg 135 gag act Glu Thr 140 act ttc ttg gaa Thr Phe Leu Giu ata Ile 145 aca gat aac cac Thr Asp Asn His gat Asp 150 cgt tca caa gga Arg Ser Gin Gly tta aga. atc ttc tgt aat gct cct Leu Arg Ile Phe Cys Asn Ala Pro gat ttc Asp Phe 21 ata tca aaa ata aag tct Ile Ser Lys Ile Lys Ser WO 99/43696 WO 9943696PCTIUS99/03826 ege att gtt etg Arg Ile Val Leu tce aaa agc agg Ser Lys Ser Arg ctg Leu 180 gat gga ttt eca Asp Gly Phe Pro gag gag Giu Giu 185 ttt tca ata Phe Ser Ile gaa aat ggc Giu Asn Gly 205 tca aat ate ate Ser Asn Ile Ile ttt aaa tac ttc Phe Lys Tyr Phe ata aag tct Ile Lys Ser 200 ttt gte tgt Phe Val Cys act ega ett gta Thr Arg Leu Val aag gaa gac aac Lys Giu Asp Asn ace ttg Thr Leu 220 gaa act ett aag Giu Thr Leu Lys gag get ate atg Giu Ala Ile Met atg Met 230 get tta aag tgt Ala Leu Lys Cys 1036 1084 1132 gge ttt aga etg etg Gly Phe Arg Leu Leu 235 ace Thr 240 age etg gat tgt Ser Leu Asp Cys tee Ser 245 aaa ggg tea att Lys Gly Ser Ile eac age gat gea His Ser Asp Ala ett Leu 255 eat ttt atc a agtaattaee tgtgteaega His Phe Ile 1177 acaaaggcaa aaataaeatg etaacggtat agactcttcc gettttgeta aeaaaaagaa aaggggetat aetggeaaaa tagtgaaaca caagcaccaa ggtattttgc ctgetacctt eaageatgca ceagetagc gtaaattcta acctaaaatg tttatttgtc geatgtaeat taatatttaa ttaactacct aaatgagatt aagcttatat tgaaaattcc caaaaaaaaa geeagcaagc tctgtactac tegctaaaga aaaaeagtaa ettaagctgt tatetatcgt aatcettttc ggagcaaaac gtaagaagae tcacagttee tagaaaaetg aaaaa ttcggaaaac agageectgc tgtccttect cettctatat ettteaatte teatttaagt tactatggca agatgtgeag attaaagcta tgtgttteat eacageatea tactaateaa etggggtgt t aetgtaaata agattgtett aaatggtaat aaaatctaca atctaaetaa ttgatttgat attagactta aagaeatccc ttaetgtgag eetaetgatc aagactgaaa gggtatttge aaaatatttt gagaaactga aaeagageta ttttceatag tagctgaatt 1237 1297 1357 1417 1477 1537 1597 1657 1717 1777 1837 1862 ettgatgaea ataaaaagta aataaaagea <210> <211> <212> <213> 12 258

PRT

H. sapiens <400> 12 Met Giu Arg Lys Ile Asn Arg Arg Giu Lys Asp Gin Giu Lys Glu Tyr Giu Gly Lys His Asn Ser Leu Giu Asp Thr Thr Leu Met Thr Leu Asn Val Gly Giy Lys Asn 25 Gly Tyr Leu Tyr Cys Lys Ser Thr Gin Lys Ile Val Asn Gin Thr Leu Thr Lys Tyr Thr Phe Leu Giu His Giy Arg Lys Ile Leu Cys Pro Asp Ala Asp Gly Asn Tyr Phe Ile Asp Gly Leu Leu Phe Arg His Val Leu Phe Leu Arg Pro Asn Gly Giu Leu Leu Giu Ala Giu 115 Leu 100 Phe Giu Gly Phe Glu Asn Gin Leu Leu Ala Gin 110 Val Lys Ser Phe Gin Leu Lys 120 Leu Ala Giu WO 99/43696 WO 9943696PCT[US99/03826 Arg Trp 130 Ile Thr Giu Lys Giu Gin Leu Thr Pro 135 Arg Glu Thr Thr Phe Leu Giu Asp Asn His Arg Lys Pro Asp Phe Ser Gin Gly Leu 155 Ile Lys Ser Arg 170 Pro Giu Giu Phe 140 Arg Ile Phe Cys Ile Val Leu Lys Ser Arg Ile Ile Gin 195 Val Leu Lys Giy Phe Ser Ile Val Ser 175 Ser Asn Arg Leu Lys Tyr Phe Ile 200 Phe Ser Giu Asn Giu Asp Asn 210 Phe Glu Thr 215 Ala Vai Cys Thr Thr Leu Lys Ala Ile Met Leu Lys Cys Gly 235 His Arg Leu Leu Leu Asp Cys Gly Ser Ile Val 250 Ser Asp Ala Leu 255 Phe Ile <210> <211> <212> 13 1877

DNA

<213> H. sapiens <220> <221> <222> <223>

CDS

(322) (1090) K+Hnov27 <400> 13 caccaecgcc cccagccgcc c gtcgggeccg aegtgaaatc c gggtcggggg aaatctgcgg c cctgtggatg cggtggtggt g gccaatgggc acagaagcac c acccaggaca gtcggcccaa t 'tcgctgggg 'gaggctgcg 'eecacttcc 'gtttccgtg aattctccc aacacttaca cccaagcgcg cccaaaagac aaacacgaec acaatagttt tCctccccaa agacagccag ccctgtacga gtctgtgttc tttgtatccg cccctcggag CCCtgcctct tcttccagaa cacctgctat tgtttccec atc act aga tcc cct Ile Thr Arg Ser Pro atg tca aga cct ctg Met Ser Arg Pro Leu gca tct cca ctg awc aac caa ggc atc Ala Ser Pro Leu Xaa Asn Gin Giy Ile cct act Pro Thr 20 eca gca caa Pro Ala Gin etc aca Leu Thr 399 aaa tec aat gcg Lys Ser Asn Ala agc agc ctg gcc Ser Ser Leu Ala cct gte cac att Pro Val His Ile gtg ggc ggc cac Val Gly Gly His atg tac ac Met Tyr Thr atc gga aga Ile Giy Arg acc ctc ace Thr Leu Thr tac ect gaa tcc Tyr Pro Giu Ser ctt ttt Leu Phe gat ggt aca gag Asp Gly Thr Giu att gtt ttg gac Ile Val Leu Asp agt Ser etc aaa eag cac Leu Lys Gin His tat Tyr ttc att gac aga Phe Ile Asp Arg gga eag atg Gly Gin Met ttc aga Phe Arg tat ate ttg aat Tyr Ile Leu Asn eta ega aca tec aaa etc etc att ect gat gat ttc Leu Arg Thr Ser Lys Leu Leu Ile Pro Asp Asp Phe 23 aag gac tac act Lys Asp Tyr Thr 639 WO 9943% PCTIUS99/03826 105 100 ttg tta zar Leu Lea Tvr gag artg aa Giu Met SIu '2 5 gag gca aaa tat Glu Ala Lys Tyr ttt Phe 115 cag ctt Cag ccc Gin Leu Gin Pro atg ttg ttg Met Leu Leu 120 ttt tca agg Phe Ser Arg aga tgg aag cag Arg Trp Lys Gin gac Asp 130 aga gaa act ggt Arg Giu Thr Gly -CCC t 'Pro Cys gag tgc ctc gtc (Slu Cys Leu Val gtg Val 145 cgt gtg gcc cca Arg Val Ala Pro gac Asp 150 ctc gga. gaa agg Leu Gly Giu Arg aq~ crta agc ggt Th~r Zeu Ser Gly aaa tcc ttg ata Lys Ser Leu Ile gaa gta ttt cca Giu Val Phe Pro gag Glu 170 atc ggc gac gtg Ile GIN, Asp Val atg Met 175 tgt aac tct gtc Cys Asn Ser Val aat Asn 180 gca ggc tgg aat Ala Gly Trp Asn cac gac His Asp 185 t og aq cac Ser 'Th 1.is :tca gtc cag Ser Val (91n 5 atc: agg ttt cca Ile Arg Phe Pro cta Leu 195 aat ggc tao tgt Asn Gly Tyr Cys cac ctc aac His Leu Asn 200 gaa. atc gtg Glu Ile Val gtc ctc gag agg Val Leu Giu Arg ttg Leu 210 cag caa aga gga Gin Gin Arg Gly ggc tcc Gly Ser 2 2X ctt cgg Leu Arg 235 tgt ggg gga gga Cys Gly Gly Gly gta Val 225 gac: tcg tcc cag Asp Ser Ser Gin ttc Phe 230 agc gaa tac gtc Ser Giu Tyr Val cgg gaa ctg Arg Giu Leu agg Arg 240 cgg acg ccc cgt Arg Thr Pro Arg ccc tcc gtc atc Pro Ser Val Ile cgg Arg 250 1023 1071 1120 ata aag caa gag Ile Lys Gin Giu cct ctg Pro Leu 255 g actaaatgga catatttctt atgcaaaaag gaaaacacac caaaccaagt acctgtattc aatatatata gccgcagttg taaacaagcc catccatatt aacaaaacac gggaccaggc aattttaaat ttactttgtt tgctccagtt caataaactc acaaccaata cctggacgta atatgggaac tatatgtcaa.

gtgctgtgat atgagtggtg tcttttttcc cttgaatcaa aggacttcag gtagtttgta ttaaaactga caagtctgct tgtttaaaaa actcaaacaa aaattgaata aattggaata aaggtaggaa ggccgtgaag aggacacagt tttgtctttc gtttgtttgt aaaaaccctc cagaagtcac tcagttttgc gctttcctac ataaaaaaaa.

aaaagggaca aaagaca cat gtgatatcct atgcaaaaaa tgtcctgggc ctccttacag tttttccttt atatggaggt atgagcacat acttttttgt caaggggcca aatttttcaa aaaaaaa ttiatgtgca ttatatccaa caaggtgtaa gaaaaaaaaa ctcccgaggc tttccattgc ttttttaaaa tccacgtctt tgcaaagatg ccacctcaca gaattattcc attttataat gt tgggacag tagagaccac aaaatatata aaaggtgaca ctctgacaaa caa caacagc aaacaaaaca tctttaggca ttagacatga gatgtgaact ttgttagaat gtattaaata 1180 1240 1300 1360 1420 1480 1540 1600 1660 1720 1780 1840 1877 <210> 14 <211> 256 <212> PRT <213> H. sapiens WO 99/43696 WO 9943696PCTIUS99/03826 <220> <221> <222> <223> <400> Met Ser Arg 1 Gin Gly Ile His Ile Asp Thr Lys Tyr Pro Ile Val Giy Gin Met Leu Ile Pro Lys Tyr Phe 115 Gin Asp Arg 130 Val Arg Vai 145 Lys Ser Leu Asn Ser Val Phe Pro Leu 195 Arg Leu Gin 210 Val Asp Ser 225 Arg Thr Pro

VARIANT

(256) Xaa Any Amino Acid 14 Pro Leu 5 Pro Thr Vai Giy Pro Giu Leu Asp Phe Arg Asp Asp 100 Gin Leu Glu Thr Ala Pro Ile Glu 165 Asn Ala 180 Asn Gly Gin Arg Ser Gin Arg Val 245 Ile Pro Gly Ser Ser 70 Tyr Phe Gin Gly Asp 150 Giu Gly Tyr Gly Phe 230 Pro Thr Arg Ala Gin His Met 40 Arg Ile 55 Leu Lys Ile Leu Lys Asp Pro Met 120 Arg Phe 135 Leu Gly Val Phe Trp Asn Cys His 200 Phe Giu 215 Ser Giu Ser Val Ser Pro 10 Leu Thr 25 Tyr Thr Giy Arg Gin His Asn Phe 90 Tyr Thr 105 Leu Leu Ser Arg Giu Arg Pro Glu 170 His Asp 185 Leu Asn Ile Vai Tyr Val Ile Arg 250 Al a Lys Ser Leu Tyr Leu Leu Glu Pro Ile 155 Ile Ser Ser Gly Leu 235 Ile Ser Pro Ser Asn Ser Leu Phe Asp Phe Ile Arg Thr Leu Tyr Met Glu 125 Cys Giu 140 Thr Leu Gly Asp Thr His Val. Gin 205 Ser Cys 220 Arg Arg Lys Gin Leu Xaa Ala Pro Ala Thr Gly Thr Asp Arg Ser Lys Glu Giu 110 Arg Trp Cys Leu Ser Gly Val Met 175 Val Ile 190 Val Leu Gly Gly Giu Leu Giu Pro 255 <210> <211> 923 <212> DNA <213> H.

<22 0> <221> CDS <222> (16~ <223> K+Hj sapiens (756) aov2 <400> gcgtggtggc aggtgcctgt agccecagct acttgggagg gaacccgggc ggcgaaggtt gagtgagccg agattgcacc acagagcgag actccatctc aaaaaaaaga gtagttatgg teg cca ggc gga aag gcc ttc tgc atg gtc tat Ser Pro Gly Giy Lys Ala Phe Cys Met Val Tyr 10 is cca gcc tcc tta get ctc gtg gcc acc ctg cge Ctgaggcagg agaatagctt actgcactcc agcctgggcg Ccac atg gcc cca cta Met Ala Pro Leu 1 gca. gcc ctg ggg ctg Ala Ala Leu Gly Leu cat tgc ctg ctg cet 120 176 224 272 WO 99/43696 WO 9943696PCTIUS99/03826 Pro Ala Ser Leu Ala Leu Val Ala Thr Leu Arg His Cys Leu Leu Pro 30 gtg Val cog Pro gcc Ala ggC Gly agc Se r cac His ott Leu ctg Leu gtg Val 165 ctg ct C Leu gcc Ala ago Ser gac Asp aco Thr ccc Pro ota Leu ccg Pro 150 act Thr agc agc Ser agg Arg agc Ser tgc Cys att Ile gtg Val gga Gly 135 cag Gin got Ala ac cgo Arg gct Ala ttt Phe ago Ser ggC Gly att Ile 120 ctc Leu gtc Val gag Giu ctg oca Pro gog Ala gtg Val ctg Leu ctg Leu 105 tac Tyr t tg Leu cgt Arg gac Asp cog cgt Arg ctg Leu Ctg Leu otg Leu 90 gag Giu oac His gc Al a gc Ala oaa Gin 170 000 gco Al a otg Leu otg Leu 75 ggg Gly gao Asp otg Leu atg Met atg Met 155 ggt Gly gog tgg Trp cag Gin 60 oca Pro gc Al a ttg Leu ggo Gly otg Leu 140 ggg Gly ggc Gly gc Ala gta Val 45 gca Ala gog Ala gto Val otg Leu cag Gin 125 otg Leu aag Lys ato Ile ooa gog Ala gtt Val otg Leu tao Tyr 000 Pro 110 oto Leu goa Ala tto Phe ota Leu got gto Val gca Ala gtg Val ttc Phe 95 ggo Gly goa Ala gtg Val tto Phe ggg Gly 175 tca oao His ctg Leu ctg Leu tgC Cys ogo Arg Ott, Leu gag Giu aga Arg 160 cag Gin gga tgg Trp gga Gly tgg Trp tto Phe ggo Gly ott Leu aoo Thr 145 000 Pro gar Asp oaa oag Gin otg Leu ggo Gly ago S er ogo Arg ggt Gly 130 tto Phe agt Ser gaa Giu gc otg Leu otg Leu ott Leu tog Ser ago Ser 115 tao Tyr tot Ser ggt Gly ctg Leu oot t oa Ser gtg Val cag Gin oto Leu 100 otg Leu ttg Leu gag Giu cot Pro got Ala 180 got 320 368 416 464 512 560 608 656 704 752 806 866 923 Leu Ser Thr Leu Pro Pro Ala Pro Ala Ser Gly Gin Ala Pro Ala tgc Cys t gaagcgtcag gtgaocgagt tcagotccgt aaggtggogg oacctgagga ggaagcagoo aggagtggot ggggaagaat otggagatgg agccgoggtg agggtgggcg ggaggcctoa ggggataotg ttaatcataa aaaaaaaaaa aaaaaaaaaa aaaaaaa <210> 16 <211> 197 <212> PRT <213> H. sapiens <400> 16 Met Ala Pro Leu Ser Pro Gly Gly Lys Ala Phe Cys Met Val Tyr Ala 1 5 10 Ala Leu Gly Leu Pro Ala Ser Leu Ala Leu Val Ala Thr Leu Arg His 25 Cys Leu Leu Pro Val Leu Ser Arg Pro Arg Ala Trp Val Ala Val His 26 WO 99/43696 WO 9943696PCTIUS99/03826 Trp Gin Gly Leu Ser Pro Ala Arg Ala Ala Leu Leu Gin Vai Ala Leu Ser Leu Val Ala Phe Val Leu Trp Leu Gly Pro Ala Leu Val Gly Leu Gin Cys Ser Leu Leu Glu Ala Val Tyr Phe Cys Phe Ser Ser Gly Arg Ser Thr Ile Gly Asp Leu Leu His Pro Val His Leu Gly Pro Gly Arg 110 Leu Ala Leu Ala Val Glu 115 Tyr Leu Gly 130 Thr Phe Leu Leu Leu Leu Ala Met Leu 140 Gly Ser Giu Leu Pro Vai Arg Ala 145 Pro Lys Phe Phe Ser Gly Pro Val 165 Ala Glu Asp Gly Ile Leu Gly Gin 175 Ser Gly Asp Glu Leu Gin Ala Pro 195 Ala Leu 180 Ala Cys Ser Thr Leu Ala Ala Pro Ala 190 <210> 17 <211> 3102 <212> DNA <213> H. sapiens <220> <221> <222> <22 3>

CDS

(274) (1705) K+Hnov11 <400> 17 gcacgcgcaa agcgcccacc gagacccctg cacccccagc Ctttcctggg aggggatcag ttcagcaccc aagacccacc aggaggcctg ccccgccagg gcgcacggcg ctctcgccga ccccgcgcgg cgcgggcggc cggcgcctcc gggtggagct tgtgttaata gaaacatacc acccctcaaa Ctcttgcccc agcccagccc ggcccgccag taatgggtag ggagaggggg cgctgttccc tccgcttcca ggtgtagcgc agc atg acc ggc cag agc ctg tgg Met Thr Gly Gin Ser Leu Trp 120 180 240 294 gac gtg tcg Asp Val Ser gag gct aac gtc gag gac ggg gag atc Glu Ala Asn Val Glu Asp Gly Glu Ile is atc aat gtg Ile Asn Val ggc ggc Gly Gly ttc aag agg agg ctg cgc tcg cac acg Phe Lys Arg Arg Leu Arg Ser His Thr ctg cgc ttc ccc Leu Arg Phe Pro gag Glu acg cgc ctg ggc Thr Arg Leu Gly ttg ctg ctc tgc Leu Leu Leu Cys tcg cgc gag gcc Ser Arg Glu Ala 438 ctg gag ctc tgc Leu Glu Leu Cys gac tac gac gac Asp Tyr Asp Asp cag cgg gag ttc Gin Arg Glu Phe tac ttc Tyr Phe gac cgc aac Asp Arg Asn gag ctc ttc Glu Leu Phe ccc tac Pro Tyr gtg ctg cat ttc Val Leu His Phe tat cac acc Tyr His Thr WO 99/43696 WO 9943696PCTfUS99/03826 ggC Gly aag ctt cac gtc atg gct gag cta tgt gtc ttc tcc ttc agc cag Lys Leu His Val Met Ala Giu Leu Cys Val Phe Ser Phe Ser Gin 95 100 gag Giu agc Ser 120 gac Asp ctt Leu aac Asn gtg Vai t cc Ser 200 gac Asp cac His gtg Val gac Asp gtg Vai 280 gtc Vai tcc Ser atc Ile 105 tac Tyr gag Glu gcc Aia ttc Phe ctg Leu 185 atc Ile agc Ser ttt Phe gcc Aia ctc Leu 265 gtg Vai ctg Leu act Thr gag Giu agc Ser cag Gin ttc Phe cgc Arg 1.70 agc Ser atc Ile cag Gin Gly cct Pro 250 atg Met gag Giu agg Arg ggc Giy tac Tyr tac Tyr agt Ser tac Tyr 155 agg Arg agg Arg acc Thr ggc Gly at t Ile 235 gac Asp tcc Ser agc Ser Ctg Leu ctc Leu 315 tgg Trp cat His gac Asp 1.40 aac Asn cag Gin gt c Vai atg Met aac Asn 220 gcc Aila ttc Phe atc Ile aca Thr atg Met 300 cgc Arg ggc Giy ggc Gly 125 cag Gin gac Asp ctg Leu ttc Phe tgC Cys 205 cct Pro tgg Trp ctc Leu gtc Val cct Pro 285 Cgg Arg tcC Ser atc Ile 110 cgc Arg gag Giu gcc Ala tgg Trp agc Ser 190 ctc Leu ggc Gly ttc Phe aag Lys ccc Pro 270 act Thr atc Ile ctg Leu aac Asn aaa Lys agc Ser tcc Ser ctg Leu 175 atc Ile aat Asn gag Giu aca Thr ttc Phe 255 ttt Phe tta Leu ttc Phe ggg Giy gag Giu gta Val acc Thr aag Lys 2.60 gcg Aia ctg Leu agc Ser gac Asp ttt Phe 240 ttc Phe tac Tyr gcc Ala cgc Arg gcc Ala 320 ttc Phe gag Giu acg Thr 145 ttc Phe ctg Leu tcC Ser ctg Leu cct.

Pro 225 gag Glu aag Lys atc Ile aac Asn atc Ile 305 act Thr ttc Phe ccc Pro 130 tct Ser gat Asp gac Asp at c Ilie ccc Pro 210 agg Arg ctg Leu aat Asn act Thr ttg Leu 290 tta Leu ttg Leu att.

Ile 115 gag Glu tcc Ser ggg Giy aac Asn ctg Leu 195 gat Asp ttc Phe gtg Vai gcc Al a ctg Leu 275 ggc Giy aag Lys aaa Lys gac Asp cag Gin ttc Phe cag Gin ccc Pro 180 gtg Val ttc Phe gaa Giu gcc Ala c ta Leu 260 gtg Val agg Arg ctg Leu tac Tyr tcc S er gag Giu gat Asp ccc Pro 165 ggc Gly gtg Val caa Gin atc Ile agg Arg 245 aac Asn gtg Vai gtg Val gcc Ala agc Ser 325 tgc Cys aag Lys gag Giu 150 ctc Leu tac Tyr atg Met atc Ile gtg Vai 230 ttt Phe ctt Leu aac Asn gcc Ala agg Arg 310 tac Tyr tgc Cys tgg Trp 2.35 atc Ile Gly tca Ser ggg Gly cct Pro 215 gag Giu gct Ala att Ile ctg Leu cag Gin 295 ca c His aaa Lys 582 630 678 726 774 822 870 918 966 1.014 1062 12.10 1158 1206 1254 1302 gaa gta ggg ctg ctc ttg ctc tac ctc tcc gtg ggq att tcc atc ttc WO 99/43696 WO 9943696PCT/US99/03826 Glu Val. Gly 330 Leu Leu Leu Leu Tyr 335 Leu Ser Val Gly Ser Ile Phe tee gtg Ser Val 345 gtg gcc tac acc Val Ala Tyr Thr at t Ile 350 gaa aag gag gag Glu Lys Giu Glu gag ggc ctg gcc Giu Gly Leu Ala atc ect gec tgc Ile Pro Ala Cys tgg Trp 365 tgg tgg gct aec Trp Trp Ala Thr gtc Val.

370 agt atg acc aca Ser Met Thr Thr 1350 1398 1446 ggg tac ggg gat Gly Tyr Gly Asp gte cca ggg ace Val Pro Gly Thr gca gga aag ctg Ala Gly Lys Leu act gcc Thr Ala 390 tct gee tgc Ser Ala Cys ttg atc ttc Leu Ile Phe 410 ttg gca gge atc Leu Ala Gly Ile gtg gtg gtc ctg Val Val Val Leu ccc ate aec Pro Ile Thr 405 aag caa ctt Lys Gin Leu 1494 1542 aat aag ttc tcc Asn Lys Phe Ser cac His 415 ttt tac egg ege Phe Tyr Arg Arg gag agt Giu Ser 425 gcc atg ege age Ala Met Arg Ser gac ttt gga gat Asp Phe Gly Asp gga Gly 435 atg aag gag gte Met Lys Giu Val.

ect Pro 440 teg gte aat tta Ser Val Asn Leu gae tat tat gee Asp Tyr Tyr Ala cat His 450 aaa gtt aaa tee Lys Val Lys Ser 1590 1638 1686 1735 atg gea age ctg Met Ala Ser Leu aae atg age agg Asn Met Ser Arg age Ser 465 tea eca agt gaa Ser Pro Ser Glu ete agt Leu Ser 470 tta aat gat Leu Asn Asp tee eta egt Ser Leu Arg 475 t ageegggagg acttgteaee etccaeeeea eattgetgag aggagtatge cagtttttag atgaaatgae tgagtaeaee eeeagtaetg eaaaaagcee gagattt tge tagttttagt etaagttgtt ttagaaegat gttaaaeatg ettcagctaa cttggttcac atgaggttte ttttgaaata.

aaaagaagtt eagtagetta ccaageagaa gtgattgeee aaaatataga acttgcattc etgeetettg e cage cccetg aatcgttttt aeteaetggt eagaatgeta tetatgagtt ceaeaagtcg teaeagtcat aeeaaaaeaa tttataaatg gtaeaetgat eagtgaagat atagtceaaa agteaageet tgatctagge tttatttttt taetgttgta ataettttgt tttagteaga tggagttcct cgtgeaegat eeactgcett tgeetetgge aggggagaga agagggtggt etttgeateg atttttetgt gtegtgetee tccagtagaa gtgaaaaeaa agagaatgca atctgtagtt gttcatctca egaatttttt ccetagggtg eettgtttee eatttgaeea aagatgttta tcgtetceet tgeetaetet taattttget geeeatgaet ggtggtgtgg t eatgggggg aeageccagg tgcatgggat gtgtetgaea tgggeataaa eeategtgta tgtttetgag atgeatctat aateteaget aagttaagea cegtggcttg taaatgtcae teeeaagaae cttaaagcea tagggtgaet aaetttgctg ggagtaaggt gaggtgaaeg gaaageteat tetaggatat ggaaaeetgg ettaeecagg tgaetgta 29 caccttatgg atgeaeeeag eeatgeettt atgtteaeet egctattcta gttgtegtgt gaggteagca etttatceat gaettgaeca eatgggtgea tctttagaga agatgtgtta agttagtgea gtagagaaat tgtetaagat cgtgttgtet ttgttgggtt eaatgagage agtatgttgt tggtatggaa atggaaaeae gaggccagga ttatggtgta gtttetttta geaeetttcc tttttecaga gtget-tgtgg gagttetgta aggatatgat tgettteaet atgeaagtct eeaateatet atgttaetta gggagagggg ggetgageee gtattteegg attageatgt teeteaaeta getageaagg eettttattt atatgatget geatgtaete tgcagttctt gaaaggaaag 1795 1855 1915 1975 2035 2095 2155 2215 2275 2335 2395 2455 2515 2575 2635 2695 2755 2815 2875 2935 2995 3055 WO 99/43696 PCT/US99/03826 agttgtaaaa taaaaaactg ctagttcata aaaaaaaaaa aaaaaaa 3102 Met 1 Gly His Cys Val Val Cys Phe Glu Thr 145 Phe Leu Ser Leu Pro 225 Glu Lys Ile Asn Ile 305 Thr Ser Glu Thr Thr 385 Val <210> 18 <211> 477 <212> PRT <213> H.

<400> 18 Thr Gly Gin Glu Ile Arg Thr Leu Leu His Ser Arg Gin Arg Glu Leu His Phe Val Phe Ser 100 Phe Ile Asp 115 Pro Giu Gin 130 Ser Ser Phe Asp Gly Gin Asp Asn Pro 180 Ile Leu Val 195 Pro Asp Phe 210 Arg Phe Glu Leu Val Ala Asn Ala Leu 260 Thr Leu Val 275 Leu Gly Arg 290 Leu Lys Leu Leu Lys Tyr Val Gly Ile 340 Glu Asn Glu 355 Val Ser Met 370 Ala Gly Lys Val Val Leu sapiens Ser 5 Ile Arg Glu Phe Tyr Phe Ser Glu Asp Pro 165 Gly Val Gin Ile Arg 245 Asn Val Val Ala Ser 325 Ser Gly Thr Leu Pro 405 Leu Trp Asp Val Ser Giu Ala Asn Val Giu Asp Asn Phe Ala Tyr 70 His Ser Cys Lys Glu 150 Leu Tyr Met Ile Val 230 Phe Leu Asn Ala Arg 310 Tyr Ile Leu Thr Thr.

390 Ile Val Pro Ile 55 Phe Thr Gin Cys Trp 135 Ile Gly Ser Gly Pro 215 Glu Ala Ile Leu Gin 295 His Lys Phe Ala Val 375 Ala Thr Gly Glu 40 Leu Asp Gly Glu Ser 120 Asp Leu Asn Val Ser 200 Asp His Val Asp Val 280 Val Ser Glu Ser Thr 360 Gly Ser Leu Gly 25 Thr Glu Arg Lys Ile 105 Tyr Glu Ala Phe Leu 185 Ile Ser Phe Ala Leu 265 Val Leu Thr Val Val 345 Ile Tyr Ala Ile Phe Arg Leu Asn Leu 90 Glu Ser Gin Phe Arg 170 Ser Ile Gin Gly Pro 250 Met Glu Arg Gly Gly 330 Val Pro Gly Cys Phe Lys Leu Cys Pro 75 His Tyr Tyr Ser Tyr 155 Arg Arg Thr Gly Ile 235 Asp Ser Ser Leu Leu 315 Leu Ala Ala Asp Ile 395 Asn Arg Gly Asp Glu Val Trp His Asp 140 Asn Gln Val Met Asn 220 Ala Phe Ile Thr Met 300 Arg Leu Tyr Cys Val 380 Leu Lys Arg Leu Arg Arg Leu Leu Asp Tyr Asp Leu Phe Pro Met Ala Glu Gly Ile Asn 110 Gly Arg Lys 125 Gin Glu Ser Asp Ala Ser Leu Trp Leu 175 Phe Ser Ile 190 Cys Leu Asn 205 Pro Gly Glu Trp Phe Thr Leu Lys Phe 255 Val Pro Phe 270 Pro Thr Leu 285 Arg Ile Phe Ser Leu Gly Leu Leu Tyr 335 Thr Ile Glu 350 Trp Trp Trp 365 Val Pro Gly Ala Gly Ile Phe Ser His Ser Leu Asp Tyr Leu Glu Val Thr Lys 160 Ala Leu Ser Asp Phe 240 Phe Tyr Ala Arg Ala 320 Leu Lys Ala Thr Leu 400 Phe 410 415 Tyr Arg Arg Gin Lys Gin Leu Glu Ser Ala Met Arg Ser Cys Asp Phe -WO 99I46%i CIS9/32 PCT/US99/03826 420 Met Lys Giu Val 425 Ser Gly AqmGlY 4:3 Ala Hd.,s Lys Ser Senr Pro 4 Val Asn Leu Arg 430 Asp Tyr Tyr Met Ser Arg Val Lys Ser Ser Glu Leu Ala Ser Leu Thr Asn 460 Leu Arg Leu Asn Asp ,cml0> 19 -Q±1 0

DNA

i~3 c=22> H. sapiens

CDS

(249) (3495) K+Hnovl4 19 gggctgtag cagggatttg tgggcggcga gccccmg cgcggacgcc ccctcgcgcg tgcgcatttgc cccccgacgg ctgcgctagg gggcgritc ccccggcgcg gagtccccgc cgcctamS atg ccg gcc atg cgg ggc Met Pro Ala Met Arg Gly gggcgcgagg ggccgcgcgc catgctccgg ccagctccgg cgcgaccccg gatcccggtc agcgcggggc ccggcggggg cggccgagct accccggagg atggggcggg cagccgcggg ctc ctg gcg ccg cag aac acc ttc Leu Leu Ala Pro Gin Asn Thr Phe ctg Leu gayc acc atc gct Asp;, Thr Ile Ala cgc ttc gac ggc Arg Phe Asp Gly cac agt aac ttc His Ser Asn Phe gtg Val ctg ggc aac gcc agt ggc ggg gct ctt .Leu Gly Asn Ala Ser Gly Gly Ala Leu gtg gtc tac tgc Val Val Tyr Cys tct, gat Ser Asp ggc ttc tgt Gly Phe Cys ctc acg ggc ttc Leu Thr Gly Phe tcc Ser cgg gct gag gtc Arg Ala Giu Val atg cag cgg Met Gin Arg gag ctc gtc Glu Leu Val ggc tgt gcc tgc tcc ttc ctt Gly Cys Ala Cys Ser Phe Leu cgc caa cag atc cgc aag gc Arg Gin Gin Ile Arg Lys Ala ggg cca gac acc Gly Pro Asp Thr ctg gac gag cac Leu Asp Giu His gag ttc aag gct Glu Phe Lys Ala 482 530 578 626 gag Giu ctg atc ctg tac Leu Ile Leu Tyr aag agc ggg ctc Lys Ser Gly Leu ttc tgg tgt ctc Phe Trp Cys Leu ctg Leu 110 gat gtg ata ccc Asp Val Ile Pro aag aat gag aaa Lys Asn Giu Lys ggg Gly 120 gag gtg gct Ctc Giiu Val Ala Leu ttc cta Phe Leu 125 gtc tct cac Val Ser His gac ate agc gaa Asp Ile Ser Giu aag aac cga Lys Asn Arg ggg ggc ccc gac Gly Gly Pro Asp 140 674 aga tgg aaa gag aca ggt ggt ggecg C9gcc cga tat ggc egg gea cga Arg Trp Lys Giu Thr Giy Gly Giy Arg Arg Arg Tyr Gly Arg Ala Arg WO 99/43696 WO 9943696PCTIUS99/03826 155 ttc aat gcc aac cgg cgg cgg agc cgg gcc gtg ctc tac tcc aaa ggc Ser Lys Gly 160 Phe Asn Ala cac His 175 aat Asn gcc Ala aga Arg gtc Val gcc Ala 255 ttc Phe tcg Ser acc Thr cta Leu acg Thr 335 tac Tyr gcc Ala Arg cts Let aac Lys gcc Ala gcc Ala act Thr 240 gcc Ala atc Ile ggc Gly acc Thr cat His 320 gtg Val tcg Ser :tg Leu ;ag 1lu tcc Ser ggg Gly atc Sle acc *Thr 225 gtg Val cgc Arg ctt Leu cag Gin tgg Trp 305 gcc Ala cgc Arg cag Gin ctc Leu atc Ile 385 9gg Giy gtg Val cgg Arg 210 tgg Trp ccc Pro ggc Gly gac Asp gtg Vai 290 ttc Phe ttc Phe ctg Leu tac Tyr gcg Ala 370 gag Gliu cac His t t Phe 195 aag Lys gat Asp tac Tyr ccg Pro att Ile 275 gtg Val ctg Leu aag Lys ctg Leu agc Ser 355 cac .iis ?,gc 3er ctg Leu 180 ggg Gly t cg Ser ggc Gly agc Ser ccc Pro 260 gtg Val ttt Phe ctg Leu gtc Val cgc Arg 340 gcc Ala tgg Trp, agc Ser Asn Arg 165 cag aag Gin Lys gag aaa Giu Lys ccc tCc Pro Phe ttc atc Phe Ile 230 gtg tgt Val Cys 245 agc gtc Ser Val ctg aat Leu Asn gcc cca Ala Pro gat gtc Asp Val 310 aac gtg Asn Val 325 ctg ctg Leu Leu gtg gtg Val Val gtc gcc Val Ala gaa. tcc Giu Ser 390 Arg cag Gin cca Pro atc Ile 215 ctg Leu gtg Val tgt Cys ttc Phe aag Lys 295 atc Ile tac Tyr cgc Arg ctg Leu tgc Dys 375 ;ag Arg ccc Pro aac Asn 200 ctg Leu ctc Leu agc Ser gac Asp cgt Arg 280 tcC Ser gca Ala ttc Phe ctg Leu aca Thr 360 gtc Val Ser aag Lys 185 ttg Leu Ctg Leu gcc Ala aca Thr ctg Leu 265 acc Thr at Ile gcg Ala ggg Gly ctt Leu 345 ctg Leu egg Trp Arg 170 ggc Gly cct.

Pro ca c His aca Thr gca.

Ala 250 gcc Ala aca Thr tgc Cys ctg Leu gcc Ala 330 ccg Pro ctc Leu

CCC

Phe Ala aag Lys gag Giu tgt Cys ctc Leu 235 cgg Arg gtg Val ttc Phe ctc Leu ccc Pro 315 cat His cgg Arg atg Met tac Tyr Val cac His tac Tyr ggg Gly 220 tat Tyr gag Glu gag Giu gtg Val1 cac His 300 ttt Phe ctg Leu ctg Leu gcc Ala att.

Ile 380 Leu aag Lys aaa Lys 205 gca Ala gtg Val ccc Pro gt c Val tC Ser 285 tac Tyr gac Asp ctg Leu gac Asp gtg Val 365 9gc Gly Tyr ctc Leu 190 gta Val ctg Leu gct Ala agt Ser ctc Leu 270 aag Lys gtc Val ctg Leu aag Lys cgg Arg 350 ttc Phe cag Gin 770 818 866 914 962 1010 1058 1106 1154 1202 1250 1298 1346 1394 1442 ctg cct gag at 3iu Leu Pro Giu le ggc Cgg ctg Gly Trp Leu WO 99/43696 WO 9943696PCTIUJS99/03826 cag gag etg gcc cgc cga ctg gag act eec tac tac Gin Giu Leu Ala Arg Arg Leu Giu Thr Pro Tyr Tyr ctg gtg gge cgg Leu Val Gly Arg 400 405 410 agg Arg 415 age Ser ctg Leu acc Thr ate Ile gtg Val 495 ttt Phe cac His gcc Ala agc Ser gag Giu 575 cgg Arg tac Tyr tet Ser cca Pro age Ser ege Arg agc Ser ttc Phe 480 ttt Phe ctg Leu cgt Arg ace Thr ctc Leu 560 gtc Val gca Ala Ct C Leu ggc Gly gct Ala gag Giu agc Ser gtg Val 465 tc Ser ggg Gly tac Tyr ate Ile tgg Trp 545 cet Pro ctg Leu ctg Leu atc Ile tcc Ser 625 gga Gly gcc Ala gcc Ala 450 ggc Gly ate Ile aac Asn cac His ccc Pro 530 gcg Ala gac Asp cag Gin tet Ser eac His 610 atg Met ggg Gly aac Asn 435 tac Tyr ttc Phe tgc Cys gtg Val agc Ser 515 aag Lys gtg Val gag Giu etg Leu ctg Leu 595 caa Gin gag Giu aac Asn 420 ggg Giy atc Ile gge Gly acc Thr aeg Thr 500 cgc Arg ec Pro aae Asn ctg Leu cca Pro 580 gcc Ala ggc Gly gtg Val age Ser acg Thr ace Thr aac Asn atg Met 485 gc Ala acg Thr etc Leu aat Asn cge Arg 565 etg Leu etg Leu gat Asp etc Leu tee gge Ser Gly ggg etg Giy Leu tee etc Ser Leu 455 gtg tee Val Ser 470 etc ate Leu Ile ate ate Ile Ile ege gae Arg Asp aag cag Lys Gin 535 gge ate Gly Ile 550 gea gac Ala Asp ttt gag Phe Giu egg c Arg Pro gee Ctg Ala Leu 615 aag ggt Lys Gly 630 eag Gin gag Giu 440 tac Tyr gee Ala ggC Gly cag Gin eag Gin 520 ege Arg gac Asp ate Ile geg Ala gee Ala 600 cag Gin gge Gly agt S er 425 etg Leu ttc Phe aa e Asn gee Ala ege Arg 505 cgc Arg atg Met acc Thr gee Ala gee Ala 585 tte Phe gee Ala ace Thr gac Asp etg Leu gca Ala aeg Thr e tg Leu 490 atg Met gac Asp etg Leu ace Thr atg Met 570 age Ser tgc Cys etc Leu gtg Val aac Asn gge Gly etc Leu gac Asp 475 atg Met tac Tyr tac Tyr gag Giu gag Giu 555 eac His ege Arg aeg Thr tae Tyr etc Leu 635 tge Cys ggc Gly age Ser 460 ace Thr cac His gee Ala ate Ile tae Tyr 540 ctg Leu etg Leu gge Gly ceg Pro ttt Phe 620 gee Ala age Ser ceg Pro 445 age Ser gag Giu geg Ala ege Arg ege Arg 525 tte Phe etg Leu cac His tge Cys ggc Gly 605 gt c Vai ate Ile age Ser 430 t eg Ser etc Leu aag Lys gtg Val ege Arg 510 ate Ile cag Gin eag Gin aag Lys etg Leu 590 gag Giu tgc Cys eta Leu 1490 1538 1586 1634 1682 1730 1778 1826 1874 1922 1970 2018 2066 2114 2162 WO 99/43696 WO 9943696PCTIUS99/03826 aag Lys 640 aag Lys ctg Leu gc Al a ggt Gly gac Asp 720 cag Gin ctg Leu tcee Ser cca Pro eca Pro 800 ccc Pro ggc Gly gaa Glu gtt Val ggc Gly gcc Ala cag Gin ceg Pro get Al a 705 aat Asn ggc Gly ctg Leu cca Pro ggc Gly 785 cgg Arg cca Pro tcg Ser tgt Cys ccc Pro 865 gac Asp aat Asn ctg Leu cge Arg 690 ggg Gly ace Thr ccc Pro tee Ser cgt Arg 770 agg Arg gcc Ala gat Asp gac Asp agc Ser 850 cat His etg Leu gc Ala get Ala 675 ttc Phe gga Gly ctt Leu acg Thr oct Pro 755 cga Arg gca Ala cta Leu c tg Leu cag Gin 835 agc Ser ggg Gly ctg Leu ctg Leu age Ser 680 ega Arg gtg Val gag Glu cca Pro tea Ser 760 cot Pro get Ala etg Leu gta.

Val ttC Phe 840 gga Gly agg Arg egg Arg 650 ta e Tyr geg Al a gag Glu ace Thr aag Lys 730 gat Asp tea.

Ser eta Leu get.

Al a ccc Pro 810 ggc Gly gtg Val gag Giu aca Thr egg Arg tgc Cys etg Leu etc Leu age Ser 715 gag Giu gag Glu get Ala ggt Gly ggc Gly 795 atg Met att Ile gge Gly age Ser gac Asp gag Giu gte Val t ac Tyr age Se r 700 tee S er aca Thr ccc Pro gee Ala ggc Gly 780 ccc Pro eca Pro gaa Giu eag Gin Gly 860 aca Thr 2210 2258 2306 2354 2402 2450 2498 2546 2594 2642 2690 2738 2786 2834 2882 2930 875 aag ett egg eag geg gtg aca gag etg tea. gag cag gtg etg eag atg WO 99/43696 WO 9943696PCTIUS99/03826 Lys Leu Arg G1~ 880 cgg gaa gga Ctc Arg Glu Gly Lei 895 ccc cac agg gac Pro His Arg G1i cca gcc agc ac( Pro Ala Ser Th 93( gca tcc tcc tac Ala Ser Ser Ty 945 act tgg ccc cac Thr Trp Pro Hi~ 960 ccc tgg ggt ccc Pro Trp Gly Prc 975 gct ttc tgg acc Ala Phe Trp Thj ctc tgc tct gac Leu Cys Ser Gli 101( ggg gct agg act Gly Ala Arg Thi 1025 agc act gga ga Ser Thr Gly Gli 1040 gac ccc cac agc Asp Pro His Se2 055 aca gtc cag tg Thr Val Gln Trj cctagaactc agcc aggcagggtg gcac tggaagcaaa ggaS aggcctctcc tcgS ggcctgagga caac ccaaattttt atat n Ala Val Thr Glu Leu Ser Glu Gin Val Leu Gln Met 885 890 g cag tca ctt cgc cag gct gtg cag ctt gtc ctg gcg u Gln Ser Leu Arg Gln Ala Val Gin Leu Val Leu Ala 900 905 910 9 ggt ccg tgc cct cgg gca tcg gga gag ggg ccg tgc ui Gly Pro Cys Pro Arg Ala Ser Gly Glu Gly Pro Cys 915 920 925 ctcc ggg ctt ctg cag cct ctg tgt gtg gac act ggg r Ser Gly Leu Leu Gln Pro Leu Cys Val Asp Thr Gly 0 935 940 *tgc ctg cag ccc cca gct ggc tct gtc ttg agt ggg Cys Leu Gln Pro Pro Ala Gly Ser Val Leu Ser Gly 950 955 *cct cgt ccg ggg cct cct ccc ctc atg gca ccc cgg *Pro Arg Pro Gly Pro Pro Pro Leu Met Ala Pro Arg 965 970 :cca gcg tct cag agc tcc ccc tgg cct cga gcc aca Pro Ala Ser Gin Ser Ser Pro Trp Pro Arg Ala Thr 980 985 990 tcc acc tca gac tca gag ccc cct gcc tca gga gac Ser Thr Ser Asp Ser Glu Pro Pro Ala Ser Gly Asp- 995 1000 1005 Sccc agc acc cct gcc tcc cct cct cct tct gag gaa aPro Ser Thr Pro Ala Ser Pro Pro Pro Ser Glu Glu 1015 1020 ggg ccc gca gag cct gtg agc cag gct gag gct acc Gly Pro Ala Glu Pro Val Ser Gin Ala Glu Ala Thr 1030 1035 ccc cca cca ggg tca ggg ggc ctg gcc ttg ccc tgg Pro Pro Pro Gly Ser Gly Gly Leu Ala Leu Pro Trp, 1045 1050 ctg gag atg gtg ctt att ggc tgc cat ggc tct ggc Leu Glu Met Val Leu Ile Gly Cys His Gly Ser Gly 1060 1065 1070 acc cag gaa gaa ggc aca ggg gtc t gagtaccagc Thr Gin Glu Giu Gly Thr Gly Val 1075 1080 ~ttgcca ggtgtgctgc catctgctgt tcggcccaac ctcagagtga ~cctccc cacggactcc atgcggcccg ctggctcagg gcagggagcc ~gacctg gctcctgact ctcagagagg ataggctgga tccctggggc rcctgct cctctgacct cccggtctcc ctctgcaggc tgggggcaga ~gaagag ctttgccatc ccctgcatgt gcccctgcct ctacctgtcc :taaaaa aaaaaataaa ataaactaaa aaaaaaaaaa aa 2978 3026 3074 3122 3170 3218 3266 3314 3362 3410 3458 3505 3565 3625 3685 3745 3805 3857 <210> <211> 1082 <212> PRT WO 99/43696 WO 9943696PCTIUS99/03826 <213> H. sapiens <400> Met Pro 1 Thr Ile Asn Ala Cys Asp Ala Cys Gin Ilie Ile Leu Ile Pro His Lys 130 Lys Giu 145 Gly Phe Ser Gly Gly Vai Ile Arg 210 Thr Trp 225 Val Pro Arg Giy Leu Asp Gin Val 290 Trp Phe 305 Ala Phe Arg Leu Gin Tyr Leu Ala 370 Ile Glu 385 Leu Ala Ala Gly Giu Ala Ser Ala 450 Ala Ala Ser Leu Ser Arg Tyr Ilie 115 Asp Thr Asn His Phe 195 Lys Asp Tyr Pro Ile 275 Val Leu Lys Leu Ser 355 His Ser Arg Gly Asn 435 Tyr Met Thr Gly Thr Phe Lys Arg 100 Lys Ile Gly Ala Leu 180 Gly Ser Gly Ser Pro 260 Vai Phe Leu Val Arg 340 Ala Trp Ser Arg Asn 420 Gly Ile Arg 5 Arg Gly Gly Leu Aia Lys Asn Ser Gly Asn 165 Gin Glu Pro Phe Val 245 Ser Leu Ala Asp Asn 325 Leu Val Val Glu Leu 405 Ser Thr Thr Gly Leu Phe Asp Ala Leu Phe Ser 55 Tyr Gly 70 Leu Asp Ser Gly Giu Lys Glu Thr 135 Gly Arg 150 Arg Arg Lys Gin Lys Pro Phe Ilie 215 Ile Leu 230 Cys Val Vai Cys Asn Phe Pro Lys 295 Val Ile 310 Val Tyr Leu Arg Val Leu Ala Cys 375 Ser Glu 390 Glu Thr Ser Gly Gly Leu Ser Leu 455 Leu Gly Pro 40 Arg Pro Giu Leu Gly 120 Lys Arg Arg Pro Asn 200 Leu Leu Ser Asp Arg 280 Ser Ala Phe Leu Thr 360 Val Leu Pro Gin Giu 440 Tyr Ala Thr 25 Val Ala Asp His Pro 105 Giu Asn Arg Ser Lys 185 Leu Leu Al a Thr Leu 265 Thr Ile Ala Gly Leu 345 Leu Trp Pro Tyr Ser 425 Leu Phe Pro 10 His Val Giu Thr Lys 90 Phe Val Arg Tyr Arg 170 Gly Pro His Thr Ala 250 Ala Thr Cys Leu Ala 330 Pro Leu Phe Glu Tyr 410 Asp Leu Ala Gin Ser Tyr Val Ser 75 Giu Trp Ala Gly Gly 155 Ala Lys Glu Cys Leu 235 Arg Val Phe Leu Pro 315 His Arg Met Tyr Ile 395 Leu Asn Gly Leu Asn Thr Asn Phe Cys Ser Met Gin Giu Leu Phe Lys Cys Leu Leu Phe 125 Gly Pro 140 Arg Ala Val Leu His Lys Tyr Lys 205 Gly Ala 220 Tyr Val Giu Pro Giu Val Val Ser 285 His Tyr 300 Phe Asp Leu Leu Leu Asp Ala Val 365 Ile Gly 380 Gly Trp Val Gly Cys Ser Gly Pro 445 Ser Ser 460 Phe Val Asp Arg Val Ala Leu 110 Leu Asp Arg Tyr Leu 190 Val Leu Ala Ser Leu 270 Lys Val Leu Lys Arg 350 Phe Gin Leu Arg Ser 430 Ser Leu Leu Leu Gly Gly Arg Giu Asp Val Arg Ser His 175 Asn Ala Arg Val Ala 255 Phe Ser Thr Leu Thr 335 Tyr Ala Arg Gin Arg 415 Ser Leu Thr Asp Gly Phe Cys Gin Leu Val Ser Trp Lys 160 Leu Lys Ala Ala Thr 240 Ala Ile Gly Thr His 320 Val Ser Leu Glu Glu 400 Pro Ser Arg Ser WO 99/43696 PCT/US99/03826 Val Gly Phe Gly Asn Val Ser Ala Asn Thr Asp Thr Glu Lys Ile Phe 465 470 475 480 Ser Ile Cys Thr Met Leu Ile Gly Ala Leu Met His Ala Val Val Phe 485 490 495 Gly Asn Val Thr Ala Ile Ile Gin Arg Met Tyr Ala Arg Arg Phe Leu 500 505 510 Tyr His Ser Arg Thr Arg Asp Gin Arg Asp Tyr Ile Arg Ile His Arg 515 520 525 Ile Pro Lys Pro Leu Lys Gin Arg Met Leu Glu Tyr Phe Gin Ala Thr 530 535 540 Trp Ala Val Asn Asn Gly Ile Asp Thr Thr Glu Leu Leu Gin Ser Leu 545 550 555 560 Pro Asp Glu Leu Arg Ala Asp Ile Ala Met His Leu His Lys Glu Val 565 570 575 Leu Gin Leu Pro Leu Phe Glu Ala Ala Ser Arg Gly Cys Leu Arg Ala 580 585 590 Leu Ser Leu Ala Leu Arg Pro Ala Phe Cys Thr Pro Gly Glu Tyr Leu 595 600 605 Ile His Gin Gly Asp Ala Leu Gin Ala Leu Tyr Phe Val Cys Ser Gly 610 615 620 Ser Met Glu Val Leu Lys Gly Gly Thr Val Leu Ala Ile Leu Gly Lys 625 630 635 640 Gly Asp Leu Ile Gly Cys Glu Leu Pro Arg Arg Glu Gin Val Val Lys 645 650 655 Ala Asn Ala Asp Val Lys Gly Leu Thr Tyr Cys Val Leu Gin Cys Leu 660 665 670 Gin Leu Ala Gly Leu His Asp Ser Leu Ala Leu Tyr Pro Glu Phe Ala 675 680 685 Pro Arg Phe Ser Arg Gly Leu Arg Gly Glu Leu Ser Tyr Asn Leu Gly 690 695 700 Ala Gly Gly Gly Ser Ala Glu Val Asp Thr Ser Ser Leu Ser Gly Asp 705 710 715 720 Asn Thr Leu Met Ser Thr Leu Glu Glu Lys Glu Thr Asp Gly Glu Gin 725 730 735 Gly Pro Thr Val Ser Pro Ala Pro Ala Asp Glu Pro Ser Ser Pro Leu 740 745 750 Leu Ser Pro Gly Cys Thr Ser Ser Ser Ser Ala Ala Lys Leu Leu Ser 755 760 765 Pro Arg Arg Thr Ala Pro Arg Pro Arg Leu Gly Gly Arg Gly Arg Pro 770 775 780 Gly Arg Ala Gly Ala Leu Lys Ala Glu Ala Gly Pro Ser Ala Pro Pro 785 790 795 800 Arg Ala Leu Glu Gly Leu Arg Leu Pro Pro Met Pro Trp Asn Val Pro 805 810 815 Pro Asp Leu Ser Pro Arg Val Val Asp Gly Ile Glu Asp Gly Cys Gly 820 825 830 Ser Asp Gin Pro Lys Phe Ser Phe Arg Val Gly Gin Ser Gly Pro Glu 835 840 845 Cys Ser Ser Ser Pro Ser Pro Gly Pro Glu Ser Gly Leu Leu Thr Val 850 855 860 Pro His Gly Pro Ser Glu Ala Arg Asn Thr Asp Thr Leu Asp Lys Leu 865 870 875 880 Arg Gin Ala Val Thr Glu Leu Ser Glu Gin Val Leu Gin Met Arg Glu 885 890 895 Gly Leu Gin Ser Leu Arg Gin Ala Val Gin Leu Val Leu Ala Pro His 900 905 910 Arg Glu Gly Pro Cys Pro Arg Ala Ser Gly Glu Gly Pro Cys Pro Ala 915 920 925 Ser Thr Ser Gly Leu Leu Gin Pro Leu Cys Val Asp Thr Gly Ala Ser 930 935 940 Ser Tyr Cys Leu Gin Pro Pro Ala Gly Ser Val Leu Ser Gly Thr Trp WO "/436% WO 9943696PCTIUS99/03826 945 Pro His Pro Gly Pro Pro Trp, Thr Ser 995 Ser Glu Pro 1010 Arg Thr Gly Arg Pro 965 Ala Ser 950 Gly Pro Pro Pro Gin Ser Ser Pro 985 Asp Ser Glu Pro 1000 Pro Ala Ser Pro 1015 Glu Pro Val Ser 955 Met Ala Pro Arg Leu 970 Trp 960 Pro Trp 975 Pro Arg Ser Ser Thr Pro Ala Pro Ala Ser Pro Pro Ser 1020 Gin Ala Giu 1035 Leu Ala Leu Ala Thr Ala Phe 990 Gly Asp Leu Cys 1005 Glu Glu Gly Ala Ala Thr Ser Thr 104 Pro Trp Asp Pro 1055 Ser Gly Thr Val 1070 1025 Gly G1u Pro 1030 Pro Pro Gly Ser 1045 Gly Gly 1050 His Ser Leu Glu Met 1060 Gin Trp Thr Gin Glu 1075 Val Leu Ile Gly Cys 1065 Glu Gly Thr Gly Val 1080 His Gly <210> 21 <211> 1800 <212> DNA <213> H. sapiens <220> <221> CDS <222> (346) (1057) <223> K+Hnov28, splice 1 <400> 21 atttgaatga ctgggttact tttctctgaa aatcttcagt acatgtagaa ggccctaggg cagctgagca aggacgagta actttcttct ctattttcct agtttccctg aaacctgggc tcctagactc ctcttagttc gaatgctttc gtttttctgg agttatatat tcttgaagac ttcctccttC oagatgggt t ttccccagat tgtttggcct gctatcatat gcatcactgg tcttaagtac agtatagttc ctctatggta ggaatacagg ctttgccctg tagtaggttt cctctgttgg gtggaaaaag gtctgttttt ctoctcttga agcag atg gat aat gga Met Asp Asn Gly 1 gac Asp tgg ggc tat atg atg act gac cca gtc aca tta aat gta ggt Trp Gly Tyr Met Met Thr Asp Pro Val Thr Leu Asn Val Gly 10 cac ttg tat aca acg tot ctc acc aoa His Leu Tyr Thr Thr Ser Leu Thr Thr atg ott gga got atg ttt ggg ggg gao Met Leu Gly Ala Met Phe Gly Gly Asp 45 ttg Leu 30 acg ogt tao cog Thr Arg Tyr Pro gat too Asp Ser ttc ccc aca gct Phe Pro Thr Ala cga gao cot Arg Asp Pro cga tat gtc Arg Tyr Val caa ggc aat Gin Gly Asn tao ttt att gat Tyr Phe Ile Asp gat gga cct ott Asp Gly Pro Leu oto aac Leu Asn tto tta aga act Phe Leu Arg Thr gaa ttg acc tta Giu Leu Thr Leu ttg gat ttt aag Leu Asp Phe Lys gaa Glu ttt gat ctg ctt Phe Asp Leu Leu aaa gaa gca gat Lys Glu Ala Asp ttt tao cag att gag ccc Phe Tyr Gin Ile Glu Pro 95 100 WO 99/43696 WO 9943696PCTfUS99/03826 ttg att cag tgt Leu Ile Gin Cys ctc Leu 105 aat gat oct aag Asn Asp Pro Lys ttg tat ccc atg Leu Tyr Pro Met gat act Asp Thr 115 ttt gaa gaa Phe Giu Glu tcc aac cca Ser Asn Pro 135 gtg gag ctg tot Vai Giu Leu Ser act cgg aag ott Thr Arg Lys Leu tot aag tao Ser Lys Tyr 130 aco act aag Thr Thr Lys gtg got gto ato Vai Ala Val Ile ata Ile 140 acg oaa ota acc Thr Gin Leu Thr gtc cat Val His 150 too tta ota gaa Ser Leu Leu Glu ggc Gly 155 ato tca aat tat Ile Ser Asn Tyr aco aag tgg aat Thr Lys Trp Asn aag Lys 165 cac atg atg gac His Met Met Asp aco Thr 170 aga gao tgo cag Arg Asp Cys Gin gtt Val 175 tcc ttt act ttt Ser Phe Thr Phe ccc tgt gat tat Pro Cys Asp Tyr cac His 185 cag gaa gtt tot Gin Glu Val Ser agg gtc cac ctg Arg Val His Leu atg gaa Met Glu 195 tao att aca Tyr Ile Thr atg agt gag MetSer Glu 215 caa ggt tto acg Gin Gly Phe Thr ato Ile 205 cgc aao acc cgg Arg Asn Thr Arg gtg oat cac Val His His 210 tgg act tto Trp, Thr Phe ogg goc aat gaa Arg Ala Asn Giu aac Asn 220 aca gtg gag cac Thr Vai Glu His aac Asn 225 1029 tgt agg Cys Arg 230 ota gcc cgg aag Leu Ala Arg Lys aca gao gao Thr Asp Asp 235 t gatotoogac ootgccacag gttcctggaa tgagatattt aagttttgtg gootgttoag tataatotao ggtccotaao tgatgcottt taagtagtat aotgttttt atctgtagoo tccotgtggt otaooagaaa aaa agactotoca tttttctttt ctttggoaga agtotocaga oottaaoaga toaaotagaa gagaaaaato tgtaatatta aoagttatga atggaaatgt agaaaaotta aaaaaaacaa ggaaatggaa aaatagttgt Otcctooatg taoctttttt gcttttctta ggotaaaaat aaaacatoat aaggaaaact oaactgtttc otgactagaa Ctctttatgc aactaataaa gatactgatt.

atttatttga ttttgttooo ataaaaagaa ttaoagtgct aoaagaatga gtagggtgac gttocaatoa tttotatgca atatttatat ctggtgcagt aaatgaaata ttttttttta aggcagtgag ttccoootga gtctgaaaat aaaatgattt aagaataagc otagtttoca tttaaaagta tataaatcaa tgaatt otga ataattccca tgaaaaaaaa aatcaoagtg gaooagaagg gtatgoatgt oattatggta ctgataaaat agagtactca aaooaataaa cttattaagt ggaaccaaat ataoaaaatg agtgtaotgt aaaaaaaaaa 1077 1137 1197 1257 1317 1377 1437 1497 1557 1617 1677 1737 1797 1800 <210> <211> <212> <213> <220> <221> <222> <223> 22 1836

DNA

H. sapiens

CDS

(382) (1093) K+Hnov28 splice 2 WO 99/43696 WO 9943696PCTIUJS99/03826 <400> 22 gaggaatgtt atgattttgt acctatagct tctctcttct ttgtagagaa aaatccattt ttatccttgt atgcctggct cctttagatg tcgctgaact tcaagaagag caaaactcaa gaagacgcat cactggagca gactatttgt agaccacatg ctgcagtggt acttgtgctg agttactata tacaaggcaa gacagctttt gttgggaaag atggttaagg gcctgtatgt aaaagtattt ttttgaagtt taatattagg gagaaagaga ataatctaac gaatgttaac cgctttcaaa t ccctgaaac tcacttttaa aaatgattac cataatcaca cccaaagact ctcccacatt ctgggctctt g atg gat aat gga Met Asp Asn Gly gac Asp tgg ggc tat atg atg Trp Gly Tyr Met Met act gac cca gtc Thr Asp Pro Val tta aat gta ggt Leu Asn Val. Gly cac ttg tat aca His Leu Tyr Thr acg tct Thr Ser ctc acc aca Leu Thr Thr ggg ggg gac Gly Gly Asp acg cgt tac ccg Thr Arg Tyr Pro gat tcc atg ctt gga gct atg ttt Asp Ser Met Leu Gly Ala Met Phe gac cct caa ggc aat tac ttt att Asp Pro Gin Gly Asn Tyr Phe Ile ttc ccc aca gct Phe Pro Thr Ala gat cga Asp Arg gat gga cct ctt ttc cga tat gtc ctc aac ttc tta aga act Asp Gly Pro Leu Phe Arg Tyr Val Leu Asn Phe Leu Arg Thr gaa ttg acc tta Giu Leu Thr Leu ttg gat ttt aag Leu Asp Phe Lys ttt gat ctg ctt Phe Asp Leu Leu aaa gaa gca gat Lys Giu Ala Asp tac cag att gag Tyr Gin Ile Giu ttg att cag tgt Leu Ile Gin Cys ctc aat Leu Asn 105 gat cct aag Asp Pro Lys ctg tct agt Leu Ser Ser 125 ttg tat ccc atg gat act ttt gaa gaa Leu Tyr Pro Met Asp Thr Phe Glu Giu gtt gtg gag Val. Val Giu 120 act cgg aag ctt Thr Arg Lys Leu tct.

Ser 130 aag tac tcc aac cca gtg gct gtc Lys Tyr Ser Asn Pro Vai Aia Val 135 atc ata Ile Ile 140 acg caa cta acc Thr Gin Leu Thr atc Ile 145 acc act aag gtc Thr Thr Lys Val cat His 150 tcc tta cta gaa Ser Leu Leu Giu ggc Giy 155 atc tca aat tat Ile Ser Asn Tyr acc aag tgg aat Thr Lys Trp Asn aag Lys 165 cac atg atg gac His Met Met Asp acc Thr 170 843 891 939 aga gac tgc cag Arg Asp Cys Gin tcc ttt act Ser Phe Thr ttt gga Phe Gly 180 ccc tgt gat tat Pro Cys Asp Tyr cac cag His Gin 185 gaa gtt tct Giu Val Ser agg gtc cac ctg Arg Vai His Leu gaa tac att. aca Giu Tyr Ile Thr aaa caa ggt Lys Gin Gly 200 ttc acg atc cgc aac acc cgg gtg cat cac atg agt gag cgg gcc aat Phe Thr Ile Arg Asn Thr Arg Va. His His Met Ser Giu Arg Ala Asn 1035 WO 99/43696 WO 9943696PCTIUS99/03826 gaa aac aca gtg gag cac aac tgg act ttc tgt agg cta gcc egg aag Glu Asn Thr Val Glu His Asn Trp Thr Phe Cys Arg Leu Ala Arg Lys 220 225 230 aca gac gac t gatctccgac cctgeeacag gttcctggaa agaetctcca Thr Asp Asp 235 1083 1133 ggaaatggaa aaatagttgt ctcctccatg tacctttttt gcttttctta ggctaaaaat aaaacatcat aaggaaaact eaactgtttc ctgaetagaa ctctttatgc aactaataaa gatactgatt atttatttga ttttgttccc ataaaaagaa ttacagtgct acaagaatga gtagggtgac gttccaatca tttctatgca atatttatat ctggtgcagt aaatgaaata ttttttttta aggcagtgag ttccccetga gtctgaaaat aaaatgattt aagaataagc ctagtttcca tttaaaagta tataaatcaa tgaattctga ataattccca tgaaaaaaaa aateacagtg gaccagaagg gtatgcatgt cattatggta ctgataaaat agagtactca aaccaataaa cttattaagt ggaaccaaat atacaaaatg agtgtactgt aaaaaaaaaa.

tgagatattt aagttttgtg gcctgttcag tataatctac ggtccctaac tgatgccttt taagtagtat actgcttttt atetgtagcc tccctgtggt ctaccagaaa aaa.

tttttctttt ctttggcaga agtetccaga ccttaacaga tcaactagaa gagaaaaatc tgtaatatta acagttatga atggaaatgt agaaaactta aaaaaaacaa 1193 1253 1313 1373 .1433 1493 1553 1613 1673 1733 1793 1836 <210> 23 <211> 1751 <212> DNA <213> H. sapiens <220> <221> CDS <222> (297) (1008) <223> K+Hnov28 splice 3 <400> 23 ccatgtttet taccatgtct tgccagagct ggttgatttg ggattgaagt gtgtgagagg aactgtttgt ttaaatgctt ttgaattgta gtatctgagc atttcteagt gtcttaaggc ctcatctata tcgttteect gaaacctggg ttagaaattt gaaetgacta gataaaaata.

tggctctcca ctcttgaaga gctctgcagt aggcagttca aattcacatt tgagtgctgg cgcatcactg ttgctttaca gtagctggga ggeatcatta ctgattgaet gagcag atg Met gat aat gga Asp Asn Gly gta ggt gga Val Gly Gly tgg ggc tat atg Trp Gly Tyr Met act gac cca gte Thr Asp Pro Val aca tta aat Thr Leu Asn aeg egt tac Thr Arg Tyr 347 395 cac ttg tat aca His Leu Tyr Thr tet cte acc aca Ser Leu Thr Thr ecg gat Pro Asp ega gac Arg Asp tcc atg ctt gga Ser Met Leu Gly atg ttt ggg ggg, Met Phe Gly Gly gac ttc ccc Asp Phe Pro gat gga cct Asp Gly Pro cct caa ggc Pro Gin Gly tac ttt att gat Tyr Phe Ile Asp aca get Thr Ala ctt ttc Leu Phe ceg ttg Pro Leu ega tat gte etc Arg Tyr Val Leu ttc tta aga act Phe Leu Arg Thr tea Ser gaa ttg ace tta Glu Leu Thr Leu WO 99/43696 WO 9943696PCTIUS99/03826 gat ttt aag Asp Phe Lys att gag ccc Ile Giu Pro 100 gaa Giu ttt gat ctg ctt Phe Asp Leu Leu aaa gaa gca gat LYS Giu Ala Asp ttt tac cag Phe Tyr Gin ttg tat ccc Leu Tyr Pro 587 635 ttg att cag tgt Leu Ile Gin Cys ctc Leu 105 aat gat cct aag Asn Asp Pro Lys atg gat Met Asp 115 act ttt gaa gaa Thr Phe Giu Giu gtg gag ctg tct Val Giu Leu Ser act cgg aag ctt Thr Arg Lys Leu aag tac tcc aac Lys Tyr Ser Asn gtg gct. gtc atc Val Ala Val Ile ata Ile 140 acg caa cta acc Thr Gin Leu Thr acc act aag gtc Thr Thr Lys Vai tcc tta cta gaa Ser Leu Leu Giu ggc Giy 155 atc tca aat tat Ile Ser Asn Tyr ttt acc Phe Thr 160 aag tgg aat Lys Trp Asn act ttt gga Thr Phe Gly 180 aag Lys 165 cac atg atg gac His Met Met Asp aga gac tgc cag Arg Asp Cys Gin gtt tcc ttt Val Ser Phe 175 agg gtc cac Arg Val His ccc tgt gat tat Pro Cys Asp Tyr cag gaa gtt tct Gin Giu Val Ser ctg atg Leu Met 195 gaa tac att aca Giu Tyr Ile Thr aaa Lys 200 caa ggt ttc acg Gin Gly Phe Thr atc Ile 205 cgc aac acc cgg Arg Asn Thr Arg gtg Val 210 cat cac atg agt gag cgg gcc aat gaa His His Met Ser Giu Arg Aia Asn Giu 215 aca gtg gag cac Thr Val Giu His aac Asn 225 tgg act ttc tgt Trp Thr Phe Cys agg Arg 230 cta gcc cgg aag Leu Aia Arg Lys aca gac gac: Thr Asp Asp 235 t gatctccgac 1018 cctgccacag gttcctggaa aatcacagtg tgagatattt gaccagaagg aagttttgtg gtatgcatgt gcctgttcag cattatggta tataatctac ctgataaaat ggtccctaac agagtactca tgatgccttt.

aaccaataaa taagtagtat cttattaagt actgcttttt ggaaccaaat atctgtagcc atacaaaatg tccctgtggt agtgtactgt ctaccagaaa aaaaaaaaaa aaa agactctcca tttttctttt, ctttggcaga agtctccaga ccttaacaga tcaactagaa gagaaaaatc tgtaatatta acagttatga atggaaatgt agaaaactta aaaaaaacaa ggaaatggaa aaatagttgt ctcctccatg tacctttttt gcttttctta ggctaaaaat aaaacatcat aaggaaaact.

caactgtttc ctgactagaa ctctttatgc aactaataaa gatactgatt atttatttga ttttgttccc ataaaaagaa ttacagtgct acaagaatga gtagggtgac gttccaatca tttctatgca atatttatat ctggtgcagt aaatgaaata ttttttttta aggcagtgag ttccccctga gtctgaaaat aaaatgattt aagaataagc ctagtttcca tttaaaagta tataaatcaa tgaattctga ataattccca tgaaaaaaaa 1078 1138 1198 1258 1318 1378 1438 1498 1558 1618 1678 1738 1751 <210> 24 <211> 1542 <212> DNA <213> H. sapiens <220> WO 99/43696 WO 9943696PCTIUS99/03826 <221> CDS <222> (88) (799) <223> K+Hnov28, splice 4 <400> 24 cgggcatctc ccggcccggc cgcagcagcc gccgccgccg cgcatttccc tgaaacctgg gctcttgaag acgcatcact ggagcag atg gat aat gga gac tgg ggc tat atg Met Asp Asn Gly Asp Trp Gly Tyr Met atg Met tct Ser ttt Phe att Ile act Thr cgqi Arg aat Asn gag Glu gtc Val gaa Glu acc Thr 170 cag Gin ggt Gly aca Thr 15 acg Thr ccc Pro cct Pro t ta Leu ttt Phe 95 ttg Leu cgg Arg cta Leu tat Tyr gtt Val 175 agg Arg aac Asn tta Leu cgt Arg aca Thr ctt Leu ccg Pro tac Tyr tat Tyr aag Lys acc Thr ttt Phe 160 tcc Ser gtc Val acc Thr aat gta ggt gga cac Asn Vai Gly Gly His 20 tac ccg gat tcc atg Tyr Pro Asp Ser Met gct cga gac cct caa Ala Arg Asp Pro Gin ttc cga tat gtc ctc Phe Arg Tyr Val Leu ttg gat ttt aag gaa Leu Asp Phe Lys Glu cag att gag ccc ttg Gin Ile Glu Pro Leu 100 ccc atg gat act ttt Pro Met Asp Thr Phe 115 ctt tct aag tac tcc Leu Ser Lys Tyr Ser 1.30 atc acc act aag gtc Ile Thr Thr Lys Val 145 acc aag tgg aat aag Thr Lys Trp Asn Lys 165 ttt act ttt gga ccc Phe Thr Phe Gly Pro 180 cac ctg atg gaa tac His Leu Met Giu Tyr 195 cgg gtg cat cac atg Arg Val His His Met 210 ttg Leu ctt Leu ggc Gly aac Asn ttt Phe at t Ile gaa Glu aac Asn cat His 150 cac His tgt Cys att Ile tat Tyr gga Gly aat Asn ttc Phe gat Asp cag Gin gaa Giu cca Pro 135 tcc Ser atg Met gat Asp aca Thr aca Thr gct Ala tac Tyr tta Leu ctg Leu tgt Cys gtt Val 120 gtg Val tta Leu atg Met tat Tyr aaa Lys 200 acg Thr atg Met ttt Phe aga Arg ctt Leu ctc Leu 105 gtg Val gct Ala cta Leu gac Asp cac His 185 caa Gin 162 210 258 306 354 402 450 498 546 594 642 690 738 agt gag egg gcc Ser Glu Arg Ala 215 WO 99/43696 WO 9943696PCT/U599/03826 aat gaa aac aca gtg gag cac aac tgg act ttc tgt agg cta gcc cgg Asn Glu Asn Thr Va1 Glu His Asn Trp Thr Phe Cys Arg Leu Ala Arg 220 225 230 aag aca gac gac t gatctccgac cctgccacag gttcctggaa agactctcca Lys Thr Asp Asp 235 ggaaatggaa aaatagttgt ctcctccatg tacctttttt gcttttctta ggctaaaaat aaaacatcat aaggaaaact caactgtttc ctgactagaa ctctttatgc aactaataaa gatactgatt atttatttga ttttgttccc ataaaaagaa ttacagtgct acaagaatga gtagggtgac gttccaatca tttctatgca atatttatat ctggtgcagt aaatgaaata ttttttttta aggcagtgag ttccccctga gtctgaaaat aaaatgattt aagaataagc ctagtttcca tttaaaagta tataaatcaa tgaattctga ataattccca tgaaaaaaaa aatcacagtg gaccagaagg gtatgcatgt cattatggta ctgataaaat agagtactca aaccaataaa cttattaagt ggaaccaaat atacaaaatg agtgtactgt aaaaaaaaaa tgagatattt aagttttgtg gcctgttcag tataatctac ggtccctaac tgatgccttt taagt agtat actgcttttt atctgtagcc tccctgtggt ctaccagaaa aaa tttttctttt ctttggcaga agtctccaga ccttaacaga tcaactagaa gagaaaaatc tgtaatatta acagttatga atgg aa a tgt agaaaactta aaaaaaacaa 899 959 1019 1079 1139 1199 1259 1319 1379 1439 1499 1542 <210> <211> <212> <213> 237

PRT

H. sapiens Met 1 Asn Tyr <400> Asp Asn Gly Val Gly GJly Pro Asp Ser Trp, Gly Tyr Met Thr Asp Pro Val Thr Leu Leu Tyr Thr Leu Thr Thr Leu Thr Arg Phe Pro Thr Met Leu Gly Ala Arg Asp Al a 40 Tyr Met Phe Gly Gly Asp Phe Ile Asp Arg Asp Pro Gin Gly Gly Pro Leu Phe Arg Tyr Val Leu Leu Arg Thr Leu Thr Leu Pro Asp Phe Lys Asp Leu Leu Glu Ala Asp Phe Tyr Gin Ile Glu Pro Met Asp 115 Leu Ser Lys Ile Gin Cys Leu 105 Val Asp Pro Lys Pro Leu Tyr 110 Thr Arg Lys Phe Glu Glu Val 120 Val Glu Leu Ser Tyr Ser Asn Ala Val Ile Gin Leu Thr 130 Ile Thr Thr Lys Val Leu Leu Giu Gly Ser Asn Tyr Phe 160 155 Arg Lys Tr-p Asn Met Met Asp Asp Cys Gin Val Ser 175 Phe Thr Phe Gly Cys Asp Tyr His 185 Gin Glu Val Ser His Leu Met 195 Arg Val His Tyr Ile Thr Lys 200 Arg Gly Phe Thr Leu Arg Val 190 Arg Asn Thr Val Glu His His Met Ser Ala Asn Glu 210 Asn Trp, 225 Asn Thr 220 Asp Asp Thr Phe Cys Ala Arg Lys Thr 235 <210> 26 <211> 3204 VO 99/43M ~wo 9i43~PCTIUS99/03826 <212 DNA <eZ13> H. sapiens 0 <<Z21> CDS (182) (1349) .z22 3> K+Hnov42 0> 26 cggcogacc ttgggtgtgg gaeagagtgo gtgcgtgtgg tgtgtceccca agggcaggaa ggtggorpag ggaggcgaat ccgagtgggt ggagggaggg gaagggeggg aggagaaaaa ggtggma ggaccaggtg ggagggtggc ggctcaetca ggacccagcg ggggcagegc g atg ag egg gtg acc ctg ttc etg aac ggc age ccc aag aac gga aag M~et Arg Arg Val Thr Leu Phe Leu Asn Gly Ser Pro Lys Asn Gly Lys 1 5 10 gtg gttt get gta tat Val agt Se r ctg Leu tgt *Cys gag Giu ggg Gly gac Asp aag Lys tte Phe 145 gat Asp att Ile Valh Ala Val aam ctc gge Lys Leu Gly att gat gat Ile Asp Asp gaa gga gag ,Gbm Gly Glu gga ttg tta Gly Leu Leu egq tac ttt Arg Tyr Phe 100 agt atg ctg Ser Net Leu 115 caa gat eat Gin Asp His 130 gaa ccc att Glu Pro Ile ggc att aat Gly Ile Asn gac tea ttg Asp Ser Leu 180 Tyr ata Ile at t Ile eea Pro gga Gly aea Thr gee Ala aga Arg ttg Leu tta Leu 165 att Ile gga Gly aaa Lys get Ala ttt Phe 70 tte Phe aet Thr eae His gga Gly aae Asn 150 tg Leu gaa Glu act tta tot gat ttg ett tet Thr gee Ala tg Leu att Ile eae His aca Thr atg Met get Ala 135 tac Tyr ggt Gly eac His Leu aecc Thr 40 ate Ile gat Asp aea Thr egg Arg ttt Phe 120 tte Phe ttg Leu gtg Val eta.

Leu Ser 25 agt Ser agg Arg ect Pro gac Asp age Ser 105 aag Lys tta Leu cgt Arg ta Leu gaa Giu 185 Asp Leu gtg tat Val Tyr gat gat Asp Asp cag aea Gin Thr 75 tgg etg Trp Leu 90 act tta Thr Leu gao aaa Asp Lys att gae Ile Asp eat gga His Giy 155 gaa gaa Giu Giu 170 gig gea Val Ala Leu Ser aat ggg Asn Gly gat gtt Asp Vai gat tet Asp Ser aca tta Thr Leu gig aat Val Asn ggt gte Gly Val 125 oga. agt Arg Ser 140 cag ete Gin Leu gca aga Ala Arg ata aag Ile Lys gtg gee age Val Ala Ser aaa ggt gga Lys Gly Gly tig tit gtt Leu Phe Val aag eet oct Lys Pro Pro aat gtt gga Asn Val Gly aaa. gaa eet Lys Glu Pro 110 tgg gga. aat Trp Gly Asn cot gag tao Pro Giu Tyr att gta aat Ile Vai Asn 160 ttt itt ggt Phe Phe Giy 175 aat tot oaa Asn Ser Gin 190 277 325 373 421 469 517 565 613 661 709 757 eea. cog gag gat eat tea eea. ata tee cga.

aag gaa ttt gte ega ttt 805 WO 99/43696 WO 9943696PCTIUS99/03826 Pro Pro Glu 195 Asp His Ser Pro Ser Arg Lys Glu Val Arg Phe ttg cta gca act cca acc Leu Leu Ala Thr Pro Thr 210 aag Lys 215 tca gaa ctg cga Ser Glu Leu Arg tgc Cys 220 cag ggt ttg aac Gin Gly Leu Asn ttc agt ggt gct gat Phe Ser Gly Ala Asp 225 aaa atg gcc aat tta Lys Met Ala Asn Leu ctt Leu 230 tct cgt ttg gac Ser Arg Leu Asp cga tac att aac Arg Tyr Ile Asn agc cgc tgt aat Ser Arg Cys Asn gca cat gca aat Ala His Ala Asn ctt tgc Leu Cys 255 tgt gca aat Cys Ala Asn gcg aat ctc Ala Asn Leu 275 gaa cga gct gat Glu Arg Ala Asp tct gga tca gtg Ser Gly Ser Val ctt gac tgt Leu Asp Cys 270 gaa gga gca Glu Gly Ala 997 1045 cag gga gtc aag Gin Gly Val Lys atg Met 280 ctc tgt tct aat Leu Cys Ser Asn tcc ctg Ser Leu 290 aaa ctg tgt aat Lys Leu Cys Asn gag gat cct tct Glu Asp Pro Ser ggt Gly 300 ctt aaa gcc aat Leu Lys Ala Asn 1093 tta Leu 305 gaa ggt gct aat Glu Gly Ala Asn aaa ggt gtg gat atg gaa gga agt cag Lys Gly Val Asp Met Glu Gly Ser Gin 315 1141 aca gga att aac Thr Gly Ile Asn aga gtg gct acc Arg Val Ala Thr aaa aat gca aag ttg aag Lys Asn Ala Lys Leu Lys 1189 1237 aac tgt aac Asn Cys Asn tgt gat ctg Cys Asp Leu 355 aga gga gca act ctg gca gga act gat Arg Gly Ala Thr Leu Ala Gly Thr Asp 345 tta gag aat Leu Giu Asn 350 aga ggg tcc Arg Gly Ser tct ggg tgt gat Ser Gly Cys Asp ctt Leu 360 caa gaa gcc aac Gin Glu Ala Asn 1285 aac gtg Asn Val 370 aag gga gct ata Lys Gly Ala Ile gaa gag atg ctg aca cca cta cac atg Giu Glu Met Leu Thr Pro Leu His Met 1333 1389 caa agt gtc aga Gin Ser Val Arg t gagaatttta ggggctggag gaagatgtaa aagatgaaaa tgttttcctt aaggaaattt aaaaaactga gtagggaaac accaggcata ggtttgagat attgaattcc aaggttgttc accgtatgaa gtttactttt atcacttttc taaaaaaaaa OtttttttCC tagatat tgc gtatctatta gcatttgagg tagatgcagt aggtttataa tatggtgaga taggacagaa tttctccacc catttagagg atattctgat tgccttttga tatttgcttt attttaattt atggatattt atagctttag tcagactccc cagtagctaa cactcagttg attatgcttg ttttaacaga atggggtagg taaataggca atggaaagca aaattgttaa tgatgcctcc taagactctt attaaagtaa tctagaagaa ttttgagtgg aaagcactca ggggtttacc tgatgtggaa caacatatgc aactttatga cctctttaaa t tcaggttca tatccagttc ataacactgt tgcataaggg tttaatagat tggttttatg ataccatctt aattatattt aaacttggaa tacctgtcac tttttataat ttactgattg 1449 1509 1569 1629 1689 1749 1809 1869 1929 1989 WO 99/43696 WO 9943696PCTfUS99/03826 agacagagtg etc tgga tgg atttcattct ttagcctagt accaaggtgc cttagaaata tagagttgcc tgaggaattt gcatttggct tttttttgtg ctctgcagca ctaccccaag caacatgagg t ttagtat tt aagggtacat agaaatgaat gagataatct tactatattt aataacctaa gattttagat aaaaaaaaaa gaaagaaaga aggaataact aggcaagttc tttctcatac atcattaata gatactaaat tgctaaaagg taaacacaca ggtccaagat gttttttttt gcagaggaag agcagggata caaggaatca acgtagctta atgcatagtg tattttcttt attttcataa t caggaat ta aactgcagaa ctaatgtata aaaaa catcattgta tacctatcac cactcaacac agtcatcaca ttcatttaat Ccagagctac caatgtaata tttgattaca gtaattttca tttaaacaaa gg CC tgtac c ttagctgtgt ttgaaaacca ttcttctata ggaggagatc gctttattat tcaatatgtg cagaatgtgg ggatctgaaa ctgcattaat catcactgtc tacaacactt cagatcaagc agcataggaa tcaaatacca tgcaatcaaa taattgcagc gccaccaaaa atcagtcagc ttttagccca tccctaccaa ccaaatgggt cctgtgtctc tctacatatg agacctttac ttttaccaag cctaaattat tattcattca gatctaaaca aaa tga tat a attccaaagg acaaatgaga aattctatct gatacttcaa aatagtttac gcttatatga tagaacccta aaatagacgt acctgtgatt attttcttga tgacttggtg tctgaattct ctttgggaga caaagctttc aagtgaagga acagagaagt atttaaatca cttaaaggta tggtgtgctt aagtgtttgt tacagtgtaa atttctcaga atttacacta aaccaaaaaa atagggccag gtgaatatgg cagtggggaa aaaaataaag cttttactta gtcattctct tccttatttt acagactcat atgacatatc cttaacagta aagcaacttc attgtattga tttcactctg cctctgtaga agaaactgca tgaaaaaaaa 2049 2109 2169 2229 2289 2349 2409 2469 2529 2589 2649 2709 2769 2829 2889 2949 3009 3069 3129 3189 3204 <210> 27 <211> 389 <212> PRT <213> H. sapiens <400> Met Arg Arg 27 Val Thr Leu Phe Leu Asn Gly Ser Pro Lys Asn 1 Var Val Ser Lys Ala Val Leu Gly Tyr Gly Thr Leu Ile Lys Ala Thr 10 Asp Gly Lysis Leu Leu Ser Val Tyr Asn Val Ala Ser Lys Gly Gly Leu Phe Vai Leu Ile Cys Giu Asp Ile Asp Ile Ala Leu Arg Asp Asp Ile Gly Giu Pro Asp Pro Gin Ser Lys Pro Giu Pro Gly Leu Leu Gly Phe His Thr Asp Leu Thr Leu Asn Val Gly Giy Arg Tyr Asp Ser Met 115 Lys Gin Asp Thr Thr Thr Arg Leu Val Asn Ala His Met Phe 120 Phe Asp Lys Giy Lys Giu Pro 110 Trp Gly Asn Pro Glu Tyr His Arg Gly 130 Phe Glu Ala 135 Tyr Leu Ile Asp Arg 140 Gin Pro Ile Leu Leu Arg His Leu Ile Val Asn 160 Gly Ile Asn Gly Val Leu Giu 170 Val Ala Arg Phe Phe Gly 175 Ile Asp Ser Pro Pro Glu 195 Leu Leu Ala Leu 180 Asp Thr Giu His Leu Glu 185 Ser Ala Ile Lys His Ser Pro Pro Thr Lys 215 Asp Leu Ser Arg Lys Glu Asn Ser Gin 190 Val Arg Phe Gly Leu Asn Glu Leu Arg 210 Phe Ser Gly Ala Arg Leu Asp Tyr Ile Asn Met Ala Asn Leu 245 Giu Arg Cys Asn Leu 250 Ser His Ala Asn Leu Cys 255 Asp Cys Cys Ala Asn Leu ArAlAsLe GySrVaLu Arg Ala Asp Leu Gly Ser Val Leu WO 99/43696 WO 9943696PCTIUS99/03826 Ala Asn Leu 275 Ser Leu Lys 290 Leu Glu Gly Gly Val Lys Met 280 Glu Cys Ser Asn 270 Glu Gly Ala Lys Ala Asn Leu Cys Asn Ala Asn Leu 310 Asn Leu Arg Asp Pro Ser Gly 300 Glu Gly Val Asp 305 Thr Met 315 Lys Gly Ser Gln Gly Ile Val Ala Thr Leu Asn Ala Lys 330 Al a Leu Lys 335 Asn Cys Asn Cys Asp Leu 355 Asn Val Lys Gly Ala Thr Leu 345 Gln Gly Thr Asp Gly Cys Asp Leu 360 Glu Glu Ala Asn Leu Glu Asn 350 Arg Gly Ser Leu His Met 370 Ser Gln 385 Ser Gly Ala Ile Val Arg Glu Met Leu Thr 380 <210> <211> <212> 28 1246

DNA

<213> H. sapiens <220> <221> <222> <223>

CDS

(432) (1092) K+Hnov44, splice 1 <400> 28 cagaaaacca cgcaggtcct tcttgatcat tctgcagaac cacgtggcta gcctgcctga ttctaatggc tgcagctgcg ctgggggctg atgtctaagc ttcacctttc ttgcgcccgc tttctcagac ccctggcctc atgcagccct gcagccggag gcgccagggg aggacagcct actacagtga tggagaccca ctagatgtgc accgagccgt g atg ctg ggg ttt gcc Met Leu Gly Phe Ala ctagaactga. ccgctccgcc ttgccaggag agttctcacc tctccaggaa ggcggggggc ggggctcccg ctgggactcc acttccgtgg aggggcatga ctcaggtgaa agggagccat tcagcatccc cgtgcaaatc acacttcagg ttcctgcctc agggaagaag agagagacag acaagaggct gccatccagt gctggagagg atg atg ggc ttc tca gtc cta atg Met Met Gly Phe Ser Val Leu Met 120 180 240 300 360 420 470 ttc ttc Phe Phe ttg ctc gga aca Leu Leu Gly Thr acc Thr 20 att cta aag cct Ile Leu Lys Pro ttt Phe atg ctc agc att Met Leu Ser Ile cag Gin aga gaa gaa tcg Arg Glu Glu Ser tgc act gcc atc Cys Thr Ala Ile aca gat atc atg Thr Asp Ile Met gac tgg ctg gac Asp Trp Leu Asp gcc ttc acc tgt Ala Phe Thr Cys gtg cac tgc cac Val His Cys His ggt cag Gly Gin ggg aag tac Gly Lys Tyr cag aaa gct Gin Lys Ala s0 tgt ctt cag gtg Cys Leu Gln Val gtg aac ctc agc Val Asn Leu Ser cat cca ggt His Pro Gly ata aat ccc Ile Asn Pro ctc cta cat tat Leu Leu His Tyr gaa gag gct gtc Glu Glu Ala Val aag tgc ttt tac aca cct aag tgc cac caa gat aga aat gat ttg ctc WO 99/43696 WO 9943696PCTIUS99/03826 Lys Cys Phe Tyr Thr Pro Lys 100 Cys His Gin Asp Arg 105 Asn Asp Leu Leu aac Asn 110 agt gct ctg gac ata aaa gaa ttc ttc Ser Ala Leu Asp Ile Lys Giu Phe Phe cac aaa aat gga His Lys Asn Gly ccc ttt tca tgc ttc tac agt eca gcc Pro Phe Ser Cys Phe Tyr Ser Pro Ala 130 agc Ser 135 caa tot. gaa gat Gin Ser Giu Asp gte att Val Ile 140 ott ata aaa aag tat gac caa atg Leu Ile Lys Lys Tyr Asp Gin Met 145 got Ala 150 ate ttc cac tgt Ile Phe His Cys tta ttt tgg Leu Phe Trp, 155 atg gtg aga Met Val Arg oct tca ctg Pro Ser Leu 160 act ctg eta ggt Thr Leu Leu Gly gcc etg att gtt Ala Leu Ile Val tta aca Leu Thr 175 caa cac ctg tcc tta ctg tgt gaa aaa Gin His Leu Ser Leu Leu Cys Glu Lys tat Tyr 185 agc act gta gte Ser Thr Val Val 998 1046 aga Arg 190 gat gag gta ggt gga aaa gta cct tat Asp Giu Val Gly Giy Lys Val Pro Tyr gaa cag cat cag Glu Gin His Gin aaa otg tge att atg agg agg age aaa Lys Leu Cys Ile Met Arg Arg Ser Lys 210 gga Gly 215 aga gca gag aaa Arg Ala Glu Lys tot t Ser 220 1092 aagaeggtgg ecaaattaaa gtgctggect cetaattatg oetgtotgea aaetaataat teatgtggga aaaaaaaaaa aaaaaaaaaa teagatgtet gtaaaaggta aaaa gtgatttetg caaetgagga ataattaaag tatcatattt 1152 1212 1246 <210> 29 <211> 1111 <212> DNA <213> H. sapiens <220> <221> CDS <222> (297) (957) <223> K+Hnov44, splice 2 <400> 29 aaaaaccatg aettgtggea ocagaagaga agataceaaa gaaggaecga gaagggeaaa aggcaggcgg caggcgtggt geaeaagaag tgccaatgac agcctttcet gceteaggga acecactaga tgtgcacaag aggetgccat goeggggact gcaaagaaga tctgagtgtg agaagagaga ecagtgctgg toaatooaag etgtacoatg aggggtctt gacagactac agaggacega aaageagaga tcetaagetg ttetctceao agtgatggag gccgtg atg Met 120 180 240 299 ctg ggg ttt gee atg atg ggc ttc tea gte eta Leu Gly Phe Aia Met Met Gly Phe Ser Val Leu 10 gga aca ace att eta aag cot ttt atg etc age Gly Thr Thr Ile Leu Lys Pro Phe Met Leu Ser 25 atg ttc tto ttg etC Met Phe Phe Leu Leu att cag aga gaa gaa Ile Gin Arg Glu Glu 347 WO 99/43696 PCTIUS99/03826 tcg acc tgc act gcc atc cac aca gat atc atg gac gac tgg ctg gac 443 Ser Thr Cys Thr Ala Ile His Thr Asp Ile Met Asp Asp Trp Leu Asp 40 tgt gcc ttc acc tgt ggt gtg cac tgc cac ggt cag ggg aag tac ccg 491 Cys Ala Phe Thr Cys Gly Val His Cys His Gly Gin Gly Lys Tyr Pro 55 60 tgt ctt cag gtg ttt gtg aac ctc agc cat cca ggt cag aaa get Ctc 539 Cys Leu Gin Val Phe Val Asn Leu Ser His Pro Giy Gin Lys Ala Leu 75 cta cat tat aat gaa gag gct gtc cag ata aat ccc aag tgc ttt tac 587 Leu His Tyr Asn Giu Giu Ala Val Gin Ile Asn Pro Lys Cys Phe Tyr 90 aca cct aag tgc cac caa gat aga aat gat ttg etc aac agt gct ctg 635 Thr Pro Lys Cys His Gin Asp Arg Asn Asp Leu Leu Asn Ser Ala Leu 100 105 110 gac ata aaa gaa ttc ttc gat cac aaa aat gga act ccc ttt tea tgc 683 Asp Ile Lys Giu Phe Phe Asp His Lys Asn Gly Thr Pro Phe Ser Cys 115 120 125 ttc tae agt eca gcc age caa tet gaa gat gte att ctt ata aaa aag 731 Phe Tyr Ser Pro Ala Ser Gin Ser Giu Asp Val Ile Leu Ile Lys Lys 130 135 140 145 tat gac caa atg get ate ttc cac tgt tta ttt tgg ect tea etg act 779 Tyr Asp Gin Met Ala Ile Phe His Cys Leu Phe Trp Pro Ser Leu Thr 150 155 160 etg eta ggt ggt gee etg att gtt ggc atg gtg aga tta aca caa cac 827 Leu Leu Gly Gly Ala Leu Ile Vai Gly Met Val Arg Leu Thr Gin His 165 170 175 etg tee tta etg tgt gaa aaa tat age aet gta gtc aga gat gag gta 875 Leu Ser Leu Leu Cys Giu Lys Tyr Ser Thr Val Val Arg Asp Glu Val 180 185 190 ggt gga aaa gta cet tat ata gaa cag eat cag ttc aaa ctg tgc att 923 Gly Gly Lys Val Pro Tyr Ile Giu Gin His Gin Phe Lys Leu Cys Ile 195 200 205 atg agg agg age aaa gga aga gea gag aaa tet t aagaeggtgg 967 Met Arg Arg Ser Lys Gly Arg Ala Glu Lys Ser 210 215 220 ccaaattaaa gtgctggcct teagatgtet gtgatttctg eaactgagga cctaattatg 1027 cctgtctgca aactaataat gtaaaaggta ataattaaag tatcatattt teatgtggga 1087 aaaaaaaaaa aaaaaaaaaa aaaa 1111 <210> <211> 220 <212> PRT <213> H. sapiens <400> Met Leu Giy Phe Ala Met Met Gly Phe Ser Vai Leu Met Phe Phe Leu 1 5 10 WO 99/43696 PCT/US99/03826 Leu Gly Thr Thr Ile Leu Lys Pro Phe Met Leu Ser Ile Gin Arg Glu 25 Glu Ser Thr Cys Thr Ala Ile His Thr Asp Ile Met Asp Asp Trp Leu 40 Asp Cys Ala Phe Thr Cys Gly Val His Cys His Gly Gin Gly Lys Tyr 55 Pro Cys Leu Gin Val Phe Val Asn Leu Ser His Pro Gly Gin Lys Ala 70 75 Leu Leu His Tyr Asn Glu Glu Ala Val Gin Ile Asn Pro Lys Cys Phe 90 Tyr Thr Pro Lys Cys His Gin Asp Arg Asn Asp Leu Leu Asn Ser Ala 100 105 110 Leu Asp Ile Lys Glu Phe Phe Asp His Lys Asn Gly Thr Pro Phe Ser 115 120 125 Cys Phe Tyr Ser Pro Ala Ser Gin Ser Glu Asp Val Ile Leu Ile Lys 130 135 140 Lys Tyr Asp Gin Met Ala Ile Phe His Cys Leu Phe Trp Pro Ser Leu 145 150 155 160 Thr Leu Leu Gly Gly Ala Leu Ile Val Gly Met Val Arg Leu Thr Gin 165 170 175 His Leu Ser Leu Leu Cys Glu Lys Tyr Ser Thr Val Val Arg Asp Glu 180 185 190 Val Gly Gly Lys Val Pro Tyr Ile Glu Gin His Gin Phe Lys Leu Cys 195 200 205 Ile Met Arg Arg Ser Lys Gly Arg Ala Glu Lys Ser 210 215 220 <210> 31 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> consensus sequences <400> 31 tatccacatc aatggacaaa gc 22 <210> 32 <211> <212> DNA <213> Artificial Sequence <400> 32 tgcataactg gctgggtgta <210> 33 <211> 22 <212> DNA <213> Artificial Sequence <400> 33 tgacatcact ggatgaactt ga 22 <210> 34 <211> <212> DNA <213> Artificial Sequence <400> 34 tgcctgcaaa gtttgaacat WO 99/43696 PCT/US99/03826 <210> <211> 22 <212> DNA <213> Artificial Sequence <400> tgacatcact ggatgaactt ga 22 <210> 36 <211> <212> DNA <213> Artificial Sequence <400> 36 tgcctgcaaa gtttgaacat <210> 37 <211> <212> DNA <213> Artificial Sequence <400> 37 acctggtggt atggaagcat <210> 38 <211> 19 <212> DNA <213> Artificial Sequence <400> 38 tttctcctgg cctctaccc 19 <210> 39 <211> 19 <212> DNA <213> Artificial Sequence <400> 39 tccctcttgg gtgaccttc 19 <210> <211> <212> DNA <213> Artificial Sequence <400> atctttgtca gccaccagct <210> 41 <211> 24 <212> DNA <213> Artificial Sequence <400> 41 aggtgtgctg ccatctgctg ttcg 24 <210> 42 <211> 24 <212> DNA <213> Artificial Sequence WO 99/43696 PCTIUS99/03826 <400> 42 agcctatcct ctctgagagt cagg 24 <210> 43 <211> 21 <212> DNA <213> Artificial Sequence <400> 43 aagcagagta ctcatgatgc c 21 <210> 44 <211> <212> DNA <213> Artificial Sequence <400> 44 tctggtagac agtacagtgg <210> <211> <212> DNA <213> Artificial Sequence <400> catttggctg gtccaagatg <210> 46 <211> <212> DNA <213> Artificial Sequence <400> 46 agtcattggt agggaggtac <210> 47 <211> <212> DNA <213> Artificial Sequence <400> 47 catgcttcta cagtccagcc <210> 48 <211> <212> DNA <213> Artificial Sequence <400> 48 ggtcctcagt tgcagaaatc <210> 49 <211> <212> DNA <213> Artificial Sequence <400> 49 tggtgggctg tggtgaccat gacaactgtg ggctatgggg acatg <210> WO 99/43696 WO 9943696PCTIUS99/03826 <211> <212> DNA <213> Artificial Sequence <400> tggtgggcag tggtcaccat gaccactgtg ggctacgggg acatg <210> 51 <211> <212> DNA <213> Artificial Sequence <400> 51 tggtgggcag tcgtctccat gacaactgta ggctatggag acatg <210> 52 <211> <212> DNA <213> Artificial Sequence <400> 52 tggtgggcag tggtaaccat gacaacagtg ggttacggcg atatg <210> 53 <211> <212> DNA <213> Artificial Sequence <400> 53 tggtgggctg tggtcaccat gacgaccctg ggctatggag acatg <210> 54 <211> <212> DNA <213> Artificial Sequence <400> 54 tggtgggggg tggtcacagt caccaccatc ggctatgggg acaag <210> <211> <212> DNA <213> Artificial Sequence <400> tggtgggcag tggtcaccat gaccacggtt ggctatgggg acatg <210> 56 <211> <212> DNA <213> Artificial Sequence <400> 56 tggtgggccg tggtcaccat gacgaccctg ggctatggag acatg <210> 57 <211> <212> DNA <213> Artificial Sequence <400> 57 WO 99/43696 WO 9943696PCTIUS99/03826 tggtgggctg tggtcaccat gacgacactg ggctacggag acatg <210> 58 <211> <212> DNA <213> Artificial Sequence <400> 58 tggtgggctg tggtgaccat gacaactgtg ggctatgggg acatg <210> 59 <2115 47 <212> DNA <213> Artificial Sequence <400> 59 ttcctgttct Ccattgagac cgaaacaacc attgggtatg gcttccg 47 <210> <211> 47 <212> DNA <213> Artificial Sequence <400> tttttattct caatagagac agaaaccacc attggttatg gctaccg 47 <210> 61 <211> 47 <212> DNA <213> Artificial Sequence <400> 61 ttcctcttct ccattgagac ccagacaacc ataggctatg gtttcag 47 <210> 62 <211> 47 <212> DNA <213> Artificial Sequence <400> 62 ttcctgttct cggtggagac gcagacgacc atcggctatg ggttccg 47 <210> 63 <211> 47 <212> DNA <213> Artificial Sequence <400> 63 ttcctcttct cccttgaatc ccaaaccacc attggctatg gcttccg 47 <210> 64 <211> 47 <212> DNA <213> Artificial Sequence <400> 64 tttctctttt ccctggaatc ccagacaacc attggctatq gagtccg 47 <210> <211> 47 <212> DNA WO 99/43696 PCT/US99/03826 <213> Artificial Sequence <400> ttccttttct ccattgaggt ccaagtgact attggctttg gggggcg 47 <210> 66 <211> 47 <212> DNA <213> Artificial Sequence <400> 66 tttctcttct ccattgaagt tcaagttacc attgggtttg gagggag 47 <210> 67 <211> <212> DNA <213> Artificial Sequence <400> 67 gcgctctact tcaccttcag cagcctcacc agtgtgggct tcggcaacgt <210> 68 <211> <212> PRT <213> Artificial Sequence <220> <223> consensus sequences <400> 68 Trp Trp Ala Val Val Ser Met Thr Thr Val Gly Tyr Gly Asp Met 1 5 10 <210> 69 <211> <212> PRT <213> Artificial Sequence <400> 69 Trp Trp Ala Val Val Thr Met Thr Thr Leu Gly Tyr Gly Asp Met 1 5 10 <210> <211> <212> PRT <213> Artificial Sequence <400> Trp Trp Gly Val Val Thr Val Thr Thr Ile Gly Tyr Gly Asp Lys 1 5 10 <210> 71 <211> <212> PRT <213> Artificial Sequence <400> 71 Trp Trp Ala Val Val Thr Met Thr Thr Val Gly Tyr Gly Asp Met 1 5 10 <210> 72 WO 99/43696 WO 9943696PCTfUS99/03826 <211> ':212> PRT <213> Artificial Sequence <400> 72 Phe Leu Phe Ser Ile Glu Val Gin Val Thr Ile Gly Phe Gly Gly 1 5 10 <210> <211> <212> <213> 73

PRT

Artificial Sequence <400> 73 Phe Leu Phe Ser Leu Giu Ser Gin Thr Thr Ile Gly Tyr Gly Val <210> 74 <211> <212> <213>

PRT

Artificial Sequence Phe

I

<400> 74 Leu Phe Ser Ile Glu Thr Glu 5 Thr Thr Ile Gly Tyr Gly Tyr 10 <210> <211> <212> <213>

PRT

Artificial Sequence <400> Phe Leu Phe Ser Ile Giu Thr Gin 1 5 Thr Thr Ile Gly Tyr Gly Phe 10 <210> 76 <211> <212> <2 13>

PRT

Artificiai Sequence <400> 76 Phe Leu Phe Ser Val Giu Thr Gin Thr Thr Ile Gly Tyr Gly Phe <210> <211> <212> <213> <400> Leu Phe 77

PRT

Artificiai Sequence 77 Ser Leu Glu Ser Gin Thr Thr Ile Gly Tyr Giy Phe 10 78

PRT

Artificial Sequence <210> <211> <212> <213> <400> 78 Leu Phe Ser Ile Glu Thr Giu Thr Thr Ile Gly Tyr Gly Phe 10 WO 99/43696 WO 9943696PCTIUS99/03826 <210> 79 <211> 16 <212> PRT <213> Artificial Sequence <400> 79 Ala Leu Tyr Phe Thr Phe Ser Ser Leu Thr Ser Val Gly Phe Gly Asn 1 5 10 <210> <211> 2571 <212> DNA <213> H. sapiens <220> <221> CDS <222> (110) (1285) <400> gctgccgcgc ctgtagcact cccggaactg gaactaggtg ccagacggtc cggaggcggg ggccacgtca gcggggccac ccagggctcg cggggtcccg gtgggtgcc atg cgg agg Met Arg Arg ggc Gly ctg Leu ctc Leu ccg Pro gcg Ala gcc Ala gcc Ala 100 act Thr ccg Pro gcg Al a ggc Gly cga Arg tgt Cys gcc Ala aac Asn agc Ser gat Asp acc Thr ctt Leu gcg Ala gcc Ala gtg Val gga Gly gcc Al a acg Thr gcg Ala acc Thr ctg Leu ctg Leu gag Glu gct Al a cgg Arg tcg Ser ctg Leu ggC Gly atg Met gcg Ala ttg Leu ctg Leu gcc Ala c tg Leu gac Asp atc Ile aag Lys 120 ctg Leu gcc Ala 10 gcg Ala acg Thr gcc Ala cgg Arg gcc Ala 90 acc Thr ttc Phe ctg Leu t tg Leu cgg Arg ctg Leu ctg Leu gtc Val 75 tgg Trp, gtg Val tcc Ser acc Thr gcc Ala ctg Leu cgg Arg gac Asp 60 gtg Val gac Asp ggc Gly atc Ile gcc Ala gcg Ala gag Glu gcg Al a 45 gcc Al a ctt Leu ttC Phe tat Tyr gcc Ala 125 tca Ser gcc Ala ccg Pro ctg Leu gtg Val aa c Asn tct Ser tac Tyr gcg Ala cag Gln gcg Ala cac His ctt Leu gag Glu gct Ala gct Ala aca Thr ctc Leu cgc Arg tac Tyr gaa Glu cag Gln cga Arg t cg Ser ctc Leu acg Thr ctg Leu ctg Leu 145 ctg Leu gcc Ala cgc Arg s0 gtg Val ggg Gly tt c Phe cca Pro ggc Gly 130 tca Ser 166 214 262 310 358 406 454 502 550 WO 9914,YM WO 994~I~PCT/US99/03826 ctg ctf act -Leu Le Thr 150 gac c- cgg Asp !Pmu Arg _gta .lt. acc Val lra Thr 180 gag gcc *Gl~u G.Thm Ala ctg t=c acc Leu Ser- Thr cag ccc tac Gin Pro Tyr 230 ctg ggc ctg Leu Gly Leu 245 tc~c 'gac ctc Ser Asp Leu 2 6f cct gCC agt Pro Ala Ser ccc cag ccg Pro Gin Pro tac gct tcc Tyr Ala Ser 310 gtg cct ggc Val Pro Gly 325 agg aat gtc Arg Asn Val 340 cgt ctc tcc Arg Leu Ser 355 ctc cct gtc Leu Pro Val 370 cac gtg ccc ctg tct tg9 ctg agc atg His Val Pro Leu Ser Trp Leu Ser Met Cgg Arg gtc Val tgg Trp atc Ile 215 cgg Arg gtg Val .ca c His ttc Phe gag Giu 295 atc Ile ctg Leu cac His ttt Phe ccc Pro gcc tgc tgg Ala Cys Trp 170 ttt ctg gtg Phe Leu Val 185 ttc ttg gat Phe Leu Asp ctg ggc gac Leu Gly Asp ctc tac aag Leu Tyr Lys 235 atg gtg ctg Met Vai Leu 250 ctc acg gag Leu Thr Giu 265 gcg gat gag Ala Asp Giu cac cag caa His Gin Gin agg tag ctg Arg Leu ctg agg ggt Leu Arg Gly 330 cac agc agg His Ser Arg 345 tcc cag cat Ser Gin His 360 tcc cgg gct Ser Arg Ala 375 cac His ccg Pro gcc Ala tac Tyr 220 gtg Val gtg Val ctc Leu gac Asp ctc Leu 300 ggg Gly 315 cca Pro tga ctg Leu cca ttg Leu gct Ala ttc Phe 205 gtg Val ctg Leu ctg Leu atc Ile gat Asp 285 tct Ser cag Gin ggc Gly tct Ser gct Al a Ctg gtg Val gtg Val 190 tac Tyr ccc Pro gtc Val cag Gin ctg Leu 270 cgg Arg gcc Ala cct Pro gac Asp tga Gly 99c gcc Ala 175 atc Ile ttc Phe ggg Gly aca Thr acc Thr 255 ctg Leu gtg Val1 agc Ser ctg Leu cag Gin ggC Gly atg Met acc cgt tgg ggc Arg Trp Gly 160 ctg ttg ggg Leu Leu Gly ttt gcc cac Phe Ala His tgc ttt atc Cys Phe Ile 210 gag gcc cct Glu Ala Pro 225 gtc tac ctc Val Tyr Leu 240 ttc cgc cac Phe Arg His ccc cct ccg Pro Pro Pro gac atc ctg Asp Ile Leu 290 tcc cac acc Ser His Thr 305 cca ggc ttg Pro Gly Leu 320 agc tgg ctg Ser Trp Leu 335 ctt gcc gtc Leu Ala Val* 350 tga agg gca *Arg Ala 365 aac ata acc tgg Trp gtc Val ctc Leu 195 tct Ser ggc Gly ttc Phe gtg Val tgc Cys 275 ggc Gly gac Asp ggt Gly tac Tyr cac His gca Ala ttg 598 646 694 742 790 838 886 934 982 1030 1078 1126 1174 1222 1270 Pro Leu Gly Thr Asn Ile Thr Leu 380 ttc tct gtc ctt tct ctcatcctct ttacactgtg tctctctggc tctctggcat 59 1325 WO 99/43696 WO 9943696PCT[US99/03826 Phe Ser Val Leu Ser 385 tctcgctgcc tctgtgtctc ctcatttcag cttgatttcc tgtgctggcc tggagcttgc gtcaggactt agtcggagaa gaggaaggga tgactcattt gcctgggcga gcccagatct tccacatttg acgtctggcc aaaatggtga gcctatacac gagactagcc ttagctgggt gatcacttga gcctgcggga gagaaagaaa tctgtctttc tcaattaacc gcaccagatt tcagctgcca ctgtgctaga agtccagtga taatggagga gcatagggac catcgaacta t tctcaggtg tagactcttc gaatggcatg tatgttgtgc tgtgtccttg tcatcataat ccagcacttt taggcaa cac gtggtggtgc ggccaggagt cagagtgaga gaaagaaaga cctcttgctg actcgtcaac ggtcgctaca aatgggaaga cagtgctgga ggtggacaga ggtgaggtgt taggcccaat agacctgaac tctccaggga ctcagcagcc ggaggtgctg cctggaatca ggcagtcaca acaacttcaa ggaaggctga agtgaggcct atgcctgtga ttgaggctgc ccctgtctga aagggaaaga tctctgtttc tgctgattct ccctggacaa atagaagaat gacatagttg cctgtcccca tgaaagcaca ccagcctgga tatgagaaat gcaggaccca tggcaggcag cccttaacca gcctggttga ctacctctct aaggatttca ggaaggagga tatctcaaca tcctggctac agtgagttat aagaaagaga tggaaggaag tcattctctt actgggctgt gtgactgccc ttgcccctaa ggggtggaga gacagtgatg ggcagagtgg aagtcaggga aggcaggaag tggagggacc gaaacagaca tgacaccatt gctcaaatcc gattttgttt ggctgagtgt tcgcttgagg acaaccacaa ttcagaggct gatggcactg gaaagaaaga gaagga tcatgttccg gggctcagac gtctctgagc acccctcctg actgccctta gcccaaaatg tcagggctga ggacttccta aagttgtacc cctggtgtag taggacccca gtaagagctg caacttagcc ccttatctgt ggtggctcac ccaggagttt aatctaaaaa gaggtggaag ctgcactcca aagaaagaga 1385 1445 1505 1565 1625 1685 1745 1805 1865 1925 1985 2045 2105 2165 2225 2285 2345 2405 2465 2525 2 571 <210> <211> <212> <213> 81 388

PRT

H. sapiens <400> 81 Met Arg Arg Gly Ala 1 5 Tyr Leu Val Leu Gly Leu Leu Ala Gly Ala 10 Ala Leu Ala Ala Tyr Ala Ala Ala Leu Leu Arg Leu Glu Glu Ala Arg Gin Arg Ser Leu Arg Ala Giu Thr Leu Arg Gly Pro His Gin Leu Leu Phe Val Giu Pro Cys Val Pro Ala Leu Asp ArcT Val Leu Ala Ala Ser Gly Ala Leu Gly Arg Val Leu Ala Asn Gly Ser Ala Ser Asp Leu Phe Phe Thr Pro Leu Thr Leu Ile Pro Ala Thr Thr 105 Ala Phe Asp Phe Ala Ser Ala Val Gly Ser Ile Asp Ala Gly Lys 120 Leu Tyr Gly Tyr Thr 110 Ala Phe Ala Leu 125 Ser Ala Gin Arg Leu Ser Met Ara Leu Gly 130 Leu Ser Pro Thr Thr Leu Leu Thr Leu Leu Leu Val Pro Leu 145 Trp Gly Trp Asp Arg Ala Ala Cys 170 Leu His Leu Val Ala Leu 175 Leu Gly Val Ala His Leu 195 Phe Ile Ser Val 180 Glu Thr Val Cys Val Pro Ala Val Ile Phe 190 Glu Ala Trp Ser 200 Gly Leu Asp Ala Leu Ser Thr 210 Ala Pro 225 Ile 215 Arg Leu Gly Asp Tyr 220 Val Phe Tyr Phe Cys 205 Val Pro Gly Giu Leu Val Thr Val Gly Gin Pro Tyr 230 Ala Leu Tyr Lys 235 WO 99/43696 WO 9943696PCT/US99/03826 Tyr Leu Phe Leu Leu Val Ala Met Val 250 Thr Leu Val Leu Gin Thr Phe Arg His Val Pro Pro Cys 275 Ile Leu Giy Leu His Gly Leu 265 Ala Glu Leu Ile 255 Leu Pro Pro Ala Ser Phe Asp Giu Asp Arg Val Asp Ala Ser Ser Pro Gin Pro His Gin Gin 290 His Thr Leu 300 Gin Asp Tyr Ala Ser Ile Pro Arg Leu Gly 315 Pro Pro Leu Pro Gly 320 Gly Val Pro Giy 325 Val Giy Leu Arg Gly 330 Gly Asp Gin Ser Trp 335 Leu Tyr Arg Asn 340 His Glu His Arg Ser Gly Leu Arg Leu Ser 355 Pro Val Pro 370 Ser Val Leu 385 Phe Vai Ser Gin His 360 Pro Ala Giy Met Ala Val His 350 Ala Aia Leu Thr Leu Phe Met Ser Arg Ala 375 Leu Gly Thr Asn 380 Ser <210> 82 <211> 3300 <212> DNA <213> H. sapiens <220> <221> CDS <222> (50) (1285) <400> 82 aaatgcctgc ecgtgcagct cggagcgcgc agccegtctc tgaataaga atg gcg gca Met Ala Ala ect gac Pro Asp etc teg Leu Ser ttg etg gat cct Leu Leu Asp Pro tct gcc get cag aac tcc aaa ccg agg Ser Ala Ala Gin Asn Ser Lys Pro Arg ttt tee acg aaa ccc aca gtg ctt Phe Ser Thr Lys Pro Thr Val Leu tce cgg gtg gag Ser Arg Val Glu gac aeg ace att aat gtt atg aaa tgg aag acg gte tee acg Asp Thr Thr Ile Asn Vai Met Lys Trp Lys Thr Val Ser Thr ata ttc Ile Phe etg gtg gtt gte etc tat etg ate Leu Val Val Val Leu Tyr Leu Ile ttg gag cag eet eat gag att tea Leu Giu Gin Pro His Glu Ile Ser ate Ile 60 gga gee ace gtg Gly Ala Thr Val ttc aaa gca Phe Lys Ala gtg ate eag Val Ile Gin eag agg ace ace Gin Arg Thr Thr aag eaa Lys Gin aca tte ata tee Thr Phe Ile Ser eat tee tgt gte His Ser Cys Val aat Asn teg aeg gag etg Ser Thr Glu Leu gat gaa etc att cag caa ata gtg gea gca ata aat gca ggg att ata Asp Giu Leu Ile Gin Gin Ile Val Ala Ala Ile Asn Ala Gly Ile Ile WO 99/43696 WO 9943696PCT/US99/03826 100 c cg Pro tcc Ser atc Ile tta Leu cag Gin 180 ttt Phe atc Ile atc Ile ttt Phe ggt Giy 260 ttc Phe att Ile gga Giy gaa Giu ttc Phe tta Leu ttc Phe tca Ser ctg Leu 165 cta Leu att Ile ata Ile ata Ile gtg Val 245 gga Giy tgg Trp gga Giy gag Giu ttc Phe 325 cag Glm gga Gly ttc Phe cca Pro 150 gga Giy ggc Gly aag Lys ttt Phe ttc Phe 230 gtt Val tcc Ser atc Ile gat Asp ttc Phe 310 aaa Lys cgg Arg aac Asn ttt Phe 135 cgc Arg at t Ile acc Thr tgg Trp ata Ile 215 aaa Lys atc Ile gat Asp ct t Leu tgg Trp, 295 aga Axg gaa Giu gcc Ala acc Thr 120 gct Aia aca Thr ccc Pro ata Ile aat Asn 200 cta Leu cac His act Thr att Ile gta Vai 280 ctc Leu gca Aia acc Thr acc Thr 105 tcc Ser ggC Giy gaa Giu ct C Leu ttt Phe 185 gtt Vai ttt Phe ata Ile cta Leu gaa Giu 265 ggg Giy cga Arg cac His agg Arg tcc Ser aat Asn act Thr ggc Giy ttt Phe 170 gga Gly agt Ser ggc Gly gaa Giu aca Thr 250 tat Tyr ctt Leu gtg Vai gct Ala agg Arg 330 atc Ile caa Gin gtt Vai Giy 155 ggt Giy aaa Lys cag Gin tgt Cys ggc Gly 235 act Thr Ctg Leu gct Aia ata Ile gct Aia 315 cga Arg aag atc Ile at t Ile 140 aaa Lys ttt Phe gga Gly acc Thr gta Vai 220 tgg Trp att Ile gac Asp tac Tyr tct Ser 300 gag Giu ctg Leu cgg agt Ser 125 aca Thr ata Ile ctc Leu att Ile aag Lys 205 ctc Leu agt Ser gga Gly ttc Phe ttt Phe 285 aaa Lys tgg 'rrp agt Ser 110 cac His acc Thr ttc Phe ttg Leu gcc Ala 190 att Ile ttt Phe gcc Ala ttt Phe tat Tyr 270 gct Aila aag Lys aca Thr gtg Val tgg Trp ata Ile tgt Cys gct Al a 175 aaa Lys cgc Arg gtg Val ctg Leu ggt Gly 255 aag Lys gct Al a aca Thr gcc Ala gag Glu 335 ga t Asp gga Giy atc Ile 160 gga Gly gtg Vai atc Ile gct Ala gac Asp 240 gac Asp cct Pro gtc Val aaa Lys aac Asn 320 att le t tg Leu ttt Phe 145 atc Ile gtt Val gaa Giu atc Ile ctg Leu 225 gcc Ala tac Tyr gtc Vai ctg Leu gaa Giu 305 gtc Vai tat Tyr gga Gly 130 gga Gly tat Tyr gga Gly ga t Asp tca Se r 210 cct Pro att Ile gtt Val gtg Val agc Ser 290 gag Giu aca Thr gac Asp 115 agt Ser aac Asn gcc Ala gat *Asp acg Thr 195 aca Thr gcg Ala tat Tyr gca Ala tgg Trp 275 atg Met gtg Val gcC Ala aag Lys 442 490 538 586 634 682 730 778 826 874 922 970 1018 aag ctc tcg gca qaa ctg gct 1114 Lys Arg Lys Leu Ser Ala Glu Leu Ala WO 99/43696 WO 9943696PCTIUS99/03826 gga aac cac aat cag gag ctg act cct tgt agg agg acc ctg tca gtg Gly Asn His Asn Gin Giu Leu Thr Pro Cys Arg Arg Thr Leu Ser Val 360 365 370 aac cac ctg acc agc gag agg gat gtc ttg cct ccc tta ctg aag act Asn His Leu Thr Ser Glu Arg Asp Vai Leu Pro Pro Leu Leu Lys Thr 375 380 385 1162 1210 gag agt atc Giu Ser Ile 390 att gct gtg Ile Ala'Vai 405 tat ctg aat ggt Tyr Leu Asn Gly acg cca cac tgt gct ggt gaa gag Thr Pro His Cys Ala Gly Giu Giu 400 1258 att gag aac atc aaa tag ccctctcttt aaataacctt Ile Giu Asn Ile Lys* 410 1305 aggcatagcc ttaaattgtg catcaagaga tccactttct gttttcctct ggtaacaatg tagatatgga atgcagcctt tctctagcta cttttacccc ctgaagtgat ctcagcgttg gagtatttat ggtaaaattg tttattaata tctatctatc gaagaaaact tcattctgat atactgccag tgggtgactt gccttctgtg ggatcactgt ttagagaaaa acataaaaga gttccaagat ttttcatact aaataatttc gggagctgta tttaaaagaa aatgtaaata aaaattttag gttccgaaaa aaagtttgta aaaaaaaaaa.

ataggtgagg catgagctca atttggaatt ttgatgagtg ctctttccct tagctttgag ccatttatgg ttacctaaga atgtgtggtt agttctccca gatgcccgaa cctagcgtta ttgactcagg gctgctcgca actatacatt tatctatcta gttaaaaatg ggaaagaaaa cttctaattg ttgccagatg ggtatacttt gactttgcac agctgttata ggctgattat tcagaaaaaa tagatctgct cctaaatata tctgaataag gcaaataaac ttcaattaat aaagtcaggc tttatatggt attaaagtca aaaaa acttctctat aagggggaac ctgagccagc gaatgacaag aatgtgccat ggatcagttc atgacaacaa aattttctgt tctccttccc tttgaatacc gatgaaatag aaggcactgc taccagtggt aacaatcccc tttaaaggca tctatctatc gatattattg tagcaaaaca ctttttgatg agaggaggtg tggagttgtg atggaaaaat gcacaattta tctttttagt ttcagtaaat gtacattgta attgcaaact tggcattcag taatagacgc ttgttaaaag tcttttagaa ggaatgcgcc aaaaaaaaaa gctctttatg aaaatagata actttctttc caatgtctga aaggcctcag ttaacttttc tttttttttt cagtgcctta tgcccccacc ataccttgct atgccaaatt agagaaatga acatatatac ttttttcctg gaagaagaaa tatctatcta gaggggattt atgtgttaca tatgaaaggc gcacagtggt acttggctgt gcagattgca aattttgaga ttaattttat gcaccccgta tatatatata gatttctttt attagggtct ttattttcca tacttttata agaaagctac atgtataaac aaaaaaaaaa actgttgctg cacccatcat tgatgatgct tgcctttttg aatgaatgag agggtctacc gtaaatgaca tcttatgaag cctaggctca ggaaacagtg agatggacat ggtgcagagg agtgtaatta gcagtatttg atctatctat tctatctaaa aaaacagtgg agtatttgct ttatataatt gagtgcaggg gagggcagaa ggcataattc gtttgctgtg atcctgtaat aattgctacc atttttaaaa acttttttgt tgaaaaataa aaatttaaat aagt taaaaa acccatttcc tgtgaattgt aaaaaaaaaa gtagcatttt ggtcat ctat tgt tgaacgg tgcccagact aattgtttct taactgagcc agaaattctt aaacagaacc cctctgcagt tgtaaaatga tgaagcaaca tggcccctct tgaccaggct gaatttatca catctatcta tgacctgaca gtgtgaatta aataaacagt ttcttttcgt cacagtccta gttgaagttg atctctgaca tttttttttc tctttggatg ctttccttta tgcagaaaga gtctgggggt acccagaatc ttaagctaga aaatccaacc tcaaataact attgacaaat aaaaaaaaaa 1365 1425 1485 1545 1605 1665 1725 1785 1845 1905 1965 2025 2085 2145 2205 2265 2325 2385 2445 2505 2565 2625 2685 2745 2805 2865 2925 2985 3045 3105 3165 3225 3285 3300 <210> 83 <211> 411 <212> PRT <213> H. sapiens <400> 83 Met Ala Ala Pro Asp Leu Leu Asp Pro Lys Ser Ala Ala Gin Asn Ser 1 5 10 Lys Pro Arg Leu Ser Phe Ser Thr Lys Pro Thr Val Leu Ala Ser Arg WO 99/43696 WO 9943696PCT/US99/03826 Val Thr Phe Val Thr Gly Leu Phe 145 Ile Val Giu Ile Leu 225 Ala Tyr Val Leu Giu 305 Val Tyr Glu Leu Leu 385 Gly Giu Ile Lys Ile Glu Ile Gly 130 Gly Tyr Gly Asp Ser 210 Pro Ile Val Val Ser 290 Giu Thr Asp Leu Ser 370 Lys Giu Ser Phe Ala Gin Leu Ile 115 Ser Asn Ala Asp Thr 195 Thr Ala Tyr Ala Trp 275 Met Val Ala Lys Ala 355 Val Thr Glu Asp Leu Leu Lys Asp 100 Pro Ser Ile Leu Gin 180 Phe Ile Ile Phe Gly 260 Phe Ile Gly Giu Phe 340 Gly Asn Giu Ile Thr Val Glu Gin Giu Leu Phe Ser Leu 165 Leu Ile Ile Ile Val 245 Gly Trp Gly Glu Phe 325 Gin Asn His Ser Ala 405 Thr Val Gin 70 Thr Leu Gly Phe Pro 150 Gly Gly Lys Phe Phe 230 Val Ser Ile Asp Phe 310 Lys Arg His Leu Ile 390 Val Ile Vai 55 Pro Phe Ile Asn Phe 135 Arg Ile Thr Trp Ile 215 Lys Ile Asp Leu Trp 295 Arg Giu Ala Asn Thr 375 Tyr Ile Asn 40 Leu His Ile Gin Thr 120 Ala Thr Pro Ile Asn 200 Leu His Thr Ile Val 280 Leu Ala Thr Thr Gin 360 Ser Leu Glu 25 Val Tyr Glu Ser Gin 105 Ser Gly Giu Leu Phe 185 Val Phe Ile Leu Giu 265 Gly Arg His Arg Ser 345 Glu Giu Asn Asn Met Leu Ile Gin 90 Ile Asn Thr Gly Phe 170 Gly Ser Gly Glu Thr 250 Tyr Leu Val Ala Arg 330 Ile Leu Arg Gly Ile 410 Lys Ile Ser 75 His Val Gin Vai Gly 155 Gly Lys Gin Cys Gly 235 Thr Leu Ala Ile Ala 315 Arg Lys Thr Asp Leu 395 Lys Trp Ile Gin Ser Al a Ile Ile 140 Lys Phe Gly Thr Val 220 Trp Ile Asp Tyr Ser 300 Glu Leu Arg Pro Val 380 Thr Lys Gly Arg Cys Ala Ser 125 Thr Ile Leu Ile Lys 205 Leu Ser Gly Phe Phe 285 Lys Trp Ser Lys Cys 365 Leu Pro Thr Ala Thr Val Ile 110 His Thr Phe Leu Ala 190 le Phe Ala Phe Tyr 270 Ala Lys Thr Vai Leu 350 Arg Pro His Val Ser Thr Val Thr Ile Asn Ser Asn Ala Trp, Asp Ile Gly Cys Ile 160 Ala Gly 175 Lys Val Arg Ile Val Ala Leu Asp 240 Gly Asp 255 Lys Pro Ala Val Thr Lys Ala Asn 320 Glu Ile 335 Ser Ala Arg Thr Pro Leu Cys Ala 400 <210> <211> <212> <213 84

DNA

H. sapiens <400> 84 catagccata ggtgaggact <210> <211> <212> DNA WO 99/43696 WO 9943696PCTIUS99/03826 <213> H. sapiens <400> gagaggaaaa cagtctgggc <210> 86 <211> .4 <212> DNA <213> H. sapiens <400> 86 ggacatcgaa ctaagacctg <210> 87 <211> <212> DNA <213> H. sapiens <400> 87 tcccatgcca ttcagatctg

Claims (11)

1. An isolated nucleic acid encoding a mammalian K+Hnov protein.

2. An isolated nucleic acid according to claim 1, wherein said K+Hnov protein has the amino acid sequence of SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 25, 27, 81 or 83.

3. An isolated nucleic acid according to claim 1, wherein said K+Hnov protein has the amino acid sequence that is substantially identical to the amino acid sequence of SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 25, 27, 30, 81 or 83.

4. An isolated nucleic acid according to claim 1, wherein the nucleotide 0o sequence of said nucleic acid is SEQ ID NO: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 22, 23, 24, 26, 28, 29, 80 or 82. An isolated nucleic acid that hybridises under stringent conditions to a nucleic acid sequence of claim 4.

6. An isolated nucleic acid encoding a mammalian K+Hnov protein, substantially as hereinbefore described with reference to the Examples.

7. An expression cassette comprising a transcriptional initiation region functional in an expression host, a nucleic acid having a sequence of the isolated nucleic acid according to any one of claims 1 to 4 or 6 under the transcriptional regulation of said transcription initiation region, and a transcriptional termination region functional in said 20 expression host.

8. An expression cassette comprising a transcriptional initiation region functional in an expression host, a nucleic acid encoding a mammalian K+Hnov protein, S. under the transcriptional regulation of said transcription initiation region, and a transcriptional termination region functional in said expression host, substantially as 25 hereinbefore described with reference to Example 3.

9. A cell comprising an expression cassette according to claim 7 or claim 8 as S* part of an extrachromosomal element or integrated into the genome of a host cell as a s*e result of introduction of said expression cassette into said host cell, and the cellular progeny of said host cell. 30 10. A method for producing mammalian K+Hnov protein, said method comprising: growing a cell according to claim 9, whereby said mammalian K+Hnov protein is expressed; and /isolating said K+Hnov protein free of other proteins. I:\DAYLIB\liba]4750.doc:sak

11. Mammalian K+Hnov protein when produced according to the method of claim

12. A purified polypeptide composition comprising at least 50 weight of the protein present as a K+Hnov protein or a fragment thereof.

13. An isolated monoclonal antibody binding specifically to a K+Hnov protein. Dated 21 March, 2002 ICAgen Incorporated Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON foo (I:\DAYLIB\Iiba]4750.doc:sak