US20030036648A1

US20030036648A1 - Human potassium channel genes

Info

Publication number: US20030036648A1
Application number: US10/121,746
Authority: US
Inventors: Andrew Miller; Ping Hu; Mark Curran; Marc Rutter; Jian-Yang Wang
Original assignee: Icagen Inc
Current assignee: Icagen Inc
Priority date: 1998-08-07
Filing date: 2002-04-11
Publication date: 2003-02-20
Also published as: US20050112663A1; US20050112662A1; US6399761B1; US20100273256A1

Abstract

Methods for isolating K+Hnov genes are provided. The K+Hnov nucleic acid compositions find use in identifying homologous or related proteins and the DNA sequences encoding such proteins; in producing compositions that modulate the expression or function of the protein; and in studying associated physiological pathways. In addition, modulation of the gene activity in vivo is used for prophylactic and therapeutic purposes, such as identification of cell type based on expression, and the like.

Description

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 (Na ⁺), chloride (Cl⁻), calcium (Ca⁺⁺) and potassium (K⁺) 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 congenital 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 protein. The mink (IsK) gene contains a single TMD, and although not a channel by itself, mink associates with different K⁺ channel subunits, such as KvLQT1 and HERG to modify the activity of these channels. The inward rectifying K+channels (GIRK, IRK, 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⁺ 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. The 6TMD, or Shaker-like channels, presently comprise the largest subset of known K⁺ channels. The slopoke (slo) related channels, or Ca⁺⁺ regulated channels 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 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 10²-10³individual 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 ^ndEd. Sunderland M A:Sinauer Associates, also reviews potassium channels.

Jan and Jan (1997) Annu. Rev. Neurosci. 20:91-123 review cloned potassium channels from eukaryotes and prokaryotes. Ackerman and Clapham (1997) N. Engl. 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 DlS235.

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 17p11-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 al. (1998) J Neurosci 1 8(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 [K+] 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 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.

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 functional regions of the proteins; and in studying associated physiological pathways. The K+Hnov gene products 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.

Characterization Of K+Hnov

The sequence data predict that the provided K+Hnov genes encode potassium channels. Table 1 summarizes the DNA sequences, corresponding SEQ ID NOs, chromosomal locations, and polymorphisms. The provided 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 α subunits, generally comprising four subunits, and frequently associated with auxiliary, β subunits. Typically such α subunits share a six-transmembrane domain structure (S1-S6), 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 α subunits include Kv1.1-1.8 (Gutman et al. (1993) Sem. Neurosci. 5:101-106); Kv2.1-2.2; Kv3.1-3.4; Kv4.14.3; 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 Kv1 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 1


				Chromosome
Name	cDNA SEQ	Protein SEQ	Polymorphisms	Position	Channel Type

K + Hnov1	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
			A401G
			CA410-411GG (Ala/Thr)
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 + Hnov12	SEQ ID NO:9	SEQ ID NO:10	C321T (Pro/Leu)	Xp21	Voltage gated K + channel
			A375G (Glu/Gly)
			C407T (Leu/Phe)
K + Hnov15	SEQ ID NO:11	SEQ ID NO:12	Alternative poly(A) tail: 1427	13q14	modulatory subunit
			A689G (Gly/Arg)
K + Hnov27	SEQ ID NO:13	SEQ ID NO:14	T365A (Ile/Asn)	18q12	modulatory subunit
K + Hnov2	SEQ ID NO:15	SEQ ID NO:16	N/A	N/A	4 transmembrane domain, 2 pore
					domain K + channel
K + Hnov11	SEQ ID NO:17	SEQ ID NO:18	N/A	N/A	Human ortholog of munne gene, 6
					transmembrane dominas, voltage
					gated, delayed rectifier K + channel
K + Hnov14	SEQ ID NO:19	SEQ ID NO:20	C3168T	12q14	6 transmembrane domain, 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	8q11	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)_nrepeats in the 3′	1q41	4T/2P channel; linked to the
			UTR sequence, starting at		disease loci for rippling muscle
			position 21 86		disease 1 (RMD1), and type II
					pseudohypoaldosteronism
K⁺Hnov59	SEQ ID NO:82	SEQ ID NO:83	N/A	chr19	4T/2P channel

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 5′, or internal regulatory sequences as sometimes found in introns, contains sequences required for proper tissue and stage specific expression.

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 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. 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 126:3541 (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 177:1204 (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 50° C. and 6×SSC (0.9 M sodium chloride/0.09 M sodium citrate) and remain bound when subjected to washing at 55° C. in 1× SSC (0.15 M sodium chloride/0.015 M sodium citrate). Sequence identity may be determined by hybridization under stringent conditions, for example, at 50° C. or higher and 0.1×SSC (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 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 non-contiguous 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 purified protein will generally be at least about 80% pure, preferably at least about 90% pure, and may be up to and including 100% pure. Pure is intended to mean free of other proteins, as well as cellular debris.

The expressed K+Hnov polypeptides are useful for the production of antibodies, where short fragments provide for antibodies specific for the particular polypeptide, 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-type or variant forms of K+Hnov. Antibodies may be raised to isolated peptides corresponding to specific domains, e.g. the pore domain and the transmembrane domain, or to the native protein.

Antibodies are prepared in accordance with conventional ways, where the expressed 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 eukaryotic proteins, or the like. Various adjuvants may be employed, with a series of injections, 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, N.Y., 1988. If desired, the mRNA encoding the heavy and light chains may be isolated and mutagenized by cloning in E. coli, 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 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 11 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 β-cell ATP-sensitive 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 1), 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.

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 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′-dimethoxy4′,5′-dichloro-6-carboxyfluorescein (JOE), 6-carboxy-X-rhodamine (ROX), 6-carboxy-2′,4′,7′,4,7-hexachlorofluorescein (HEX), 5-carboxyfluorescein (5-FAM) 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. Pat. No. 5,445,934, or in WO95/35505, 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 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 20 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 14:441447; Lockhart et al. (1996) Nature Biotechnol. 14:1675-1680; and De Risi et al. (1996) Nature Genetics 14:457460.

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 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 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 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 antisense complementation.

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

Among useful changes in the backbone chemistry are phosphorothioates; phosphorodithioates, 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, 3′-S-5′-O-phosphorothioate, 3′-CH2-5′-O-phosphonate and 3′-NH-5′-O-phosphoroamidate. Peptide nucleic acids replace the entire ribose phosphodiester backbone with a peptide linkage. Sugar modifications are also used to enhance stability and affinity. The α-anomer of deoxyribose may be used, where the base is inverted with respect to the natural β-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 9523225, and Beigelman et al. (1995) Nucl. Acids Res 23:443442). Examples of oligonucleotides with catalytic activity are described in WO 9506764. Conjugates of anti-sense ODN with a metal complex, e.g. terpyridylCu(II), capable of mediating mRNA hydrolysis are described in Bashkin et al. (1995) Appl 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 known in the art. For various techniques for transfecting mammalian cells, see Keown et al. (1990) Methods in Enzymology 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.

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 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, carbonyl, 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 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 40° C. 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 0.1-100 wt.%. 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 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 “a”, “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 “a”, “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 admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention.

Experimental

The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the subject invention, and are not intended to limit the scope of what is regarded as the invention. Efforts have been made to ensure accuracy with respect to the numbers used (e.g. amounts, temperature, concentrations, etc.) but some experimental errors and deviations should be allowed for. Unless otherwise indicated, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees centigrade; and pressure is at or near atmospheric.

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 subfamilies 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	TGGTGGGCTGTGGTGACCATGACAACTGTGGGCTATGGGGACATG

50	M60451	TGGTGGGCAGTGGTCACCATGACCACTGTGGGCTACGGGGACATG

51	L02752	TGGTGGGCAGTCGTCTCCATGACAACTGTAGGCTATGGAGACATG

52	M55515	TGGTGGGCAGTGGTAACCATGACAACAGTGGGTTACGGCGATATG

53	Z11585	TGGTGGGCTGTGGTCACCATGACGACCCTGGGCTATGGAGACATG

54	U40990	TGGTGGGGGGTGGTCACAGTCACCACCATCGGCTATGGGGACAAG

55	I26643	TGGTGGGCAGTGGTCACCATGACCACGGTTGGCTATGGGGACATG

56	M96747	TGGTGGGCCGTGGTCACCATGACGACCCTGGGCTATGGAGACATG

57	M64676	TGGTGGGCTGTGGTCACCATGACGACACTGGGCTACGGAGACATG

58	M55514	TGGTGGGCTGTGGTGACCATGACAACTGTGGGCTATGGGGACATG

59	X83582	TTCCTGTTCTCCATTGAGACCGAAACAACCATTGGGTATGGCTTCCG

60	S78684	TTTTTATTCTCAATAGAGACAGAAACCACCATTGGTTATGGCTACCG

61	U22413	TTCCTCTTCTCCATTGAGACCCAGACAACCATAGGCTATGGTTTCAG

62	U24056	TTCCTGTTCTCGGTGGAGACGCAGACGACCATCGGCTATGGGTTCCG

63	U52155	TTCCTCTTCTCCCTTGAATCCCAAACCACCATTGGCTATGGCTTCCG

64	D87291	TTTCTCTTTTCCCTGGAATCCCAGACAACCATTGGCTATGGAGTCCG

65	D50582	TTCCTTTTCTCCATTGAGGTCCAAGTGACTATTGGCTTTGGGGGGCG

66	D50315	TTTCTCTTCTCCATTGAAGTTCAAGTTACCATTGGGTTTGGAGGGAG

67	U04270	GCGCTCTACTTCACCTTCAGCAGCCTCACCAGTGTGGGCTTCGGCAAC

The unique pore peptides sequences are shown in Table 3

TABLE 3


SEQ ID NO	Amino acid sequence

68	WWAVVSMTTVGYGDM

69	WWAVVTMTTLGYGDM

70	WWGVVTVTTIGYGDK

71	WWAVVTMTTVGYGDM

72	FLFSIEVQVTIGFGG

73	FLFSLESQTTIGYGV

74	FLFSIETETTIGYGY

75	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 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, i.e., 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				IMAGE Plate
Accesaion#	K + Hnov	clone ID	Trace	Coordinates	Read 5′/3′

N39619	K + Hnov2	277113	yy51h05.s1	611p10	3′
N46767	K + Hnov2	277113	yy51h05.r1	611p10	5′
R19352	K + Hnov11	33144	yg24f12.r1	155o24	5′
R44628	K + Hnov11	33144	yg24f12.s1	155o24	3′
R35526	K + Hnov14	37299	yg64e08.r1	165o15	5′
R73353	K + Hnov14	157854	yl10e04.r1	251g07	5′
AA397616	K + Hnov14	728558	zt79c08.r1	1787j15	5′
AA286692	K + Hnov28	700757	zs48h03.r1	1715d6	5′
AA150494	K + Hnov42	491748	z108e07.s1	1170o13	3′
AA156697	K + Hnov42	491748	z108e07.r1	1170o13	5′
AA191752	K + Hnov42	626699	zp82d06.r1	1522f12	5′
AA216446	K + Hnov42	626699	zp82d06.s1	1522f12	3′
AA430591	K + Hnov42	773611	zw51f10.r1	1904o20	5′
AA236930	K + Hnov44	683888	zs01a05.s1	1671e9	3′
AA236968	K + Hnov44	683888	zs01a05.r1	1671e9	5′

EXAMPLE 2

Chromosomal Localization

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+Hnov1 on GB4
(SEQ ID NO:31) F: 5′ TATCCACATCAATGGACAAAGC 3′

(SEQ ID NO:32) R: 5′ TGCATAACTGGCTGGGTGTA 3′
Results: 1.71 cR from D2S331, Cytogenetic location of 2q37

K+Hnov2 on G3
F: 5′ GTCAGGTGACCGAGTTCA 3′

R: 5′ GCTCCATCTCCAGATTCTTC 3′
Results: 0.0 cR from SHGC-1320, Cytogenetic location of 11q12

K+Hnov6 on GB4
(SEQ ID NO:33) F: 5′ TGACATCACTGGATGAACTTGA 3′

(SEQ ID NO:34) R: 5′ TGCCTGCAAAGTTTGAACAT 3′
Results: 5.23 cR from WI-5509, Cytogenetic location of 2p23

K+Hnov9 on G64
(SEQ ID NO:35) F: 5′ TGACATCACTGGATGAACTTGA 3′

(SEQ ID NO:36) R: 5′ TGCCTGCAAAGTTTGAACAT 3′
Results 1.21 cR from AFM200VC7. Cytogenetic location of 8q23

K+Hnov11 on G84
(SEQ ID NO:37) F: 5′ ACCTGGTGGTATGGAAGCAT 3′

(SEQ ID NO:38) R: 5′ TTTCTCCTGGCCTCTACCC 3′
Results. 2.43 cR from WI-6756, Cytogenetic location of 8q23

K+Hnov12 on G3
(SEQ ID N0:39) F: 5′ TCCCTCTTGGGTGACCTTC 3′

(SEQ ID NO:40) R: 5′ ATCTTTGTCAGCCACCAGCT 3′
Results. 7.45 cR from SHGC-32925, Cytogenetic location of Xp21

K+Hnov14 on G84
(SEQ ID NO:41) F: 5′ AGGTGTGCTGCCATCTGCTGTTCG3′

(SEQ ID NO:42) R: 5′ AGCCTATCCTCTCTGAGAGTCAGG
Results: 7.69 cR from WI-7107, Cytogenetic location of 12q14

K+Hnov28 on G84
(SEQ ID NO:43) F: 5′AAGCAGAGTACTCATGATGCC 3′

(SEQ ID NO:44) R: 5′TCTGGTAGACAGTACAGTGG 3′
Results: 35.38 cR from WI-9695, Cytogenetic location of 3q29

K+Hnov42 on G3
(SEQ ID NO:45) F: 5′CATTTGGCTGGTCCAAGATG 3′

(SEQ ID NO:46) R: 5′AGTCATTGGTAGGGAGGTAC 3′
Results: 7.45 cR from SHGC-32925, Cytogenetic location of Xp21

K+Hnov44 on G3
(SEQ ID NO:47) F: 5′CATGCTTCTACAGTCCAGCC 3′

(SEQ ID NO:48) R: 5′GGTCCTCAGTTGCAGAAATC 3′
Results: 7.45 CR from SHGC-32925, Cytogenetic location of Xp21

Map positions for K+Hnov15 and K+Hnov27 were obtained from public databases. K+Hnov2 and K+Hnov4 have not been mapped. [0097]

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 cDNk Total RNA was purchased (Clontech, Invitrogen) and used to synthesize first strand cONA using M-MLV reverse transcriptase and the supplied buffer (Gibco-BRL). The 20 μl reaction contained 5 μg total RNA, 100 ng of random primers, 10 mM DTT. 0.5 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 95° C. These cDNAs, along with control ccDNA synthesis reactions without reverse transcriptase, were diluted 1:5 and 2 μl 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 μl PCR reactions with standard conditions, 2.5 mM MgCl[0098] ₂, 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


Anchor		Adrenal			Cere-			Esopha-	Fetal	Fetal
name	Adipose	Gland	Bladder	Brain	bellum	Cervix	Colon	gus	Brain	Liver

K + Hnov1	+	+	+	+	+	−	+	+	+	+
K + Hnov2	+		+	+	+	+	+	+	−	+
K + Hnov4		−	−	+	+		+		+	−
K + Hnov6		+	+	+	+		+	+	+	−
K + Hnov9		+	−	+	+		−		−	−
K + Hnov11			+	+	+		−		+	+
K + Hnov12	+	+	+	−	−	−	−	−	+	−
K + Hnov14	−	+	+	−	+	+	+	+	+	+
K + Hnov15		+	+	+	+		+		+	+
K + Hnov27	+	+	+	+	+	+	+	+	+	+
K + Hnov28	−	+	+	+	+		+	+	+	+
K + Hnov42
K + Hnov44	+	+	+	+	+	+	+	+	+	+

He La

Mammary

Pan-

Salvary

Heart

Cell

Kidney

Liver

Lung

Gland

creas

Placenta

Prostate

Rectum

Gland

K + Hnov1	+	+	+	+	+	+	+	+	+		+
K + Hnov2	+	+	+	+	+	+	−	+	+	+	−
K + Hnov4	−	−	−	−	−	+	−	−	+		+
K + Hnov6	+	−	+	+	+	+	+	+	+	+	+
K + Hnov9	−	−	+	−	−	−	+	−		−	+
K + Hnov11	+	+	+	+	+	+	+	+	+		+
K + Hnov12	−	−	−	+	−	−	−	−	−	−	−
K + Hnov14	−	+	+	+	+	+	+	+	+	+	+
K + Hnov15	+	+	+	+	+	+	+	+	+		+
K + Hnov27	+	+	+	+	+	+	+	+	+	+	+
K + Hnov28	+	+	+	+	+	+	+	+	+		+
K + Hnov42
K + Hnov44	+	+	+	+	++	+	+	+	+	+

Skeletal		Small
Muscle	Skin	Intestine	Spleen	Stomach	Testis	Thymus	Trachea	Uterus

K + Hnov1	+		+	+	+	+	+	+	+
K + Hnov2	+	−	+		+	+	+	−	+
K + Hnov4	+		+	−	−	−	−	−	−
K + Hnov6	+	+	+	+	+	+	+	+	+
K + Hnov9		−	−	+	−	+	+	+
K + Hnov11			+		+		−	+	+
K + Hnov12	−	−	−	+	−	−	−	−	+
K + Hnov14	+	+	+	−	−	+	+	+	+
K + Hnov15	+		+	+	+	+	+	+	+
K + Hnov27	+	+	+	+	+	+	+	+	+
K + Hnov28	+		+	+	+	+	+	+	+
K + Hnov42
K + Hnov44	+	+	+	+	+	+	+	+	+


K+Hnov49 on Whitehead GB4 RH mapping panel:
Primer 1: (SEQ ID NO:5): 5′ - CATAGCCATAGGTGAGGACT - 3′

Primer 2: (SEQ ID NO: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 [0101]
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 [[0102] ³²P]dCTP (Amersham) by the random primer method. Adult human Multiple Tissue Northern (MTM™) Blots (Clontech) were hybridized with the [³²P]-labeled fragment in ExpressHyb™ solution (Clontech) for four hours, washed to a final stringency of 0.1× SSC, 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. [0103]

TABLE 4

Adipose Adrenal Gland Bladder Brain Cerebellum Cervix

#49

#59

Colon Esophagus Fetal Brain Fetal Liver Heart

#49

#59

HeLa Cell Kidney Liver Lung Mammary Gland Pancreas

#49

#59

Salivary Skeletal Small

Placenta Prostate Rectum Gland Muscle Skin intestine

#49

#59

Spleen Stomach Testis Thymus Trachea Uterus

#49

#59
[0104]
1 87 1 2932 DNA H. sapiens CDS (103)...(1180) K+Hnov1 1 attaaaatta tctgatcaaa aaggcagact ctgtaaattt ccttaagacc taccttggca 60 taaaggctga cccagcaaaa gaactgagaa atacagcctg ag atg gac agc agt 114 Met Asp Ser Ser 1 aat tgc aaa gtt att gct cct ctc cta agt caa aga tac cgg agg atg 162 Asn Cys Lys Val Ile Ala Pro Leu Leu Ser Gln Arg Tyr Arg Arg Met 5 10 15 20 gtc acc aag gat ggc cac agc aca ctt caa atg gat ggc gct caa aga 210 Val Thr Lys Asp Gly His Ser Thr Leu Gln Met Asp Gly Ala Gln Arg 25 30 35 ggt ctt gca tat ctt cga gat gct tgg gga atc cta atg gac atg cgc 258 Gly Leu Ala Tyr Leu Arg Asp Ala Trp Gly Ile Leu Met Asp Met Arg 40 45 50 tgg cgt tgg atg atg ttg gtc ttt tct gct tct ttt gtt gtc cac tgg 306 Trp Arg Trp Met Met Leu Val Phe Ser Ala Ser Phe Val Val His Trp 55 60 65 ctt gtc ttt gca gtg ctc tgg tat gtt ctg gct gag atg aat ggt gat 354 Leu Val Phe Ala Val Leu Trp Tyr Val Leu Ala Glu Met Asn Gly Asp 70 75 80 ctg gaa cta gat cat gat gcc cca cct gaa aac cac act atc tgt gtc 402 Leu Glu Leu Asp His Asp Ala Pro Pro Glu Asn His Thr Ile Cys Val 85 90 95 100 aag tat atc acc agt ttc aca gct gca ttc tcc ttc tcc ctg gag aca 450 Lys Tyr Ile Thr Ser Phe Thr Ala Ala Phe Ser Phe Ser Leu Glu Thr 105 110 115 caa ctc aca att ggt tat ggt acc atg ttc ccc agt ggt gac tgt cca 498 Gln Leu Thr Ile Gly Tyr Gly Thr Met Phe Pro Ser Gly Asp Cys Pro 120 125 130 agt gca atc gcc tta ctt gcc ata caa atg ctc cta ggc ctc atg cta 546 Ser Ala Ile Ala Leu Leu Ala Ile Gln Met Leu Leu Gly Leu Met Leu 135 140 145 gag gct ttt atc aca ggt gct ttt gtg gcg aag att gcc cgg cca aaa 594 Glu Ala Phe Ile Thr Gly Ala Phe Val Ala Lys Ile Ala Arg Pro Lys 150 155 160 aat cga gct ttt tca att cgc ttt act gac aca gca gta gta gct cac 642 Asn Arg Ala Phe Ser Ile Arg Phe Thr Asp Thr Ala Val Val Ala His 165 170 175 180 atg gat ggc aaa cct aat ctt atc ttc caa gtg gcc aac acc cga cct 690 Met Asp Gly Lys Pro Asn Leu Ile Phe Gln Val Ala Asn Thr Arg Pro 185 190 195 agc cct cta acc agt gtc cgg gtc tca gct gta ctc tat cag gaa aga 738 Ser Pro Leu Thr Ser Val Arg Val Ser Ala Val Leu Tyr Gln Glu Arg 200 205 210 gaa aat ggc aaa ctc tac cag acc agt gtg gat ttc cac ctt gat ggc 786 Glu Asn Gly Lys Leu Tyr Gln Thr Ser Val Asp Phe His Leu Asp Gly 215 220 225 atc agt tct gac gaa tgt cca ttc ttc atc ttt cca cta acg tac tat 834 Ile Ser Ser Asp Glu Cys Pro Phe Phe Ile Phe Pro Leu Thr Tyr Tyr 230 235 240 cac tcc att aca cca tca agt cct ctg gct act ctg ctc cag cat gaa 882 His Ser Ile Thr Pro Ser Ser Pro Leu Ala Thr Leu Leu Gln His Glu 245 250 255 260 aat cct tct cac ttt gaa tta gtt gta ttc ctt tca gca atg cag gag 930 Asn Pro Ser His Phe Glu Leu Val Val Phe Leu Ser Ala Met Gln Glu 265 270 275 ggc act gga gaa ata tgc caa agg agg aca tcc tac cta ccg tct gaa 978 Gly Thr Gly Glu Ile Cys Gln Arg Arg Thr Ser Tyr Leu Pro Ser Glu 280 285 290 atc atg tta cat cac tgt ttt gca tct ctg ttg acc cga ggt tcc aaa 1026 Ile Met Leu His His Cys Phe Ala Ser Leu Leu Thr Arg Gly Ser Lys 295 300 305 ggt gaa tat caa atc aag atg gag aat ttt gac aag act gtc cct gaa 1074 Gly Glu Tyr Gln Ile Lys Met Glu Asn Phe Asp Lys Thr Val Pro Glu 310 315 320 ttt cca act cct ctg gtt tct aaa agc cca aac agg act gac ctg gat 1122 Phe Pro Thr Pro Leu Val Ser Lys Ser Pro Asn Arg Thr Asp Leu Asp 325 330 335 340 atc cac atc aat gga caa agc att gac aat ttt cag atc tct gaa aca 1170 Ile His Ile Asn Gly Gln Ser Ile Asp Asn Phe Gln Ile Ser Glu Thr 345 350 355 gga ctg aca g aataagactt atccattttt taatgtatta aatacaccca 1220 Gly Leu Thr gccagttatg cagctacttt ttctttactg tatctcatgt tttctttttt caatgctaat 1280 tatagctctc tacatcacgg taatcatgcc tatgcctaca taagaatggc tgagctaaca 1340 atacacattc tggaaacata acactctaca ttacaaagtt tgttacctgc tgaaatcaat 1400 gtaactcaac ttgacagaca cttatacaga aatgttgctg gtgaatttat aagaatgtgg 1460 tatgatacta gtaatgaagg caaaatggac agtgaagttt aacacaactg aactctaaga 1520 aaatcaacca ttaatctctc attttcatct gcaaattgaa gcaacagttt agtttcaaac 1580 ctagctccct gggtggaatg acgacttcac tatacttagt gaatatcctt taagagctgg 1640 gatttttttc aagacaacaa agatcattca tttggttctt tatactatga aacttgagta 1700 agtattacct ccttaatttt taacaactaa gaacaaaaat taacgagaaa aacaacaaag 1760 tacagattta tacataaacc taaaagcatt tgaacatgac acccgaacac atacatatat 1820 gttcacttat ttgtggcaga aggtgatcag ataagctcca gcccaaatgg aacctgtggg 1880 gtggtatttt gcattgcaag gagacgcaaa attttatttt aaaactgtcc tccataataa 1940 tcaaacggtg attcatctaa atgacttcta gcaacctaag taaaaacatt cccctcctat 2000 gtatgattca tttgatcata taaaacatca tgatggctct aattcataaa tacaaaaata 2060 tatttaagtc tttatagata taaagcttta cttagatata acttgagtga gtagggaaaa 2120 aaatctacag tagataaagc aaaagataat taggcaacaa agcattttca aactcaaatt 2180 cctgtttcca acttcaaata gttttttcta taaacacaaa atcagtgttt attcaccagt 2240 aggaggttgg actagatgaa ctctattatt tctttctaaa tctaatagtc tataaaaatt 2300 atgtttcctc tgttttttat tttatctatg ctaaaatgag ccctttccct tatgtccagt 2360 ttaagatgat catttgcatg attttcattt caataaaaaa aagagaaact gtccttaaaa 2420 caaaacaaaa accaaaaaag tcaccctatc aggtttcaaa cagatttgtg gctgttcttt 2480 tctgaaattt cccttattca ggtttctgtg ggaaaaatga aagattaacc ttccccactg 2540 gtgatgacct aggcaggaat catctcttga aataaatact agctgagtaa aggcaagcag 2600 gtgtgaagag cagggctcag cagcaagtca catttttcta ctatttgacc aaaaggaaaa 2660 gaaaataaag aagaactctg gagtggtcta agactgataa tagcagaaga atatcaagaa 2720 cacagaaact taattattgt gaacttttgc tgtttgaaaa tcttagacat tcattcttaa 2780 gtagaaatca gaccaacaga ttttcccaac ccaagactat tgtaacacat aaagacagca 2840 agaattctta tttctataat aaattaacaa gattcaccta acctttgaaa ataaagtagt 2900 attgaagact taaaaaaaaa aaaaaaaaaa aa 2932 2 359 PRT H. sapiens 2 Met Asp Ser Ser Asn Cys Lys Val Ile Ala Pro Leu Leu Ser Gln Arg 1 5 10 15 Tyr Arg Arg Met Val Thr Lys Asp Gly His Ser Thr Leu Gln Met Asp 20 25 30 Gly Ala Gln Arg Gly Leu Ala Tyr Leu Arg Asp Ala Trp Gly Ile Leu 35 40 45 Met Asp Met Arg Trp Arg Trp Met Met Leu Val Phe Ser Ala Ser Phe 50 55 60 Val Val His Trp Leu Val Phe Ala Val Leu Trp Tyr Val Leu Ala Glu 65 70 75 80 Met Asn Gly Asp Leu Glu Leu Asp His Asp Ala Pro Pro Glu Asn His 85 90 95 Thr Ile Cys Val Lys Tyr Ile Thr Ser Phe Thr Ala Ala Phe Ser Phe 100 105 110 Ser Leu Glu Thr Gln Leu Thr Ile Gly Tyr Gly Thr Met Phe Pro Ser 115 120 125 Gly Asp Cys Pro Ser Ala Ile Ala Leu Leu Ala Ile Gln Met Leu Leu 130 135 140 Gly Leu Met Leu Glu Ala Phe Ile Thr Gly Ala Phe Val Ala Lys Ile 145 150 155 160 Ala Arg Pro Lys Asn Arg Ala Phe Ser Ile Arg Phe Thr Asp Thr Ala 165 170 175 Val Val Ala His Met Asp Gly Lys Pro Asn Leu Ile Phe Gln Val Ala 180 185 190 Asn Thr Arg Pro Ser Pro Leu Thr Ser Val Arg Val Ser Ala Val Leu 195 200 205 Tyr Gln Glu Arg Glu Asn Gly Lys Leu Tyr Gln Thr Ser Val Asp Phe 210 215 220 His Leu Asp Gly Ile Ser Ser Asp Glu Cys Pro Phe Phe Ile Phe Pro 225 230 235 240 Leu Thr Tyr Tyr His Ser Ile Thr Pro Ser Ser Pro Leu Ala Thr Leu 245 250 255 Leu Gln His Glu Asn Pro Ser His Phe Glu Leu Val Val Phe Leu Ser 260 265 270 Ala Met Gln Glu Gly Thr Gly Glu Ile Cys Gln Arg Arg Thr Ser Tyr 275 280 285 Leu Pro Ser Glu Ile Met Leu His His Cys Phe Ala Ser Leu Leu Thr 290 295 300 Arg Gly Ser Lys Gly Glu Tyr Gln Ile Lys Met Glu Asn Phe Asp Lys 305 310 315 320 Thr Val Pro Glu Phe Pro Thr Pro Leu Val Ser Lys Ser Pro Asn Arg 325 330 335 Thr Asp Leu Asp Ile His Ile Asn Gly Gln Ser Ile Asp Asn Phe Gln 340 345 350 Ile Ser Glu Thr Gly Leu Thr 355 3 1927 DNA H. sapiens CDS (105)...(1908) K+Hnov4 3 ggagccccgc agcgcttctt atgatcagct cggtgtgtgt ctcctcctac cgcgggcgca 60 agtcggggaa caagcctccg tccaaaacat gtctgaagga ggag atg gcc aag ggc 116 Met Ala Lys Gly 1 gag gcg tcg gag aag atc atc atc aac gtg ggc ggc acg cga cat gag 164 Glu Ala Ser Glu Lys Ile Ile Ile Asn Val Gly Gly Thr Arg His Glu 5 10 15 20 acc tac cgc agc acc ctg cgc acc cta ccg gga acc cgc ctc gcc tgg 212 Thr Tyr Arg Ser Thr Leu Arg Thr Leu Pro Gly Thr Arg Leu Ala Trp 25 30 35 ctg gcc gac ccc gac ggc ggg ggc cgg ccc gag acc gat ggc ggc ggt 260 Leu Ala Asp Pro Asp Gly Gly Gly Arg Pro Glu Thr Asp Gly Gly Gly 40 45 50 gtg ggt agc agc ggc agc agc ggc ggc ggg ggc tgc gag ttc ttc ttc 308 Val Gly Ser Ser Gly Ser Ser Gly Gly Gly Gly Cys Glu Phe Phe Phe 55 60 65 gac agg cac ccg ggc gtc ttc gcc tac gtg ctc aac tac tac cgc acc 356 Asp Arg His Pro Gly Val Phe Ala Tyr Val Leu Asn Tyr Tyr Arg Thr 70 75 80 ggc aag ctg cac tgc ccc gca gac gtg tgc ggg ccg ctc ttc gag gag 404 Gly Lys Leu His Cys Pro Ala Asp Val Cys Gly Pro Leu Phe Glu Glu 85 90 95 100 gag ctg gcc ttc tgg ggc atc gac gag acc gac gtg gag ccc tgc tgc 452 Glu Leu Ala Phe Trp Gly Ile Asp Glu Thr Asp Val Glu Pro Cys Cys 105 110 115 tgg atg acc tac cgg cag cac cgc gac gcc gag gag gcg ctg gac atc 500 Trp Met Thr Tyr Arg Gln His Arg Asp Ala Glu Glu Ala Leu Asp Ile 120 125 130 ttc gag acc ccc gac ctc att ggc ggc gac ccc ggc gac gac gag gac 548 Phe Glu Thr Pro Asp Leu Ile Gly Gly Asp Pro Gly Asp Asp Glu Asp 135 140 145 ctg gcg gcc aag agg ctg ggc atc gag gac gcg gcg ggg ctc ggg ggc 596 Leu Ala Ala Lys Arg Leu Gly Ile Glu Asp Ala Ala Gly Leu Gly Gly 150 155 160 ccc gac ggc aaa tct ggc cgc tgg agg agg ctg cag ccc cgc atg tgg 644 Pro Asp Gly Lys Ser Gly Arg Trp Arg Arg Leu Gln Pro Arg Met Trp 165 170 175 180 gcc ctc ttc gaa gac ccc tac tcg tcc aga gcc gcc agg ttt att gct 692 Ala Leu Phe Glu Asp Pro Tyr Ser Ser Arg Ala Ala Arg Phe Ile Ala 185 190 195 ttt gct tct tta ttc ttc atc ctg gtt tca att aca act ttt tgc ctg 740 Phe Ala Ser Leu Phe Phe Ile Leu Val Ser Ile Thr Thr Phe Cys Leu 200 205 210 gaa aca cat gaa gct ttc aat att gtt aaa aac aag aca gaa cca gtc 788 Glu Thr His Glu Ala Phe Asn Ile Val Lys Asn Lys Thr Glu Pro Val 215 220 225 atc aat ggc aca agt gtt gtt cta cag tat gaa att gaa acg gat cct 836 Ile Asn Gly Thr Ser Val Val Leu Gln Tyr Glu Ile Glu Thr Asp Pro 230 235 240 gcc ttg acg tat gta gaa gga gtg tgt gtg gtg tgg ttt act ttt gaa 884 Ala Leu Thr Tyr Val Glu Gly Val Cys Val Val Trp Phe Thr Phe Glu 245 250 255 260 ttt tta gtc cgt att gtt ttt tca ccc aat aaa ctt gaa ttc atc aaa 932 Phe Leu Val Arg Ile Val Phe Ser Pro Asn Lys Leu Glu Phe Ile Lys 265 270 275 aat ctc ttg aat atc att gac ttt gtg gcc atc cta cct ttc tac tta 980 Asn Leu Leu Asn Ile Ile Asp Phe Val Ala Ile Leu Pro Phe Tyr Leu 280 285 290 gag gtg gga ctc agt ggg ctg tca tcc aaa gct gct aaa gat gtg ctt 1028 Glu Val Gly Leu Ser Gly Leu Ser Ser Lys Ala Ala Lys Asp Val Leu 295 300 305 ggc ttc ctc agg gtg gta agg ttt gtg agg atc ctg aga att ttc aag 1076 Gly Phe Leu Arg Val Val Arg Phe Val Arg Ile Leu Arg Ile Phe Lys 310 315 320 ctc acc cgc cat ttt gta ggt ctg agg gtg ctt gga cat act ctt cga 1124 Leu Thr Arg His Phe Val Gly Leu Arg Val Leu Gly His Thr Leu Arg 325 330 335 340 gct agt act aat gaa ttt ttg ctg ctg ata att ttc ctg gct cta gga 1172 Ala Ser Thr Asn Glu Phe Leu Leu Leu Ile Ile Phe Leu Ala Leu Gly 345 350 355 gtt ttg ata ttt gct acc atg atc tac tat gcc gag aga gtg gga gct 1220 Val Leu Ile Phe Ala Thr Met Ile Tyr Tyr Ala Glu Arg Val Gly Ala 360 365 370 caa cct aac gac cct tca gct agt gag cac aca cag ttc aaa aac att 1268 Gln Pro Asn Asp Pro Ser Ala Ser Glu His Thr Gln Phe Lys Asn Ile 375 380 385 ccc att ggg ttc tgg tgg gct gta gtg acc atg act acc ctg ggt tat 1316 Pro Ile Gly Phe Trp Trp Ala Val Val Thr Met Thr Thr Leu Gly Tyr 390 395 400 ggg gat atg tac ccc caa aca tgg tca ggc atg ctg gtg gga gcc ctg 1364 Gly Asp Met Tyr Pro Gln Thr Trp Ser Gly Met Leu Val Gly Ala Leu 405 410 415 420 tgt gct ctg gct gga gtg ctg aca ata gcc atg cca gtg cct gtc att 1412 Cys Ala Leu Ala Gly Val Leu Thr Ile Ala Met Pro Val Pro Val Ile 425 430 435 gtc aat aat ttt gga atg tac tac tcc ttg gca atg gca aag cag aaa 1460 Val Asn Asn Phe Gly Met Tyr Tyr Ser Leu Ala Met Ala Lys Gln Lys 440 445 450 ctt cca agg aaa aga aag aag cac atc cct cct gct cct cag gca agc 1508 Leu Pro Arg Lys Arg Lys Lys His Ile Pro Pro Ala Pro Gln Ala Ser 455 460 465 tca cct act ttt tgc aag aca gaa tta aat atg gcc tgc aat agt aca 1556 Ser Pro Thr Phe Cys Lys Thr Glu Leu Asn Met Ala Cys Asn Ser Thr 470 475 480 cag agt gac aca tgt ctg ggc aaa gac aat cga ctt ctg gaa cat aac 1604 Gln Ser Asp Thr Cys Leu Gly Lys Asp Asn Arg Leu Leu Glu His Asn 485 490 495 500 aga tca gtg tta tca ggt gac gac agt aca gga agt gag ccg cca cta 1652 Arg Ser Val Leu Ser Gly Asp Asp Ser Thr Gly Ser Glu Pro Pro Leu 505 510 515 tca ccc cca gaa agg ctc ccc atc aga cgc tct agt acc aga gac aaa 1700 Ser Pro Pro Glu Arg Leu Pro Ile Arg Arg Ser Ser Thr Arg Asp Lys 520 525 530 aac aga aga ggg gaa aca tgt ttc cta ctg acg aca ggt gat tac acg 1748 Asn Arg Arg Gly Glu Thr Cys Phe Leu Leu Thr Thr Gly Asp Tyr Thr 535 540 545 tgt gct tct gat gga ggg atc agg aaa gga tat gaa aaa tcc cga agc 1796 Cys Ala Ser Asp Gly Gly Ile Arg Lys Gly Tyr Glu Lys Ser Arg Ser 550 555 560 tta aac aac ata gcg ggc ttg gca ggc aat gct ctg agg ctc tct cca 1844 Leu Asn Asn Ile Ala Gly Leu Ala Gly Asn Ala Leu Arg Leu Ser Pro 565 570 575 580 gta aca tca ccc tac aac tct cct tgt cct ctg agg cgc tct cga tct 1892 Val Thr Ser Pro Tyr Asn Ser Pro Cys Pro Leu Arg Arg Ser Arg Ser 585 590 595 ccc atc cca tct atc t tgtaaaccaa accctcgtg 1927 Pro Ile Pro Ser Ile 600 4 601 PRT H. sapiens 4 Met Ala Lys Gly Glu Ala Ser Glu Lys Ile Ile Ile Asn Val Gly Gly 1 5 10 15 Thr Arg His Glu Thr Tyr Arg Ser Thr Leu Arg Thr Leu Pro Gly Thr 20 25 30 Arg Leu Ala Trp Leu Ala Asp Pro Asp Gly Gly Gly Arg Pro Glu Thr 35 40 45 Asp Gly Gly Gly Val Gly Ser Ser Gly Ser Ser Gly Gly Gly Gly Cys 50 55 60 Glu Phe Phe Phe Asp Arg His Pro Gly Val Phe Ala Tyr Val Leu Asn 65 70 75 80 Tyr Tyr Arg Thr Gly Lys Leu His Cys Pro Ala Asp Val Cys Gly Pro 85 90 95 Leu Phe Glu Glu Glu Leu Ala Phe Trp Gly Ile Asp Glu Thr Asp Val 100 105 110 Glu Pro Cys Cys Trp Met Thr Tyr Arg Gln His Arg Asp Ala Glu Glu 115 120 125 Ala Leu Asp Ile Phe Glu Thr Pro Asp Leu Ile Gly Gly Asp Pro Gly 130 135 140 Asp Asp Glu Asp Leu Ala Ala Lys Arg Leu Gly Ile Glu Asp Ala Ala 145 150 155 160 Gly Leu Gly Gly Pro Asp Gly Lys Ser Gly Arg Trp Arg Arg Leu Gln 165 170 175 Pro Arg Met Trp Ala Leu Phe Glu Asp Pro Tyr Ser Ser Arg Ala Ala 180 185 190 Arg Phe Ile Ala Phe Ala Ser Leu Phe Phe Ile Leu Val Ser Ile Thr 195 200 205 Thr Phe Cys Leu Glu Thr His Glu Ala Phe Asn Ile Val Lys Asn Lys 210 215 220 Thr Glu Pro Val Ile Asn Gly Thr Ser Val Val Leu Gln Tyr Glu Ile 225 230 235 240 Glu Thr Asp Pro Ala Leu Thr Tyr Val Glu Gly Val Cys Val Val Trp 245 250 255 Phe Thr Phe Glu Phe Leu Val Arg Ile Val Phe Ser Pro Asn Lys Leu 260 265 270 Glu Phe Ile Lys Asn Leu Leu Asn Ile Ile Asp Phe Val Ala Ile Leu 275 280 285 Pro Phe Tyr Leu Glu Val Gly Leu Ser Gly Leu Ser Ser Lys Ala Ala 290 295 300 Lys Asp Val Leu Gly Phe Leu Arg Val Val Arg Phe Val Arg Ile Leu 305 310 315 320 Arg Ile Phe Lys Leu Thr Arg His Phe Val Gly Leu Arg Val Leu Gly 325 330 335 His Thr Leu Arg Ala Ser Thr Asn Glu Phe Leu Leu Leu Ile Ile Phe 340 345 350 Leu Ala Leu Gly Val Leu Ile Phe Ala Thr Met Ile Tyr Tyr Ala Glu 355 360 365 Arg Val Gly Ala Gln Pro Asn Asp Pro Ser Ala Ser Glu His Thr Gln 370 375 380 Phe Lys Asn Ile Pro Ile Gly Phe Trp Trp Ala Val Val Thr Met Thr 385 390 395 400 Thr Leu Gly Tyr Gly Asp Met Tyr Pro Gln Thr Trp Ser Gly Met Leu 405 410 415 Val Gly Ala Leu Cys Ala Leu Ala Gly Val Leu Thr Ile Ala Met Pro 420 425 430 Val Pro Val Ile Val Asn Asn Phe Gly Met Tyr Tyr Ser Leu Ala Met 435 440 445 Ala Lys Gln Lys Leu Pro Arg Lys Arg Lys Lys His Ile Pro Pro Ala 450 455 460 Pro Gln Ala Ser Ser Pro Thr Phe Cys Lys Thr Glu Leu Asn Met Ala 465 470 475 480 Cys Asn Ser Thr Gln Ser Asp Thr Cys Leu Gly Lys Asp Asn Arg Leu 485 490 495 Leu Glu His Asn Arg Ser Val Leu Ser Gly Asp Asp Ser Thr Gly Ser 500 505 510 Glu Pro Pro Leu Ser Pro Pro Glu Arg Leu Pro Ile Arg Arg Ser Ser 515 520 525 Thr Arg Asp Lys Asn Arg Arg Gly Glu Thr Cys Phe Leu Leu Thr Thr 530 535 540 Gly Asp Tyr Thr Cys Ala Ser Asp Gly Gly Ile Arg Lys Gly Tyr Glu 545 550 555 560 Lys Ser Arg Ser Leu Asn Asn Ile Ala Gly Leu Ala Gly Asn Ala Leu 565 570 575 Arg Leu Ser Pro Val Thr Ser Pro Tyr Asn Ser Pro Cys Pro Leu Arg 580 585 590 Arg Ser Arg Ser Pro Ile Pro Ser Ile 595 600 5 2293 DNA H. sapiens CDS (330)...(1800) K+Hnov6 5 gggaagagcg aacccagggc ccttgctctc gtgcagcgct gcgccctggg tggggacggc 60 gtgaggcttg cagcgcaggt gagagtgatt ttccagtgat tgctttggcc tgtacaacca 120 gagaacagga ttcttccctt ctttttggcc accaaatgcc tatgtgcacc acacattcca 180 gtgtgctgag aagggcagag cttcttggat gatgatggac gtcccaccgg gcaggatgaa 240 ggcagagcgt gtggcatctc cacctcaagg gtgcagcctg atcttcctct tctcccttgc 300 cagccagcac tctgccttct gtatccacc atg gtg ttt ggt gag ttt ttc cat 353 Met Val Phe Gly Glu Phe Phe His 1 5 cgc cct gga caa gac gag gaa ctt gtc aac ctg aat gtg ggg ggc ttt 401 Arg Pro Gly Gln Asp Glu Glu Leu Val Asn Leu Asn Val Gly Gly Phe 10 15 20 aag cag tct gtt gac caa agc acc ctc ctg cgg ttt cct cac acc aga 449 Lys Gln Ser Val Asp Gln Ser Thr Leu Leu Arg Phe Pro His Thr Arg 25 30 35 40 ctg ggg aag ctg ctt act tgc cat tct gaa gag gcc att ctg gag ctg 497 Leu Gly Lys Leu Leu Thr Cys His Ser Glu Glu Ala Ile Leu Glu Leu 45 50 55 tgt gat gat tac agt gtg gcc gat aag gaa tac tac ttt gat cgg aat 545 Cys Asp Asp Tyr Ser Val Ala Asp Lys Glu Tyr Tyr Phe Asp Arg Asn 60 65 70 ccc tcc ttg ttc aga tat gtt ttg aat ttt tat tac acg ggg aag ctg 593 Pro Ser Leu Phe Arg Tyr Val Leu Asn Phe Tyr Tyr Thr Gly Lys Leu 75 80 85 cat gtc atg gag gag ctg tgc gta ttc tca ttc tgc cag gag atc gag 641 His Val Met Glu Glu Leu Cys Val Phe Ser Phe Cys Gln Glu Ile Glu 90 95 100 tac tgg ggc atc aac gag ctc ttc att gat tct tgc tgc agc aat cgc 689 Tyr Trp Gly Ile Asn Glu Leu Phe Ile Asp Ser Cys Cys Ser Asn Arg 105 110 115 120 tac cag gaa cgc aag gag gaa aac cac gag aag gac tgg gac cag aaa 737 Tyr Gln Glu Arg Lys Glu Glu Asn His Glu Lys Asp Trp Asp Gln Lys 125 130 135 agc cat gat gtg agt acc gac tcc tcg ttt gaa gag tcg tct ctg ttt 785 Ser His Asp Val Ser Thr Asp Ser Ser Phe Glu Glu Ser Ser Leu Phe 140 145 150 gag aaa gag ctg gag aag ttt gac aca ctg cga ttt ggt cag ctc cgg 833 Glu Lys Glu Leu Glu Lys Phe Asp Thr Leu Arg Phe Gly Gln Leu Arg 155 160 165 aag aaa atc tgg att aga atg gag aat cca gcg tac tgc ctg tcc gct 881 Lys Lys Ile Trp Ile Arg Met Glu Asn Pro Ala Tyr Cys Leu Ser Ala 170 175 180 aag ctt atc gct atc tcc tcc ttg agc gtg gtg ctg gcc tcc atc gtg 929 Lys Leu Ile Ala Ile Ser Ser Leu Ser Val Val Leu Ala Ser Ile Val 185 190 195 200 gcc atg tgc gtt cac agc atg tcg gag ttc cag aat gag gat gga gaa 977 Ala Met Cys Val His Ser Met Ser Glu Phe Gln Asn Glu Asp Gly Glu 205 210 215 gtg gat gat ccg gtg ctg gaa gga gtg gag atc gcg tgc att gcc tgg 1025 Val Asp Asp Pro Val Leu Glu Gly Val Glu Ile Ala Cys Ile Ala Trp 220 225 230 ttc acc ggg gag ctt gcc gtc cgg ctg gct gcc gct cct tgt caa aag 1073 Phe Thr Gly Glu Leu Ala Val Arg Leu Ala Ala Ala Pro Cys Gln Lys 235 240 245 aaa ttc tgg aaa aac cct ctg aac atc att gac ttt gtc tct att att 1121 Lys Phe Trp Lys Asn Pro Leu Asn Ile Ile Asp Phe Val Ser Ile Ile 250 255 260 ccc ttc tat gcc acg ttg gct gta gac acc aag gag gaa gag agt gag 1169 Pro Phe Tyr Ala Thr Leu Ala Val Asp Thr Lys Glu Glu Glu Ser Glu 265 270 275 280 gat att gag aac atg ggc aag gtg gtc cag atc cta cgg ctt atg agg 1217 Asp Ile Glu Asn Met Gly Lys Val Val Gln Ile Leu Arg Leu Met Arg 285 290 295 att ttc cga att cta aag ctt gcc cgg cac tcg gta gga ctt cgg tct 1265 Ile Phe Arg Ile Leu Lys Leu Ala Arg His Ser Val Gly Leu Arg Ser 300 305 310 cta ggt gcc aca ctg aga cac agc tac cat gaa gtt ggg ctt ctg ctt 1313 Leu Gly Ala Thr Leu Arg His Ser Tyr His Glu Val Gly Leu Leu Leu 315 320 325 ctc ttc ctc tct gtg ggc att tcc att ttc tct gtg ctt atc tac tcc 1361 Leu Phe Leu Ser Val Gly Ile Ser Ile Phe Ser Val Leu Ile Tyr Ser 330 335 340 gtg gag aaa gat gac cac aca tcc agc ctc acc agc atc ccc atc tgc 1409 Val Glu Lys Asp Asp His Thr Ser Ser Leu Thr Ser Ile Pro Ile Cys 345 350 355 360 tgg tgg tgg gcc acc atc agc atg aca act gtg ggc tat gga gac acc 1457 Trp Trp Trp Ala Thr Ile Ser Met Thr Thr Val Gly Tyr Gly Asp Thr 365 370 375 cac ccg gtc acc ttg gcg gga aag ctc atc gcc agc aca tgc atc atc 1505 His Pro Val Thr Leu Ala Gly Lys Leu Ile Ala Ser Thr Cys Ile Ile 380 385 390 tgt ggc atc ttg gtg gtg gcc ctt ccc atc acc atc atc ttc aac aag 1553 Cys Gly Ile Leu Val Val Ala Leu Pro Ile Thr Ile Ile Phe Asn Lys 395 400 405 ttt tcc aag tac tac cag aag caa aag gac att gat gtg gac cag tgc 1601 Phe Ser Lys Tyr Tyr Gln Lys Gln Lys Asp Ile Asp Val Asp Gln Cys 410 415 420 agt gag gat gca cca gag aag tgt cat gag cta cct tac ttt aac att 1649 Ser Glu Asp Ala Pro Glu Lys Cys His Glu Leu Pro Tyr Phe Asn Ile 425 430 435 440 agg gat ata tat gca cag cgg atg cac gcc ttc att acc agt ctc tct 1697 Arg Asp Ile Tyr Ala Gln Arg Met His Ala Phe Ile Thr Ser Leu Ser 445 450 455 tct gta ggc att gtg gtg agc gat cct gac tcc aca gat gct tca agc 1745 Ser Val Gly Ile Val Val Ser Asp Pro Asp Ser Thr Asp Ala Ser Ser 460 465 470 att gaa gac aat gag gac att tgt aac acc acc tcc ttg gag aat tgc 1793 Ile Glu Asp Asn Glu Asp Ile Cys Asn Thr Thr Ser Leu Glu Asn Cys 475 480 485 aca gca a aatgagcggg ggtgtttgtg cctgtttctc ttatcctttc ccaacattag 1850 Thr Ala 490 gttaacacag ctttataaac ctcagtgggt tcgttaaaat catttaattc tcagggtgta 1910 cctttcagcc atagttggac attcattgct gaattctgaa atgatagaat tgtctttatt 1970 tttctctgtg aggtcaatta aatgccttgt tctgaaattt attttttaca agagagagtt 2030 gtgatagagt ttggaatata agataaatgg tattgggtgg ggtttgtggc tacagcttat 2090 gcatcattct gtgtttgtca tttactcaca ttgagctaac tttaaattac tgacaagtag 2150 aatcaaaggt gcagctgact gagacgacat gcatgtaaga tccacaaaat gagacaatgc 2210 atgtaaatcc atgctcatgt tctaaacatg gaaactagga gcctaataaa cttcctaatt 2270 cagaaaaaaa aaaaaaaaaa aaa 2293 6 490 PRT H. sapiens 6 Met Val Phe Gly Glu Phe Phe His Arg Pro Gly Gln Asp Glu Glu Leu 1 5 10 15 Val Asn Leu Asn Val Gly Gly Phe Lys Gln Ser Val Asp Gln Ser Thr 20 25 30 Leu Leu Arg Phe Pro His Thr Arg Leu Gly Lys Leu Leu Thr Cys His 35 40 45 Ser Glu Glu Ala Ile Leu Glu Leu Cys Asp Asp Tyr Ser Val Ala Asp 50 55 60 Lys Glu Tyr Tyr Phe Asp Arg Asn Pro Ser Leu Phe Arg Tyr Val Leu 65 70 75 80 Asn Phe Tyr Tyr Thr Gly Lys Leu His Val Met Glu Glu Leu Cys Val 85 90 95 Phe Ser Phe Cys Gln Glu Ile Glu Tyr Trp Gly Ile Asn Glu Leu Phe 100 105 110 Ile Asp Ser Cys Cys Ser Asn Arg Tyr Gln Glu Arg Lys Glu Glu Asn 115 120 125 His Glu Lys Asp Trp Asp Gln Lys Ser His Asp Val Ser Thr Asp Ser 130 135 140 Ser Phe Glu Glu Ser Ser Leu Phe Glu Lys Glu Leu Glu Lys Phe Asp 145 150 155 160 Thr Leu Arg Phe Gly Gln Leu Arg Lys Lys Ile Trp Ile Arg Met Glu 165 170 175 Asn Pro Ala Tyr Cys Leu Ser Ala Lys Leu Ile Ala Ile Ser Ser Leu 180 185 190 Ser Val Val Leu Ala Ser Ile Val Ala Met Cys Val His Ser Met Ser 195 200 205 Glu Phe Gln Asn Glu Asp Gly Glu Val Asp Asp Pro Val Leu Glu Gly 210 215 220 Val Glu Ile Ala Cys Ile Ala Trp Phe Thr Gly Glu Leu Ala Val Arg 225 230 235 240 Leu Ala Ala Ala Pro Cys Gln Lys Lys Phe Trp Lys Asn Pro Leu Asn 245 250 255 Ile Ile Asp Phe Val Ser Ile Ile Pro Phe Tyr Ala Thr Leu Ala Val 260 265 270 Asp Thr Lys Glu Glu Glu Ser Glu Asp Ile Glu Asn Met Gly Lys Val 275 280 285 Val Gln Ile Leu Arg Leu Met Arg Ile Phe Arg Ile Leu Lys Leu Ala 290 295 300 Arg His Ser Val Gly Leu Arg Ser Leu Gly Ala Thr Leu Arg His Ser 305 310 315 320 Tyr His Glu Val Gly Leu Leu Leu Leu Phe Leu Ser Val Gly Ile Ser 325 330 335 Ile Phe Ser Val Leu Ile Tyr Ser Val Glu Lys Asp Asp His Thr Ser 340 345 350 Ser Leu Thr Ser Ile Pro Ile Cys Trp Trp Trp Ala Thr Ile Ser Met 355 360 365 Thr Thr Val Gly Tyr Gly Asp Thr His Pro Val Thr Leu Ala Gly Lys 370 375 380 Leu Ile Ala Ser Thr Cys Ile Ile Cys Gly Ile Leu Val Val Ala Leu 385 390 395 400 Pro Ile Thr Ile Ile Phe Asn Lys Phe Ser Lys Tyr Tyr Gln Lys Gln 405 410 415 Lys Asp Ile Asp Val Asp Gln Cys Ser Glu Asp Ala Pro Glu Lys Cys 420 425 430 His Glu Leu Pro Tyr Phe Asn Ile Arg Asp Ile Tyr Ala Gln Arg Met 435 440 445 His Ala Phe Ile Thr Ser Leu Ser Ser Val Gly Ile Val Val Ser Asp 450 455 460 Pro Asp Ser Thr Asp Ala Ser Ser Ile Glu Asp Asn Glu Asp Ile Cys 465 470 475 480 Asn Thr Thr Ser Leu Glu Asn Cys Thr Ala 485 490 7 3080 DNA H. sapiens CDS (480)...(1977) K+Hnov9 7 gtctctcctc ttcctcctcc tccgccccac atctccctcc ttcctccctt ccccaacccc 60 tccacccacc aagtagcgag tcattcaatc tgtacacctc ctgggctggg aatcgcaatt 120 gcgaagttgg gaggcggggt gacaacgttt gggaagggcc agggcgaccg gcagtgtgca 180 cagggactgt gtcgggcttg gacctcacct gatcctctct cttagcgcga cccttcctct 240 gctccctgtc tcctctttct gccacttgtg cgctgcttcc gcgcactccc ggctccctag 300 cggcaggagg aggaaggcgc acagcgggtg gagagggtgc gccaaggaga ggtaacccct 360 tcgggagccc ggggaatccc ggccgccacc aggggccgtg ccaccgccct cgcgggacca 420 aagcttccgg cgtgtcccca actttgtggc gccctcaggc cgcggcgact gggttagag 479 atg cct tcc agc ggc aga gcg ctg ctg gac tcg ccg ctg gac agc ggc 527 Met Pro Ser Ser Gly Arg Ala Leu Leu Asp Ser Pro Leu Asp Ser Gly 1 5 10 15 tcc ctg acc tcc ctg gac tct agt gtc ttc tgc agc gag ggt gaa ggg 575 Ser Leu Thr Ser Leu Asp Ser Ser Val Phe Cys Ser Glu Gly Glu Gly 20 25 30 gag ccc ttg gcg ctc ggg gac tgc ttc acg gtc aac gtg ggc ggc agc 623 Glu Pro Leu Ala Leu Gly Asp Cys Phe Thr Val Asn Val Gly Gly Ser 35 40 45 cgc ttc gtg ctc tcg cag cag gcg ctg tcc tgc ttc ccg cac acg cgc 671 Arg Phe Val Leu Ser Gln Gln Ala Leu Ser Cys Phe Pro His Thr Arg 50 55 60 ctt ggc aag ctg gcc gtg gtg gtg gct tcc tac cgc cgc ccc ggg gcc 719 Leu Gly Lys Leu Ala Val Val Val Ala Ser Tyr Arg Arg Pro Gly Ala 65 70 75 80 ctg gcc gcc gtg ccc agc cct ctg gag ctt tgc gac gat gcc aac ccc 767 Leu Ala Ala Val Pro Ser Pro Leu Glu Leu Cys Asp Asp Ala Asn Pro 85 90 95 gtg gac aac gag tac ttc ttc gac cgc agc tcg cag gcg ttc cga tat 815 Val Asp Asn Glu Tyr Phe Phe Asp Arg Ser Ser Gln Ala Phe Arg Tyr 100 105 110 gtc ctg cac tac tac cgc acc ggc cgc ctg cat gtc atg gag cag ctg 863 Val Leu His Tyr Tyr Arg Thr Gly Arg Leu His Val Met Glu Gln Leu 115 120 125 tgc gcg ctc tcc ttc ctg cag gag atc cag tac tgg ggc atc gat gag 911 Cys Ala Leu Ser Phe Leu Gln Glu Ile Gln Tyr Trp Gly Ile Asp Glu 130 135 140 ctc agc atc gat tcc tgc tgc agg gac aga tac ttc aga agg aaa gag 959 Leu Ser Ile Asp Ser Cys Cys Arg Asp Arg Tyr Phe Arg Arg Lys Glu 145 150 155 160 ctg agt gaa act tta gac ttc aag aag gac aca gaa gac cag gaa agt 1007 Leu Ser Glu Thr Leu Asp Phe Lys Lys Asp Thr Glu Asp Gln Glu Ser 165 170 175 caa cat gag agt gaa cag gac ttc tcc caa gga cct tgt ccc act gtt 1055 Gln His Glu Ser Glu Gln Asp Phe Ser Gln Gly Pro Cys Pro Thr Val 180 185 190 cgc cag aag ctc tgg aat atc ctg gag aaa cct gga tct tcc aca gct 1103 Arg Gln Lys Leu Trp Asn Ile Leu Glu Lys Pro Gly Ser Ser Thr Ala 195 200 205 gcc cgt atc ttt ggc gtc atc tcc att atc ttc gtg gtg gtg tcc atc 1151 Ala Arg Ile Phe Gly Val Ile Ser Ile Ile Phe Val Val Val Ser Ile 210 215 220 att aac atg gcc ctg atg tca gct gag tta agc tgg ctg gac ctg cag 1199 Ile Asn Met Ala Leu Met Ser Ala Glu Leu Ser Trp Leu Asp Leu Gln 225 230 235 240 ctg ctg gaa atc ctg gag tat gtg tgc att agc tgg ttc acc ggg gag 1247 Leu Leu Glu Ile Leu Glu Tyr Val Cys Ile Ser Trp Phe Thr Gly Glu 245 250 255 ttt gtc ctc cgc ttc ctg tgt gtg cgg gac agg tgt cgc ttc cta aga 1295 Phe Val Leu Arg Phe Leu Cys Val Arg Asp Arg Cys Arg Phe Leu Arg 260 265 270 aag gtg cca aac atc ata gac ctc ctt gcc atc ttg ccc ttc tac atc 1343 Lys Val Pro Asn Ile Ile Asp Leu Leu Ala Ile Leu Pro Phe Tyr Ile 275 280 285 act ctt ctg gta gag agc cta agt ggg agc cag acc acg cag gag ctg 1391 Thr Leu Leu Val Glu Ser Leu Ser Gly Ser Gln Thr Thr Gln Glu Leu 290 295 300 gag aac gtg ggg cgc att gtc cag gtg ttg agg ctg ctc agg gct ctg 1439 Glu Asn Val Gly Arg Ile Val Gln Val Leu Arg Leu Leu Arg Ala Leu 305 310 315 320 cgc atg cta aag ctg ggc aga cat tcc aca gga tta cgc tcc ctt ggg 1487 Arg Met Leu Lys Leu Gly Arg His Ser Thr Gly Leu Arg Ser Leu Gly 325 330 335 atg aca atc acc cag tgt tac gaa gaa gtc ggc cta ctg ctc cta ttt 1535 Met Thr Ile Thr Gln Cys Tyr Glu Glu Val Gly Leu Leu Leu Leu Phe 340 345 350 cta tcc gtg gga atc tct ata ttt tca act gta gaa tac ttt gct gag 1583 Leu Ser Val Gly Ile Ser Ile Phe Ser Thr Val Glu Tyr Phe Ala Glu 355 360 365 caa agc att cct gac aca acc ttc aca agt gtc cct tgt gca tgg tgg 1631 Gln Ser Ile Pro Asp Thr Thr Phe Thr Ser Val Pro Cys Ala Trp Trp 370 375 380 tgg gcc acc acc tct atg act act gtg gga tat ggg gac att aga cca 1679 Trp Ala Thr Thr Ser Met Thr Thr Val Gly Tyr Gly Asp Ile Arg Pro 385 390 395 400 gac acc acc aca ggc aaa atc gtg gcc ttc atg tgt ata tta tcg gga 1727 Asp Thr Thr Thr Gly Lys Ile Val Ala Phe Met Cys Ile Leu Ser Gly 405 410 415 att ctt gtc ttg gcc ttg cct att gct att att aac gat cgc ttc tct 1775 Ile Leu Val Leu Ala Leu Pro Ile Ala Ile Ile Asn Asp Arg Phe Ser 420 425 430 gct tgc tac ttc acc ttg aaa ctc aag gaa gca gct gtt aga cag cgt 1823 Ala Cys Tyr Phe Thr Leu Lys Leu Lys Glu Ala Ala Val Arg Gln Arg 435 440 445 gaa gcc cta aag aag ctt acc aag aat ata gcc act gac tca tat atc 1871 Glu Ala Leu Lys Lys Leu Thr Lys Asn Ile Ala Thr Asp Ser Tyr Ile 450 455 460 agt gtt aac ttg aga gat gtc tat gcc cgg agt atc atg gag atg ctg 1919 Ser Val Asn Leu Arg Asp Val Tyr Ala Arg Ser Ile Met Glu Met Leu 465 470 475 480 cga ctg aaa ggc aga gaa aga gca agt act agg agc agc ggg gga gat 1967 Arg Leu Lys Gly Arg Glu Arg Ala Ser Thr Arg Ser Ser Gly Gly Asp 485 490 495 gat ttc tgg t tttgaattaa ttttcaattt atttacaaaa gctatgtaca 2017 Asp Phe Trp attaactaaa atgataaagc agtgatgtgg atttctgtat tctgatgatg agtctcttca 2077 gagtactgct catcttaatt aatttttgct gatatattgc ttcatctact agaatatttc 2137 acatcaccta taacaactgc acagtgttct gacacatttg agtgtccaaa atagccaatt 2197 aacacaacca aatacaactg ggccaatata aacatgtttg aattgtcaaa tataaaataa 2257 tgttattgca atacatacaa aaaagttaaa gattttatgt atcactaaca ttagaagttt 2317 tttgcaccac taatttttta aaaatggaag gtaaactgca tagcccagag aaagataagt 2377 aaatatttaa gaacatattg aacaactttg ctatttaaag atattatcca agtacataaa 2437 ttactccgtt ctctatcagt taaagctatt gaatataata cttagcttta caagagaaaa 2497 cccatatttg atgggcagag attatatccc tatcttcttt ttcatgtaaa ccactggtca 2557 caaatgaact gatctctgta tcccattatt actataagag gtgggaatcc caaaactgct 2617 tagattgcag tacatgagtc tacacaaaga cttcaacaat tgcacatctt cattctccca 2677 actgagtgta gtatgtggag cataaaacag catatttctt agtatttcat gaatatcaga 2737 tggtctttaa atgtctcttt atggatgtat tgttcacatt atggctttaa aataatgaat 2797 atgtaaaagt gaggtagtga acatcctaaa tttctacact ggaattacta aataatctta 2857 tttcataaat gggaaatata tgttaaatga catcactgga tgaacttgaa gatcttttac 2917 ttgttaacaa aaaaatacta tggacagctt tctgattgtt ggggtaaata gcaaatgttc 2977 aaactttgca ggcattttga cattcatcat aacaacacaa ttcctagaca ttgtattata 3037 taattaaagc caaaacctct aaagctaaaa aaaaaaaaaa aaa 3080 8 499 PRT H. sapiens 8 Met Pro Ser Ser Gly Arg Ala Leu Leu Asp Ser Pro Leu Asp Ser Gly 1 5 10 15 Ser Leu Thr Ser Leu Asp Ser Ser Val Phe Cys Ser Glu Gly Glu Gly 20 25 30 Glu Pro Leu Ala Leu Gly Asp Cys Phe Thr Val Asn Val Gly Gly Ser 35 40 45 Arg Phe Val Leu Ser Gln Gln Ala Leu Ser Cys Phe Pro His Thr Arg 50 55 60 Leu Gly Lys Leu Ala Val Val Val Ala Ser Tyr Arg Arg Pro Gly Ala 65 70 75 80 Leu Ala Ala Val Pro Ser Pro Leu Glu Leu Cys Asp Asp Ala Asn Pro 85 90 95 Val Asp Asn Glu Tyr Phe Phe Asp Arg Ser Ser Gln Ala Phe Arg Tyr 100 105 110 Val Leu His Tyr Tyr Arg Thr Gly Arg Leu His Val Met Glu Gln Leu 115 120 125 Cys Ala Leu Ser Phe Leu Gln Glu Ile Gln Tyr Trp Gly Ile Asp Glu 130 135 140 Leu Ser Ile Asp Ser Cys Cys Arg Asp Arg Tyr Phe Arg Arg Lys Glu 145 150 155 160 Leu Ser Glu Thr Leu Asp Phe Lys Lys Asp Thr Glu Asp Gln Glu Ser 165 170 175 Gln His Glu Ser Glu Gln Asp Phe Ser Gln Gly Pro Cys Pro Thr Val 180 185 190 Arg Gln Lys Leu Trp Asn Ile Leu Glu Lys Pro Gly Ser Ser Thr Ala 195 200 205 Ala Arg Ile Phe Gly Val Ile Ser Ile Ile Phe Val Val Val Ser Ile 210 215 220 Ile Asn Met Ala Leu Met Ser Ala Glu Leu Ser Trp Leu Asp Leu Gln 225 230 235 240 Leu Leu Glu Ile Leu Glu Tyr Val Cys Ile Ser Trp Phe Thr Gly Glu 245 250 255 Phe Val Leu Arg Phe Leu Cys Val Arg Asp Arg Cys Arg Phe Leu Arg 260 265 270 Lys Val Pro Asn Ile Ile Asp Leu Leu Ala Ile Leu Pro Phe Tyr Ile 275 280 285 Thr Leu Leu Val Glu Ser Leu Ser Gly Ser Gln Thr Thr Gln Glu Leu 290 295 300 Glu Asn Val Gly Arg Ile Val Gln Val Leu Arg Leu Leu Arg Ala Leu 305 310 315 320 Arg Met Leu Lys Leu Gly Arg His Ser Thr Gly Leu Arg Ser Leu Gly 325 330 335 Met Thr Ile Thr Gln Cys Tyr Glu Glu Val Gly Leu Leu Leu Leu Phe 340 345 350 Leu Ser Val Gly Ile Ser Ile Phe Ser Thr Val Glu Tyr Phe Ala Glu 355 360 365 Gln Ser Ile Pro Asp Thr Thr Phe Thr Ser Val Pro Cys Ala Trp Trp 370 375 380 Trp Ala Thr Thr Ser Met Thr Thr Val Gly Tyr Gly Asp Ile Arg Pro 385 390 395 400 Asp Thr Thr Thr Gly Lys Ile Val Ala Phe Met Cys Ile Leu Ser Gly 405 410 415 Ile Leu Val Leu Ala Leu Pro Ile Ala Ile Ile Asn Asp Arg Phe Ser 420 425 430 Ala Cys Tyr Phe Thr Leu Lys Leu Lys Glu Ala Ala Val Arg Gln Arg 435 440 445 Glu Ala Leu Lys Lys Leu Thr Lys Asn Ile Ala Thr Asp Ser Tyr Ile 450 455 460 Ser Val Asn Leu Arg Asp Val Tyr Ala Arg Ser Ile Met Glu Met Leu 465 470 475 480 Arg Leu Lys Gly Arg Glu Arg Ala Ser Thr Arg Ser Ser Gly Gly Asp 485 490 495 Asp Phe Trp 9 3424 DNA H. sapiens CDS (257)...(2195) K+Hnov12 9 ctcttctcca tgtccccaag gcccttctca gtccctcaga acattgccca ggcccctcct 60 aggttctgta aatgtccccc agactccttc ccatctcttt agttcttcct cctggttcct 120 cttggcctct ctagacaccc ccagtttcct tgtttgggtg gctcaaggtg tctccaagcc 180 cccaccatcc tggagacagc cacattctcc taaacgccac cctcactaag tctccctggg 240 cttggggagt ggcacg atg gcg gca ggc ctg gcc acg tgg ctg cct ttt gct 292 Met Ala Ala Gly Leu Ala Thr Trp Leu Pro Phe Ala 1 5 10 cgg gca gca gca gtg ggc tgg ctg ccc ccg gcc cag caa ccc ctg ccc 340 Arg Ala Ala Ala Val Gly Trp Leu Pro Pro Ala Gln Gln Pro Leu Pro 15 20 25 ccg gca ccg ggg gtg aag gca tct cga gga gat grg gtt ctg gtg gtg 388 Pro Ala Pro Gly Val Lys Ala Ser Arg Gly Asp Xaa Val Leu Val Val 30 35 40 aac gtg agc gga cgg cgc ttt gag act tgg aag aat acg ctg gac cgc 436 Asn Val Ser Gly Arg Arg Phe Glu Thr Trp Lys Asn Thr Leu Asp Arg 45 50 55 60 tac cca gac acc ttg ctg ggc agc tcg gag aag gaa ttc ttc tac gat 484 Tyr Pro Asp Thr Leu Leu Gly Ser Ser Glu Lys Glu Phe Phe Tyr Asp 65 70 75 gct gac tca ggc gag tac ttc ttc gat cgc gac cct gac atg ttc cgc 532 Ala Asp Ser Gly Glu Tyr Phe Phe Asp Arg Asp Pro Asp Met Phe Arg 80 85 90 cat gtg ctg aac ttc tac cga acg ggg cgg ctg cat tgc cca cgg cag 580 His Val Leu Asn Phe Tyr Arg Thr Gly Arg Leu His Cys Pro Arg Gln 95 100 105 gag tgc atc cag gcc ttc gac gaa gag ctg gct ttc tac ggc ctg gtt 628 Glu Cys Ile Gln Ala Phe Asp Glu Glu Leu Ala Phe Tyr Gly Leu Val 110 115 120 ccc gag cta gtc ggt gac tgc tgc ctt gaa gag tat cgg gac cga aag 676 Pro Glu Leu Val Gly Asp Cys Cys Leu Glu Glu Tyr Arg Asp Arg Lys 125 130 135 140 aag gag aat gcc gag cgc ctg gca gag gat gag gag gca gag cag gcc 724 Lys Glu Asn Ala Glu Arg Leu Ala Glu Asp Glu Glu Ala Glu Gln Ala 145 150 155 ggg gac ggc cca gcc ctg cca gca ggc agc tcc ctg cgg cag cgg ctc 772 Gly Asp Gly Pro Ala Leu Pro Ala Gly Ser Ser Leu Arg Gln Arg Leu 160 165 170 tgg cgg gcc ttc gag aat cca cac acg agc acc gca gcc ctc gtt ttc 820 Trp Arg Ala Phe Glu Asn Pro His Thr Ser Thr Ala Ala Leu Val Phe 175 180 185 tac tat gtg acc ggc ttc ttc atc gcc gtg tcg gtc atc gcc aat gtg 868 Tyr Tyr Val Thr Gly Phe Phe Ile Ala Val Ser Val Ile Ala Asn Val 190 195 200 gtg gag acc atc cca tgc cgc ggc tct gca cgc agg tcc tca agg gag 916 Val Glu Thr Ile Pro Cys Arg Gly Ser Ala Arg Arg Ser Ser Arg Glu 205 210 215 220 cag ccc tgt ggc gaa cgc ttc cca cag gcc ttt ttc tgc atg gac aca 964 Gln Pro Cys Gly Glu Arg Phe Pro Gln Ala Phe Phe Cys Met Asp Thr 225 230 235 gcc tgt gta ctc ata ttc aca ggt gaa tac ctc ctg cgg ctg ttt gcc 1012 Ala Cys Val Leu Ile Phe Thr Gly Glu Tyr Leu Leu Arg Leu Phe Ala 240 245 250 gcc ccc 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 ctt ttg gtg ccc aag aac 1108 Val Val Ala Ile Leu Pro Tyr Tyr Ile Gly Leu Leu Val Pro Lys Asn 270 275 280 gac gat gtc tct ggc gcc ttt gtc acc ctg cgt 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 Gln Gly Leu Arg Ile Leu Gly 305 310 315 tac aca ctc aag agc tgt gcc tct gag ctg ggc ttt ctc ctc ttt tcc 1252 Tyr Thr Leu Lys Ser Cys Ala Ser Glu Leu Gly Phe Leu Leu Phe Ser 320 325 330 cta acc atg gcc atc atc atc ttt gcc act gtc atg ttt tat gct gag 1300 Leu Thr Met Ala Ile Ile Ile Phe Ala Thr Val Met Phe Tyr Ala Glu 335 340 345 aag ggc aca aac aag acc aac ttt aca agc atc cct gcg gcc ttc tgg 1348 Lys Gly Thr Asn Lys Thr Asn Phe Thr Ser Ile Pro Ala Ala Phe Trp 350 355 360 tat acc att gtc acc atg acc acg ctt ggc tac gga gac atg gtg ccc 1396 Tyr Thr Ile Val Thr Met Thr Thr Leu Gly Tyr Gly Asp Met Val Pro 365 370 375 380 agc acc att gct ggc aag att ttc ggg tcc atc tgc tca ctc agt ggc 1444 Ser Thr Ile Ala Gly Lys Ile Phe Gly Ser Ile Cys Ser Leu Ser Gly 385 390 395 gtc ttg gtc att gcc ctg cct gtg cca gtc att gtg tcc aac ttt agc 1492 Val Leu Val Ile Ala Leu Pro Val Pro Val Ile Val Ser Asn Phe Ser 400 405 410 cgc atc tac cac cag aac cag cgg gct gac aag cgc cga gca cag cag 1540 Arg Ile Tyr His Gln Asn Gln Arg Ala Asp Lys Arg Arg Ala Gln Gln 415 420 425 aag gtg cgc ttg gca agg atc cga ttg gca aag agt ggt acc acc aat 1588 Lys Val Arg Leu Ala Arg Ile Arg Leu Ala Lys Ser Gly Thr Thr Asn 430 435 440 gcc ttc ctg cag tac aag cag aat ggg ggc ctt gag gac agc ggc agt 1636 Ala Phe Leu Gln Tyr Lys Gln Asn Gly Gly Leu Glu Asp Ser Gly Ser 445 450 455 460 ggc gag gaa cag gct ctt tgt gtc agg aac cgt tct gcc ttt gaa cag 1684 Gly Glu Glu Gln Ala Leu Cys Val Arg Asn Arg Ser Ala Phe Glu Gln 465 470 475 caa cat cac cac ttg ctg cac tgt cta gag aag aca acg tgc cat gag 1732 Gln His His His Leu Leu His Cys Leu Glu Lys Thr Thr Cys His Glu 480 485 490 ttc aca gat gag ctc acc ttc agt gaa gcc ctg gga gcc gtc tcg ccg 1780 Phe Thr Asp Glu Leu Thr Phe Ser Glu Ala Leu Gly Ala Val Ser Pro 495 500 505 ggt ggc cgc acc agc cgt agc acc tct gtg tct tcc cag cca gtg gga 1828 Gly Gly Arg Thr Ser Arg Ser Thr Ser Val Ser Ser Gln Pro Val Gly 510 515 520 ccc gga agc ctg ctg tct tct tgc tgc cct cgc agg gcc aag cgc cgc 1876 Pro Gly Ser Leu Leu Ser Ser Cys Cys Pro Arg Arg Ala Lys Arg Arg 525 530 535 540 gcc atc cgc ctt gcc aac tcc act gcc tca gtc agc cgt ggc agc atg 1924 Ala Ile Arg Leu Ala Asn Ser Thr Ala Ser Val Ser Arg Gly Ser Met 545 550 555 cag gag ctg gac atg ctg gca ggg ctg cgc agg agc cat gcc cct cag 1972 Gln Glu Leu Asp Met Leu Ala Gly Leu Arg Arg Ser His Ala Pro Gln 560 565 570 agc cgc tcc agc ctc aat gcc aag ccc cat gac agc ctt gac ctg aac 2020 Ser Arg Ser Ser Leu Asn Ala Lys Pro His Asp Ser Leu Asp Leu Asn 575 580 585 tgc gac agc cgg gac ttc gtg gct gcc att atc agc atc cct acc cct 2068 Cys Asp Ser Arg Asp Phe Val Ala Ala Ile Ile Ser Ile Pro Thr Pro 590 595 600 cct gcc aac acc cca gat gag agc caa cct tcc tcc cct ggc ggc ggt 2116 Pro Ala Asn Thr Pro Asp Glu Ser Gln Pro Ser Ser Pro Gly Gly Gly 605 610 615 620 ggc agg gcc ggc agc acc ctc agg aac tcc agc ctg ggt acc cct tgc 2164 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 2215 Leu Phe Pro Glu Thr Val Lys Ile Ser Ser 640 645 attcagaggg tcctcttcat ttttgggaac tcctttccaa agccatattt ttgggaggca 2275 gagaggggca ggcttgggca ccccttctgc cccccccact gagaactatg caatggagtt 2335 tcatgaaatg gtccacatag tggggaagta gccaggaaat gagaaacttc ctcccacccc 2395 agacattttt cctggtggga gctgaagcac tgggcttcca caggcccctg gcctccttgc 2455 cctagcacac tgggactggc cccactctcc cagctggact cctgcatgct cctccccttg 2515 ggctctcaga tgaaggcaaa gctttgatcc gacatctgag ctctagccta agaaggagag 2575 ttgagatttc ctcctccctc tggctgggat atggagcttt ggaggttcag agaagagaac 2635 cctcacctct gatctggcct ctacgagagg tcctcatctc catctggccc aacaattccc 2695 agattctgaa gcttggaatg caaacacagg cttcatgggc tgtggcctct gcagcgacct 2755 gccatcccca ggccttgcct gaggggtcag gctgcctctc ccaacacaca ctcagatagc 2815 acaaattcta ccatcccctt ccctggctgc tggaaatgga ccccgcaacc ctgtcctctg 2875 ctgggccccc agcaaactct agcaatagca gctgctgccg tgtcattatg caaagcctct 2935 gaccagtttg ctgcagcatt tacatctgcc ctaatcagag gggccacctc taactcctcc 2995 tcctcctctc ttctcctctg gtttgcgtcc ttcctgggtt gggctggagt ctggactggc 3055 tgagataaga gcctggcaac cagcaagagc tgggctgtat ttggagatca tgggctgatt 3115 ccatgttctt gggcaacagt ccagaagcat caggggctcc ggcctgggat gtttctgaac 3175 tttgggagtt ataggagaca ggaggaactt ctcctcctcc tcctccccta caattccttt 3235 tcacatattc ctttcttctc cctcttgggt gaccttccaa aactctgctc tcaggctgaa 3295 atctggcatc atctcaggtt ccctgtcccc agcactgtcc ccatggagct ggtggctgac 3355 aaagatgtag tttccatcag tcaataaaac ctgagaggag agatgaggaa aaaaaaaaaa 3415 aaaaaaaaa 3424 10 646 PRT H. sapiens VARIANT (1)...(646) Xaa = Any Amino Acid 10 Met Ala Ala Gly Leu Ala Thr Trp Leu Pro Phe Ala Arg Ala Ala Ala 1 5 10 15 Val Gly Trp Leu Pro Pro Ala Gln Gln Pro Leu Pro Pro Ala Pro Gly 20 25 30 Val Lys Ala Ser Arg Gly Asp Xaa Val Leu Val Val Asn Val Ser Gly 35 40 45 Arg Arg Phe Glu Thr Trp Lys Asn Thr Leu Asp Arg Tyr Pro Asp Thr 50 55 60 Leu Leu Gly Ser Ser Glu Lys Glu Phe Phe Tyr Asp Ala Asp Ser Gly 65 70 75 80 Glu Tyr Phe Phe Asp Arg Asp Pro Asp Met Phe Arg His Val Leu Asn 85 90 95 Phe Tyr Arg Thr Gly Arg Leu His Cys Pro Arg Gln Glu Cys Ile Gln 100 105 110 Ala Phe Asp Glu Glu Leu Ala Phe Tyr Gly Leu Val Pro Glu Leu Val 115 120 125 Gly Asp Cys Cys Leu Glu Glu Tyr Arg Asp Arg Lys Lys Glu Asn Ala 130 135 140 Glu Arg Leu Ala Glu Asp Glu Glu Ala Glu Gln Ala Gly Asp Gly Pro 145 150 155 160 Ala Leu Pro Ala Gly Ser Ser Leu Arg Gln Arg Leu Trp Arg Ala Phe 165 170 175 Glu Asn Pro His Thr Ser Thr Ala Ala Leu Val Phe Tyr Tyr Val Thr 180 185 190 Gly Phe Phe Ile Ala Val Ser Val Ile Ala Asn Val Val Glu Thr Ile 195 200 205 Pro Cys Arg Gly Ser Ala Arg Arg Ser Ser Arg Glu Gln Pro Cys Gly 210 215 220 Glu Arg Phe Pro Gln Ala Phe Phe Cys Met Asp Thr Ala Cys Val Leu 225 230 235 240 Ile Phe Thr Gly Glu Tyr Leu Leu Arg Leu Phe Ala Ala Pro Ser Arg 245 250 255 Cys Arg Phe Leu Arg Ser Val Met Ser Leu Ile Asp Val Val Ala Ile 260 265 270 Leu Pro Tyr Tyr Ile Gly Leu Leu Val Pro Lys Asn Asp Asp Val Ser 275 280 285 Gly Ala Phe Val Thr Leu Arg Val Phe Arg Val Phe Arg Ile Phe Lys 290 295 300 Phe Ser Arg His Ser Gln Gly Leu Arg Ile Leu Gly Tyr Thr Leu Lys 305 310 315 320 Ser Cys Ala Ser Glu Leu Gly Phe Leu Leu Phe Ser Leu Thr Met Ala 325 330 335 Ile Ile Ile Phe Ala Thr Val Met Phe Tyr Ala Glu Lys Gly Thr Asn 340 345 350 Lys Thr Asn Phe Thr Ser Ile Pro Ala Ala Phe Trp Tyr Thr Ile Val 355 360 365 Thr Met Thr Thr Leu Gly Tyr Gly Asp Met Val Pro Ser Thr Ile Ala 370 375 380 Gly Lys Ile Phe Gly Ser Ile Cys Ser Leu Ser Gly Val Leu Val Ile 385 390 395 400 Ala Leu Pro Val Pro Val Ile Val Ser Asn Phe Ser Arg Ile Tyr His 405 410 415 Gln Asn Gln Arg Ala Asp Lys Arg Arg Ala Gln Gln Lys Val Arg Leu 420 425 430 Ala Arg Ile Arg Leu Ala Lys Ser Gly Thr Thr Asn Ala Phe Leu Gln 435 440 445 Tyr Lys Gln Asn Gly Gly Leu Glu Asp Ser Gly Ser Gly Glu Glu Gln 450 455 460 Ala Leu Cys Val Arg Asn Arg Ser Ala Phe Glu Gln Gln His His His 465 470 475 480 Leu Leu His Cys Leu Glu Lys Thr Thr Cys His Glu Phe Thr Asp Glu 485 490 495 Leu Thr Phe Ser Glu Ala Leu Gly Ala Val Ser Pro Gly Gly Arg Thr 500 505 510 Ser Arg Ser Thr Ser Val Ser Ser Gln Pro Val Gly Pro Gly Ser Leu 515 520 525 Leu Ser Ser Cys Cys Pro Arg Arg Ala Lys Arg Arg Ala Ile Arg Leu 530 535 540 Ala Asn Ser Thr Ala Ser Val Ser Arg Gly Ser Met Gln Glu Leu Asp 545 550 555 560 Met Leu Ala Gly Leu Arg Arg Ser His Ala Pro Gln Ser Arg Ser Ser 565 570 575 Leu Asn Ala Lys Pro His Asp Ser Leu Asp Leu Asn Cys Asp Ser Arg 580 585 590 Asp Phe Val Ala Ala Ile Ile Ser Ile Pro Thr Pro Pro Ala Asn Thr 595 600 605 Pro Asp Glu Ser Gln Pro Ser Ser Pro Gly Gly Gly Gly Arg Ala Gly 610 615 620 Ser Thr Leu Arg Asn Ser Ser Leu Gly Thr Pro Cys Leu Phe Pro Glu 625 630 635 640 Thr Val Lys Ile Ser Ser 645 11 1862 DNA H. sapiens CDS (383)...(1157) K+Hnov15 11 cagctgaatg tggaggcctt taagagaact tccagctcct gtaaaaaccc agaccagagg 60 actactgacc aacatttcag gctgatcctc cagacctcga agttactctc cttactctcc 120 tgactcttaa ttacatcaca cctgtgtcga cactctctgg gaaaagactg aagaaataat 180 cttttcaaga agcagaaagc tcctgcatac ataggctgat acgccaccta ctgcaaaacc 240 gagctgacag cgcaggcgat gctgccagcg tttccattcc atcaccaggc tggggctgaa 300 taaaggcgtg cttgtgtggt agtgtctctt tttaaaaaat ctcaaagcca agaagaacaa 360 gctgaaatag catcttcaaa aa atg gag cgt aaa ata aac aga aga gaa aaa 412 Met Glu Arg Lys Ile Asn Arg Arg Glu Lys 1 5 10 gaa aag gag tat gaa ggg aaa cac aac agc ctg gaa gat act gat caa 460 Glu Lys Glu Tyr Glu Gly Lys His Asn Ser Leu Glu Asp Thr Asp Gln 15 20 25 gga aag aac tgc aaa tcc aca ctg atg acc ctc aac gtt ggt gga tat 508 Gly Lys Asn Cys Lys Ser Thr Leu Met Thr Leu Asn Val Gly Gly Tyr 30 35 40 tta tac att act caa aaa caa aca ctg acc aag tac cca gac act ttc 556 Leu Tyr Ile Thr Gln Lys Gln Thr Leu Thr Lys Tyr Pro Asp Thr Phe 45 50 55 ctt gaa ggt ata gta aat gga aaa atc ctc tgc ccg ttt gat gct gat 604 Leu Glu Gly Ile Val Asn Gly Lys Ile Leu Cys Pro Phe Asp Ala Asp 60 65 70 ggt cat tat ttc ata gac agg gat ggt ctc ctc ttc agg cat gtc cta 652 Gly His Tyr Phe Ile Asp Arg Asp Gly Leu Leu Phe Arg His Val Leu 75 80 85 90 aac ttc cta cga aat gga gaa ctt cta ttg ccc gaa ggg ttt cga gaa 700 Asn Phe Leu Arg Asn Gly Glu Leu Leu Leu Pro Glu Gly Phe Arg Glu 95 100 105 aat caa ctt ctt gca caa gaa gca gaa ttc ttt cag ctc aag gga ctg 748 Asn Gln Leu Leu Ala Gln Glu Ala Glu Phe Phe Gln Leu Lys Gly Leu 110 115 120 gca gag gaa gtg aaa tcc agg tgg gag aaa gaa cag cta aca ccc aga 796 Ala Glu Glu Val Lys Ser Arg Trp Glu Lys Glu Gln Leu Thr Pro Arg 125 130 135 gag act act ttc ttg gaa ata aca gat aac cac gat cgt tca caa gga 844 Glu Thr Thr Phe Leu Glu Ile Thr Asp Asn His Asp Arg Ser Gln Gly 140 145 150 tta aga atc ttc tgt aat gct cct gat ttc ata tca aaa ata aag tct 892 Leu Arg Ile Phe Cys Asn Ala Pro Asp Phe Ile Ser Lys Ile Lys Ser 155 160 165 170 cgc att gtt ctg gtg tcc aaa agc agg ctg gat gga ttt cca gag gag 940 Arg Ile Val Leu Val Ser Lys Ser Arg Leu Asp Gly Phe Pro Glu Glu 175 180 185 ttt tca ata tcg tca aat atc atc caa ttt aaa tac ttc ata aag tct 988 Phe Ser Ile Ser Ser Asn Ile Ile Gln Phe Lys Tyr Phe Ile Lys Ser 190 195 200 gaa aat ggc act cga ctt gta cta aag gaa gac aac acc ttt gtc tgt 1036 Glu Asn Gly Thr Arg Leu Val Leu Lys Glu Asp Asn Thr Phe Val Cys 205 210 215 acc ttg gaa act ctt aag ttt gag gct atc atg atg gct tta aag tgt 1084 Thr Leu Glu Thr Leu Lys Phe Glu Ala Ile Met Met Ala Leu Lys Cys 220 225 230 ggc ttt aga ctg ctg acc agc ctg gat tgt tcc aaa ggg tca att gtt 1132 Gly Phe Arg Leu Leu Thr Ser Leu Asp Cys Ser Lys Gly Ser Ile Val 235 240 245 250 cac agc gat gca ctt cat ttt atc a agtaattacc tgtgtcacga 1177 His Ser Asp Ala Leu His Phe Ile 255 acaaaggcaa caagcatgca gccagcaagc ttcggaaaac cacagcatca aagacatccc 1237 aaataacatg cccagctagc tctgtactac agagccctgc tactaatcaa ttactgtgag 1297 ctaacggtat gtaaattcta tcgctaaaga tgtccttcct ctggggtgtt cctactgatc 1357 agactcttcc acctaaaatg aaaacagtaa ccttctatat actgtaaata aagactgaaa 1417 gcttttgcta tttatttgtc cttaagctgt ctttcaattc agattgtctt gggtatttgc 1477 acaaaaagaa gcatgtacat tatctatcgt tcatttaagt aaatggtaat aaaatatttt 1537 aaggggctat taatatttaa aatccttttc tactatggca aaaatctaca gagaaactga 1597 actggcaaaa ttaactacct ggagcaaaac agatgtgcag atctaactaa aacagagcta 1657 tagtgaaaca aaatgagatt gtaagaagac attaaagcta ttgatttgat ttttccatag 1717 caagcaccaa aagcttatat tcacagttcc tgtgtttcat attagactta tagctgaatt 1777 ggtattttgc tgaaaattcc tagaaaactg cttgatgaca ataaaaagta aataaaagca 1837 ctgctacctt caaaaaaaaa aaaaa 1862 12 258 PRT H. sapiens 12 Met Glu Arg Lys Ile Asn Arg Arg Glu Lys Glu Lys Glu Tyr Glu Gly 1 5 10 15 Lys His Asn Ser Leu Glu Asp Thr Asp Gln Gly Lys Asn Cys Lys Ser 20 25 30 Thr Leu Met Thr Leu Asn Val Gly Gly Tyr Leu Tyr Ile Thr Gln Lys 35 40 45 Gln Thr Leu Thr Lys Tyr Pro Asp Thr Phe Leu Glu Gly Ile Val Asn 50 55 60 Gly Lys Ile Leu Cys Pro Phe Asp Ala Asp Gly His Tyr Phe Ile Asp 65 70 75 80 Arg Asp Gly Leu Leu Phe Arg His Val Leu Asn Phe Leu Arg Asn Gly 85 90 95 Glu Leu Leu Leu Pro Glu Gly Phe Arg Glu Asn Gln Leu Leu Ala Gln 100 105 110 Glu Ala Glu Phe Phe Gln Leu Lys Gly Leu Ala Glu Glu Val Lys Ser 115 120 125 Arg Trp Glu Lys Glu Gln Leu Thr Pro Arg Glu Thr Thr Phe Leu Glu 130 135 140 Ile Thr Asp Asn His Asp Arg Ser Gln Gly Leu Arg Ile Phe Cys Asn 145 150 155 160 Ala Pro Asp Phe Ile Ser Lys Ile Lys Ser Arg Ile Val Leu Val Ser 165 170 175 Lys Ser Arg Leu Asp Gly Phe Pro Glu Glu Phe Ser Ile Ser Ser Asn 180 185 190 Ile Ile Gln Phe Lys Tyr Phe Ile Lys Ser Glu Asn Gly Thr Arg Leu 195 200 205 Val Leu Lys Glu Asp Asn Thr Phe Val Cys Thr Leu Glu Thr Leu Lys 210 215 220 Phe Glu Ala Ile Met Met Ala Leu Lys Cys Gly Phe Arg Leu Leu Thr 225 230 235 240 Ser Leu Asp Cys Ser Lys Gly Ser Ile Val His Ser Asp Ala Leu His 245 250 255 Phe Ile 13 1877 DNA H. sapiens CDS (322)...(1090) K+Hnov27 13 caccaccgcc cccagccgcc ctcgctgggg aacacttaca tcctccccaa agacagccag 60 gtcgggcccg acgtgaaatc cgaggctgcg cccaagcgcg ccctgtacga gtctgtgttc 120 gggtcggggg aaatctgcgg ccccacttcc cccaaaagac tttgtatccg cccctcggag 180 cctgtggatg cggtggtggt ggtttccgtg aaacacgacc ccctgcctct tcttccagaa 240 gccaatgggc acagaagcac caattctccc acaatagttt cacctgctat tgtttccccc 300 acccaggaca gtcggcccaa t atg tca aga cct ctg atc act aga tcc cct 351 Met Ser Arg Pro Leu Ile Thr Arg Ser Pro 1 5 10 gca tct cca ctg awc aac caa ggc atc cct act cca gca caa ctc aca 399 Ala Ser Pro Leu Xaa Asn Gln Gly Ile Pro Thr Pro Ala Gln Leu Thr 15 20 25 aaa tcc aat gcg cct gtc cac att gat gtg ggc ggc cac atg tac acc 447 Lys Ser Asn Ala Pro Val His Ile Asp Val Gly Gly His Met Tyr Thr 30 35 40 agc agc ctg gcc acc ctc acc aaa tac cct gaa tcc aga atc gga aga 495 Ser Ser Leu Ala Thr Leu Thr Lys Tyr Pro Glu Ser Arg Ile Gly Arg 45 50 55 ctt ttt gat ggt aca gag ccc att gtt ttg gac agt ctc aaa cag cac 543 Leu Phe Asp Gly Thr Glu Pro Ile Val Leu Asp Ser Leu Lys Gln His 60 65 70 tat ttc att gac aga gat gga cag atg ttc aga tat atc ttg aat ttt 591 Tyr Phe Ile Asp Arg Asp Gly Gln Met Phe Arg Tyr Ile Leu Asn Phe 75 80 85 90 cta cga aca tcc aaa ctc ctc att cct gat gat ttc aag gac tac act 639 Leu Arg Thr Ser Lys Leu Leu Ile Pro Asp Asp Phe Lys Asp Tyr Thr 95 100 105 ttg tta tat gaa gag gca aaa tat ttt cag ctt cag ccc atg ttg ttg 687 Leu Leu Tyr Glu Glu Ala Lys Tyr Phe Gln Leu Gln Pro Met Leu Leu 110 115 120 gag atg gaa aga tgg aag cag gac aga gaa act ggt cga ttt tca agg 735 Glu Met Glu Arg Trp Lys Gln Asp Arg Glu Thr Gly Arg Phe Ser Arg 125 130 135 ccc tgt gag tgc ctc gtc gtg cgt gtg gcc cca gac ctc gga gaa agg 783 Pro Cys Glu Cys Leu Val Val Arg Val Ala Pro Asp Leu Gly Glu Arg 140 145 150 atc acg cta agc ggt gac aaa tcc ttg ata gaa gaa gta ttt cca gag 831 Ile Thr Leu Ser Gly Asp Lys Ser Leu Ile Glu Glu Val Phe Pro Glu 155 160 165 170 atc ggc gac gtg atg tgt aac tct gtc aat gca ggc tgg aat cac gac 879 Ile Gly Asp Val Met Cys Asn Ser Val Asn Ala Gly Trp Asn His Asp 175 180 185 tcg acg cac gtc atc agg ttt cca cta aat ggc tac tgt cac ctc aac 927 Ser Thr His Val Ile Arg Phe Pro Leu Asn Gly Tyr Cys His Leu Asn 190 195 200 tca gtc cag gtc ctc gag agg ttg cag caa aga gga ttt gaa atc gtg 975 Ser Val Gln Val Leu Glu Arg Leu Gln Gln Arg Gly Phe Glu Ile Val 205 210 215 ggc tcc tgt ggg gga gga gta gac tcg tcc cag ttc agc gaa tac gtc 1023 Gly Ser Cys Gly Gly Gly Val Asp Ser Ser Gln Phe Ser Glu Tyr Val 220 225 230 ctt cgg cgg gaa ctg agg cgg acg ccc cgt gta ccc tcc gtc atc cgg 1071 Leu Arg Arg Glu Leu Arg Arg Thr Pro Arg Val Pro Ser Val Ile Arg 235 240 245 250 ata aag caa gag cct ctg g actaaatgga catatttctt atgcaaaaag 1120 Ile Lys Gln Glu Pro Leu 255 gaaaacacac acaaccaata actcaaacaa aaaagggaca tttatgtgca gttgggacag 1180 caaaccaagt cctggacgta aaattgaata aaagacacat ttatatccaa tagagaccac 1240 acctgtattc atatgggaac aattggaata gtgatatcct caaggtgtaa aaaatatata 1300 aatatatata tatatgtcaa aaggtaggaa atgcaaaaaa gaaaaaaaaa aaaggtgaca 1360 gccgcagttg gtgctgtgat ggccgtgaag tgtcctgggc ctcccgaggc ctctgacaaa 1420 taaacaagcc atgagtggtg aggacacagt ctccttacag tttccattgc caacaacagc 1480 catccatatt tcttttttcc tttgtctttc tttttccttt ttttttaaaa aaacaaaaca 1540 aacaaaacac cttgaatcaa gtttgtttgt atatggaggt tccacgtctt tctttaggca 1600 gggaccaggc aggacttcag aaaaaccctc atgagcacat tgcaaagatg ttagacatga 1660 aattttaaat gtagtttgta cagaagtcac acttttttgt ccacctcaca gatgtgaact 1720 ttactttgtt ttaaaactga tcagttttgc caaggggcca gaattattcc ttgttagaat 1780 tgctccagtt caagtctgct gctttcctac aatttttcaa attttataat gtattaaata 1840 caataaactc tgtttaaaaa ataaaaaaaa aaaaaaa 1877 14 256 PRT H. sapiens VARIANT (1)...(256) Xaa = Any Amino Acid 14 Met Ser Arg Pro Leu Ile Thr Arg Ser Pro Ala Ser Pro Leu Xaa Asn 1 5 10 15 Gln Gly Ile Pro Thr Pro Ala Gln Leu Thr Lys Ser Asn Ala Pro Val 20 25 30 His Ile Asp Val Gly Gly His Met Tyr Thr Ser Ser Leu Ala Thr Leu 35 40 45 Thr Lys Tyr Pro Glu Ser Arg Ile Gly Arg Leu Phe Asp Gly Thr Glu 50 55 60 Pro Ile Val Leu Asp Ser Leu Lys Gln His Tyr Phe Ile Asp Arg Asp 65 70 75 80 Gly Gln Met Phe Arg Tyr Ile Leu Asn Phe Leu Arg Thr Ser Lys Leu 85 90 95 Leu Ile Pro Asp Asp Phe Lys Asp Tyr Thr Leu Leu Tyr Glu Glu Ala 100 105 110 Lys Tyr Phe Gln Leu Gln Pro Met Leu Leu Glu Met Glu Arg Trp Lys 115 120 125 Gln Asp Arg Glu Thr Gly Arg Phe Ser Arg Pro Cys Glu Cys Leu Val 130 135 140 Val Arg Val Ala Pro Asp Leu Gly Glu Arg Ile Thr Leu Ser Gly Asp 145 150 155 160 Lys Ser Leu Ile Glu Glu Val Phe Pro Glu Ile Gly Asp Val Met Cys 165 170 175 Asn Ser Val Asn Ala Gly Trp Asn His Asp Ser Thr His Val Ile Arg 180 185 190 Phe Pro Leu Asn Gly Tyr Cys His Leu Asn Ser Val Gln Val Leu Glu 195 200 205 Arg Leu Gln Gln Arg Gly Phe Glu Ile Val Gly Ser Cys Gly Gly Gly 210 215 220 Val Asp Ser Ser Gln Phe Ser Glu Tyr Val Leu Arg Arg Glu Leu Arg 225 230 235 240 Arg Thr Pro Arg Val Pro Ser Val Ile Arg Ile Lys Gln Glu Pro Leu 245 250 255 15 923 DNA H. sapiens CDS (165)...(756) K+Hnov2 15 gcgtggtggc aggtgcctgt agccccagct acttgggagg ctgaggcagg agaatagctt 60 gaacccgggc ggcgaaggtt gagtgagccg agattgcacc actgcactcc agcctgggcg 120 acagagcgag actccatctc aaaaaaaaga gtagttatgg ccac atg gcc cca cta 176 Met Ala Pro Leu 1 tcg cca ggc gga aag gcc ttc tgc atg gtc tat gca gcc ctg ggg ctg 224 Ser Pro Gly Gly Lys Ala Phe Cys Met Val Tyr Ala Ala Leu Gly Leu 5 10 15 20 cca gcc tcc tta gct ctc gtg gcc acc ctg cgc cat tgc ctg ctg cct 272 Pro Ala Ser Leu Ala Leu Val Ala Thr Leu Arg His Cys Leu Leu Pro 25 30 35 gtg ctc agc cgc cca cgt gcc tgg gta gcg gtc cac tgg cag ctg tca 320 Val Leu Ser Arg Pro Arg Ala Trp Val Ala Val His Trp Gln Leu Ser 40 45 50 ccg gcc agg gct gcg ctg ctg cag gca gtt gca ctg gga ctg ctg gtg 368 Pro Ala Arg Ala Ala Leu Leu Gln Ala Val Ala Leu Gly Leu Leu Val 55 60 65 gcc agc agc ttt gtg ctg ctg cca gcg ctg gtg ctg tgg ggc ctt cag 416 Ala Ser Ser Phe Val Leu Leu Pro Ala Leu Val Leu Trp Gly Leu Gln 70 75 80 ggc gac tgc agc ctg ctg ggg gcc gtc tac ttc tgc ttc agc tcg ctc 464 Gly Asp Cys Ser Leu Leu Gly Ala Val Tyr Phe Cys Phe Ser Ser Leu 85 90 95 100 agc acc att ggc ctg gag gac ttg ctg ccc ggc cgc ggc cgc agc ctg 512 Ser Thr Ile Gly Leu Glu Asp Leu Leu Pro Gly Arg Gly Arg Ser Leu 105 110 115 cac ccc gtg att tac cac ctg ggc cag ctc gca ctt ctt ggt tac ttg 560 His Pro Val Ile Tyr His Leu Gly Gln Leu Ala Leu Leu Gly Tyr Leu 120 125 130 ctt cta gga ctc ttg gcc atg ctg ctg gca gtg gag acc ttc tct gag 608 Leu Leu Gly Leu Leu Ala Met Leu Leu Ala Val Glu Thr Phe Ser Glu 135 140 145 ctg ccg cag gtc cgt gcc atg ggg aag ttc ttc aga ccc agt ggt cct 656 Leu Pro Gln Val Arg Ala Met Gly Lys Phe Phe Arg Pro Ser Gly Pro 150 155 160 gtg act gct gag gac caa ggt ggc atc cta ggg cag gat gaa ctg gct 704 Val Thr Ala Glu Asp Gln Gly Gly Ile Leu Gly Gln Asp Glu Leu Ala 165 170 175 180 ctg agc acc ctg ccg ccc gcg gcc cca gct tca gga caa gcc cct gct 752 Leu Ser Thr Leu Pro Pro Ala Ala Pro Ala Ser Gly Gln Ala Pro Ala 185 190 195 tgc t gaagcgtcag gtgaccgagt tcagctccgt aaggtggcgg cacctgagga 806 Cys ggaagcagcc aggagtggct ggggaagaat ctggagatgg agccgcggtg agggtgggcg 866 ggaggcctca ggggatactg ttaatcataa aaaaaaaaaa aaaaaaaaaa aaaaaaa 923 16 197 PRT H. sapiens 16 Met Ala Pro Leu Ser Pro Gly Gly Lys Ala Phe Cys Met Val Tyr Ala 1 5 10 15 Ala Leu Gly Leu Pro Ala Ser Leu Ala Leu Val Ala Thr Leu Arg His 20 25 30 Cys Leu Leu Pro Val Leu Ser Arg Pro Arg Ala Trp Val Ala Val His 35 40 45 Trp Gln Leu Ser Pro Ala Arg Ala Ala Leu Leu Gln Ala Val Ala Leu 50 55 60 Gly Leu Leu Val Ala Ser Ser Phe Val Leu Leu Pro Ala Leu Val Leu 65 70 75 80 Trp Gly Leu Gln Gly Asp Cys Ser Leu Leu Gly Ala Val Tyr Phe Cys 85 90 95 Phe Ser Ser Leu Ser Thr Ile Gly Leu Glu Asp Leu Leu Pro Gly Arg 100 105 110 Gly Arg Ser Leu His Pro Val Ile Tyr His Leu Gly Gln Leu Ala Leu 115 120 125 Leu Gly Tyr Leu Leu Leu Gly Leu Leu Ala Met Leu Leu Ala Val Glu 130 135 140 Thr Phe Ser Glu Leu Pro Gln Val Arg Ala Met Gly Lys Phe Phe Arg 145 150 155 160 Pro Ser Gly Pro Val Thr Ala Glu Asp Gln Gly Gly Ile Leu Gly Gln 165 170 175 Asp Glu Leu Ala Leu Ser Thr Leu Pro Pro Ala Ala Pro Ala Ser Gly 180 185 190 Gln Ala Pro Ala Cys 195 17 3102 DNA H. sapiens CDS (274)...(1705) K+Hnov11 17 gcacgcgcaa agcgcccacc gagacccctg gggtggagct tgtgttaata gaaacatacc 60 cacccccagc ctttcctggg aggggatcag acccctcaaa ctcttgcccc agcccagccc 120 ttcagcaccc aagacccacc aggaggcctg ggcccgccag taatgggtag ggagaggggg 180 ccccgccagg gcgcacggcg ctctcgccga cgctgttccc tccgcttcca ggtgtagcgc 240 ccccgcgcgg cgcgggcggc cggcgcctcc agc atg acc ggc cag agc ctg tgg 294 Met Thr Gly Gln Ser Leu Trp 1 5 gac gtg tcg gag gct aac gtc gag gac ggg gag atc cgc atc aat gtg 342 Asp Val Ser Glu Ala Asn Val Glu Asp Gly Glu Ile Arg Ile Asn Val 10 15 20 ggc ggc ttc aag agg agg ctg cgc tcg cac acg ctg ctg cgc ttc ccc 390 Gly Gly Phe Lys Arg Arg Leu Arg Ser His Thr Leu Leu Arg Phe Pro 25 30 35 gag acg cgc ctg ggc cgc ttg ctg ctc tgc cac tcg cgc gag gcc att 438 Glu Thr Arg Leu Gly Arg Leu Leu Leu Cys His Ser Arg Glu Ala Ile 40 45 50 55 ctg gag ctc tgc gat gac tac gac gac gtc cag cgg gag ttc tac ttc 486 Leu Glu Leu Cys Asp Asp Tyr Asp Asp Val Gln Arg Glu Phe Tyr Phe 60 65 70 gac cgc aac cct gag ctc ttc ccc tac gtg ctg cat ttc tat cac acc 534 Asp Arg Asn Pro Glu Leu Phe Pro Tyr Val Leu His Phe Tyr His Thr 75 80 85 ggc aag ctt cac gtc atg gct gag cta tgt gtc ttc tcc ttc agc cag 582 Gly Lys Leu His Val Met Ala Glu Leu Cys Val Phe Ser Phe Ser Gln 90 95 100 gag atc gag tac tgg ggc atc aac gag ttc ttc att gac tcc tgc tgc 630 Glu Ile Glu Tyr Trp Gly Ile Asn Glu Phe Phe Ile Asp Ser Cys Cys 105 110 115 agc tac agc tac cat ggc cgc aaa gta gag ccc gag cag gag aag tgg 678 Ser Tyr Ser Tyr His Gly Arg Lys Val Glu Pro Glu Gln Glu Lys Trp 120 125 130 135 gac gag cag agt gac cag gag agc acc acg tct tcc ttc gat gag atc 726 Asp Glu Gln Ser Asp Gln Glu Ser Thr Thr Ser Ser Phe Asp Glu Ile 140 145 150 ctt gcc ttc tac aac gac gcc tcc aag ttc gat ggg cag ccc ctc ggc 774 Leu Ala Phe Tyr Asn Asp Ala Ser Lys Phe Asp Gly Gln Pro Leu Gly 155 160 165 aac ttc cgc agg cag ctg tgg ctg gcg ctg gac aac ccc ggc tac tca 822 Asn Phe Arg Arg Gln Leu Trp Leu Ala Leu Asp Asn Pro Gly Tyr Ser 170 175 180 gtg ctg agc agg gtc ttc agc atc ctg tcc atc ctg gtg gtg atg ggg 870 Val Leu Ser Arg Val Phe Ser Ile Leu Ser Ile Leu Val Val Met Gly 185 190 195 tcc atc atc acc atg tgc ctc aat agc ctg ccc gat ttc caa atc cct 918 Ser Ile Ile Thr Met Cys Leu Asn Ser Leu Pro Asp Phe Gln Ile Pro 200 205 210 215 gac agc cag ggc aac cct ggc gag gac cct agg ttc gaa atc gtg gag 966 Asp Ser Gln Gly Asn Pro Gly Glu Asp Pro Arg Phe Glu Ile Val Glu 220 225 230 cac ttt ggc att gcc tgg ttc aca ttt gag ctg gtg gcc agg ttt gct 1014 His Phe Gly Ile Ala Trp Phe Thr Phe Glu Leu Val Ala Arg Phe Ala 235 240 245 gtg gcc cct gac ttc ctc aag ttc ttc aag aat gcc cta aac ctt att 1062 Val Ala Pro Asp Phe Leu Lys Phe Phe Lys Asn Ala Leu Asn Leu Ile 250 255 260 gac ctc atg tcc atc gtc ccc ttt tac atc act ctg gtg gtg aac ctg 1110 Asp Leu Met Ser Ile Val Pro Phe Tyr Ile Thr Leu Val Val Asn Leu 265 270 275 gtg gtg gag agc aca cct act tta gcc aac ttg ggc agg gtg gcc cag 1158 Val Val Glu Ser Thr Pro Thr Leu Ala Asn Leu Gly Arg Val Ala Gln 280 285 290 295 gtc ctg agg ctg atg cgg atc ttc cgc atc tta aag ctg gcc agg cac 1206 Val Leu Arg Leu Met Arg Ile Phe Arg Ile Leu Lys Leu Ala Arg His 300 305 310 tcc act ggc ctc cgc tcc ctg ggg gcc act ttg aaa tac agc tac aaa 1254 Ser Thr Gly Leu Arg Ser Leu Gly Ala Thr Leu Lys Tyr Ser Tyr Lys 315 320 325 gaa gta ggg ctg ctc ttg ctc tac ctc tcc gtg ggg att tcc atc ttc 1302 Glu Val Gly Leu Leu Leu Leu Tyr Leu Ser Val Gly Ile Ser Ile Phe 330 335 340 tcc gtg gtg gcc tac acc att gaa aag gag gag aac gag ggc ctg gcc 1350 Ser Val Val Ala Tyr Thr Ile Glu Lys Glu Glu Asn Glu Gly Leu Ala 345 350 355 acc atc cct gcc tgc tgg tgg tgg gct acc gtc agt atg acc aca gtg 1398 Thr Ile Pro Ala Cys Trp Trp Trp Ala Thr Val Ser Met Thr Thr Val 360 365 370 375 ggg tac ggg gat gtg gtc cca ggg acc acg gca gga aag ctg act gcc 1446 Gly Tyr Gly Asp Val Val Pro Gly Thr Thr Ala Gly Lys Leu Thr Ala 380 385 390 tct gcc tgc atc ttg gca ggc atc ctc gtg gtg gtc ctg ccc atc acc 1494 Ser Ala Cys Ile Leu Ala Gly Ile Leu Val Val Val Leu Pro Ile Thr 395 400 405 ttg atc ttc aat aag ttc tcc cac ttt tac cgg cgc caa aag caa ctt 1542 Leu Ile Phe Asn Lys Phe Ser His Phe Tyr Arg Arg Gln Lys Gln Leu 410 415 420 gag agt gcc atg cgc agc tgt gac ttt gga gat gga atg aag gag gtc 1590 Glu Ser Ala Met Arg Ser Cys Asp Phe Gly Asp Gly Met Lys Glu Val 425 430 435 cct tcg gtc aat tta agg gac tat tat gcc cat aaa gtt aaa tcc ctt 1638 Pro Ser Val Asn Leu Arg Asp Tyr Tyr Ala His Lys Val Lys Ser Leu 440 445 450 455 atg gca agc ctg acg aac atg agc agg agc tca cca agt gaa ctc agt 1686 Met Ala Ser Leu Thr Asn Met Ser Arg Ser Ser Pro Ser Glu Leu Ser 460 465 470 tta aat gat tcc cta cgt t agccgggagg acttgtcacc ctccacccca 1735 Leu Asn Asp Ser Leu Arg 475 cattgctgag ctgcctcttg tgcctctggc acagcccagg caccttatgg ttatggtgta 1795 aggagtatgc ccagcccctg aggggagaga tgcatgggat atgcacccag gtttctttta 1855 cagtttttag aatcgttttt agagggtggt gtgtctgaca ccatgccttt gcacctttcc 1915 atgaaatgac actcactggt ctttgcatcg tgggcataaa atgttcacct tttttccaga 1975 tgagtacacc cagaatgcta atttttctgt ccatcgtgta cgctattcta gtgcttgtgg 2035 cccagtactg tctatgagtt gtcgtgctcc tgtttctgag gttgtcgtgt gagttctgta 2095 caaaaagccc ccacaagtcg tccagtagaa atgcatctat gaggtcagca aggatatgat 2155 gagattttgc tcacagtcat gtgaaaacaa aatctcagct ctttatccat tgctttcact 2215 tagttttagt accaaaacaa agagaatgca aagttaagca gacttgacca atgcaagtct 2275 ctaagttgtt tttataaatg atctgtagtt ccgtggcttg catgggtgca ccaatcatct 2335 ttagaacgat gtacactgat gttcatctca taaatgtcac tctttagaga atgttactta 2395 gttaaacatg cagtgaagat cgaatttttt tcccaagaac agatgtgtta gggagagggg 2455 cttcagctaa atagtccaaa ccctagggtg cttaaagcca agttagtgca ggctgagccc 2515 cttggttcac agtcaagcct ccttgtttcc tagggtgact gtagagaaat gtatttccgg 2575 atgaggtttc tgatctaggc catttgacca aactttgctg tgtctaagat attagcatgt 2635 ttttgaaata tttatttttt aagatgttta ggagtaaggt cgtgttgtct tcctcaacta 2695 aaaagaagtt tactgttgta tcgtctccct gaggtgaacg ttgttgggtt gctagcaagg 2755 cagtagctta atacttttgt tgcctactct gaaagctcat caatgagagc ccttttattt 2815 ccaagcagaa tttagtcaga taattttgct tctaggatat agtatgttgt atatgatgct 2875 gtgattgccc tggagttcct gcccatgact ggaaacctgg tggtatggaa gcatgtactc 2935 aaaatataga cgtgcacgat ggtggtgtgg cttacccagg atggaaacac tgcagttctt 2995 acttgcattc ccactgcctt tcatgggggg tgactgggta gaggccagga gaaaggaaag 3055 agttgtaaaa taaaaaactg ctagttcata aaaaaaaaaa aaaaaaa 3102 18 477 PRT H. sapiens 18 Met Thr Gly Gln Ser Leu Trp Asp Val Ser Glu Ala Asn Val Glu Asp 1 5 10 15 Gly Glu Ile Arg Ile Asn Val Gly Gly Phe Lys Arg Arg Leu Arg Ser 20 25 30 His Thr Leu Leu Arg Phe Pro Glu Thr Arg Leu Gly Arg Leu Leu Leu 35 40 45 Cys His Ser Arg Glu Ala Ile Leu Glu Leu Cys Asp Asp Tyr Asp Asp 50 55 60 Val Gln Arg Glu Phe Tyr Phe Asp Arg Asn Pro Glu Leu Phe Pro Tyr 65 70 75 80 Val Leu His Phe Tyr His Thr Gly Lys Leu His Val Met Ala Glu Leu 85 90 95 Cys Val Phe Ser Phe Ser Gln Glu Ile Glu Tyr Trp Gly Ile Asn Glu 100 105 110 Phe Phe Ile Asp Ser Cys Cys Ser Tyr Ser Tyr His Gly Arg Lys Val 115 120 125 Glu Pro Glu Gln Glu Lys Trp Asp Glu Gln Ser Asp Gln Glu Ser Thr 130 135 140 Thr Ser Ser Phe Asp Glu Ile Leu Ala Phe Tyr Asn Asp Ala Ser Lys 145 150 155 160 Phe Asp Gly Gln Pro Leu Gly Asn Phe Arg Arg Gln Leu Trp Leu Ala 165 170 175 Leu Asp Asn Pro Gly Tyr Ser Val Leu Ser Arg Val Phe Ser Ile Leu 180 185 190 Ser Ile Leu Val Val Met Gly Ser Ile Ile Thr Met Cys Leu Asn Ser 195 200 205 Leu Pro Asp Phe Gln Ile Pro Asp Ser Gln Gly Asn Pro Gly Glu Asp 210 215 220 Pro Arg Phe Glu Ile Val Glu His Phe Gly Ile Ala Trp Phe Thr Phe 225 230 235 240 Glu Leu Val Ala Arg Phe Ala Val Ala Pro Asp Phe Leu Lys Phe Phe 245 250 255 Lys Asn Ala Leu Asn Leu Ile Asp Leu Met Ser Ile Val Pro Phe Tyr 260 265 270 Ile Thr Leu Val Val Asn Leu Val Val Glu Ser Thr Pro Thr Leu Ala 275 280 285 Asn Leu Gly Arg Val Ala Gln Val Leu Arg Leu Met Arg Ile Phe Arg 290 295 300 Ile Leu Lys Leu Ala Arg His Ser Thr Gly Leu Arg Ser Leu Gly Ala 305 310 315 320 Thr Leu Lys Tyr Ser Tyr Lys Glu Val Gly Leu Leu Leu Leu Tyr Leu 325 330 335 Ser Val Gly Ile Ser Ile Phe Ser Val Val Ala Tyr Thr Ile Glu Lys 340 345 350 Glu Glu Asn Glu Gly Leu Ala Thr Ile Pro Ala Cys Trp Trp Trp Ala 355 360 365 Thr Val Ser Met Thr Thr Val Gly Tyr Gly Asp Val Val Pro Gly Thr 370 375 380 Thr Ala Gly Lys Leu Thr Ala Ser Ala Cys Ile Leu Ala Gly Ile Leu 385 390 395 400 Val Val Val Leu Pro Ile Thr Leu Ile Phe Asn Lys Phe Ser His Phe 405 410 415 Tyr Arg Arg Gln Lys Gln Leu Glu Ser Ala Met Arg Ser Cys Asp Phe 420 425 430 Gly Asp Gly Met Lys Glu Val Pro Ser Val Asn Leu Arg Asp Tyr Tyr 435 440 445 Ala His Lys Val Lys Ser Leu Met Ala Ser Leu Thr Asn Met Ser Arg 450 455 460 Ser Ser Pro Ser Glu Leu Ser Leu Asn Asp Ser Leu Arg 465 470 475 19 3857 DNA H. sapiens CDS (249)...(3495) K+Hnov14 19 gggctggtag cagggatttg tgggcggcga gggcgcgagg ggccgcgcgc catgctccgg 60 gccccgacgg cgcggacgcc ccctcgcgcg ccagctccgg cgcgaccccg gatcccggtc 120 tgcgcattgc cccccgacgg ctgcgctagg agcgcggggc ccggcggggg cggccgagct 180 gggcgccctc ccccggcgcg gagtccccgc accccggagg atggggcggg cagccgcggg 240 cgcctaag atg ccg gcc atg cgg ggc ctc ctg gcg ccg cag aac acc ttc 290 Met Pro Ala Met Arg Gly Leu Leu Ala Pro Gln Asn Thr Phe 1 5 10 ctg gac acc atc gct acg cgc ttc gac ggc acg cac agt aac ttc gtg 338 Leu Asp Thr Ile Ala Thr Arg Phe Asp Gly Thr His Ser Asn Phe Val 15 20 25 30 ctg ggc aac gcc agt ggc ggg gct ctt ccc gtg gtc tac tgc tct gat 386 Leu Gly Asn Ala Ser Gly Gly Ala Leu Pro Val Val Tyr Cys Ser Asp 35 40 45 ggc ttc tgt gac ctc acg ggc ttc tcc cgg gct gag gtc atg cag cgg 434 Gly Phe Cys Asp Leu Thr Gly Phe Ser Arg Ala Glu Val Met Gln Arg 50 55 60 ggc tgt gcc tgc tcc ttc ctt tat ggg cca gac acc agt gag ctc gtc 482 Gly Cys Ala Cys Ser Phe Leu Tyr Gly Pro Asp Thr Ser Glu Leu Val 65 70 75 cgc caa cag atc cgc aag gcc ctg gac gag cac aag gag ttc aag gct 530 Arg Gln Gln Ile Arg Lys Ala Leu Asp Glu His Lys Glu Phe Lys Ala 80 85 90 gag ctg atc ctg tac cgg aag agc ggg ctc ccg ttc tgg tgt ctc ctg 578 Glu Leu Ile Leu Tyr Arg Lys Ser Gly Leu Pro Phe Trp Cys Leu Leu 95 100 105 110 gat gtg ata ccc ata aag aat gag aaa ggg gag gtg gct ctc ttc cta 626 Asp Val Ile Pro Ile Lys Asn Glu Lys Gly Glu Val Ala Leu Phe Leu 115 120 125 gtc tct cac aag gac atc agc gaa acc aag aac cga ggg ggc ccc gac 674 Val Ser His Lys Asp Ile Ser Glu Thr Lys Asn Arg Gly Gly Pro Asp 130 135 140 aga tgg aaa gag aca ggt ggt ggc cgg cgc cga tat ggc cgg gca cga 722 Arg Trp Lys Glu Thr Gly Gly Gly Arg Arg Arg Tyr Gly Arg Ala Arg 145 150 155 tcc aaa ggc ttc aat gcc aac cgg cgg cgg agc cgg gcc gtg ctc tac 770 Ser Lys Gly Phe Asn Ala Asn Arg Arg Arg Ser Arg Ala Val Leu Tyr 160 165 170 cac ctg tcc ggg cac ctg cag aag cag ccc aag ggc aag cac aag ctc 818 His Leu Ser Gly His Leu Gln Lys Gln Pro Lys Gly Lys His Lys Leu 175 180 185 190 aat aag ggg gtg ttt ggg gag aaa cca aac ttg cct gag tac aaa gta 866 Asn Lys Gly Val Phe Gly Glu Lys Pro Asn Leu Pro Glu Tyr Lys Val 195 200 205 gcc gcc atc cgg aag tcg ccc ttc atc ctg ttg cac tgt ggg gca ctg 914 Ala Ala Ile Arg Lys Ser Pro Phe Ile Leu Leu His Cys Gly Ala Leu 210 215 220 aga gcc acc tgg gat ggc ttc atc ctg ctc gcc aca ctc tat gtg gct 962 Arg Ala Thr Trp Asp Gly Phe Ile Leu Leu Ala Thr Leu Tyr Val Ala 225 230 235 gtc act gtg ccc tac agc gtg tgt gtg agc aca gca cgg gag ccc agt 1010 Val Thr Val Pro Tyr Ser Val Cys Val Ser Thr Ala Arg Glu Pro Ser 240 245 250 gcc gcc cgc ggc ccg ccc agc gtc tgt gac ctg gcc gtg gag gtc ctc 1058 Ala Ala Arg Gly Pro Pro Ser Val Cys Asp Leu Ala Val Glu Val Leu 255 260 265 270 ttc atc ctt gac att gtg ctg aat ttc cgt acc aca ttc gtg tcc aag 1106 Phe Ile Leu Asp Ile Val Leu Asn Phe Arg Thr Thr Phe Val Ser Lys 275 280 285 tcg ggc cag gtg gtg ttt gcc cca aag tcc att tgc ctc cac tac gtc 1154 Ser Gly Gln Val Val Phe Ala Pro Lys Ser Ile Cys Leu His Tyr Val 290 295 300 acc acc tgg ttc ctg ctg gat gtc atc gca gcg ctg ccc ttt gac ctg 1202 Thr Thr Trp Phe Leu Leu Asp Val Ile Ala Ala Leu Pro Phe Asp Leu 305 310 315 cta cat gcc ttc aag gtc aac gtg tac ttc ggg gcc cat ctg ctg aag 1250 Leu His Ala Phe Lys Val Asn Val Tyr Phe Gly Ala His Leu Leu Lys 320 325 330 acg gtg cgc ctg ctg cgc ctg ctg cgc ctg ctt ccg cgg ctg gac cgg 1298 Thr Val Arg Leu Leu Arg Leu Leu Arg Leu Leu Pro Arg Leu Asp Arg 335 340 345 350 tac tcg cag tac agc gcc gtg gtg ctg aca ctg ctc atg gcc gtg ttc 1346 Tyr Ser Gln Tyr Ser Ala Val Val Leu Thr Leu Leu Met Ala Val Phe 355 360 365 gcc ctg ctc gcg cac tgg gtc gcc tgc gtc tgg ttt tac att ggc cag 1394 Ala Leu Leu Ala His Trp Val Ala Cys Val Trp Phe Tyr Ile Gly Gln 370 375 380 cgg gag atc gag agc agc gaa tcc gag ctg cct gag att ggc tgg ctg 1442 Arg Glu Ile Glu Ser Ser Glu Ser Glu Leu Pro Glu Ile Gly Trp Leu 385 390 395 cag gag ctg gcc cgc cga ctg gag act ccc tac tac ctg gtg ggc cgg 1490 Gln Glu Leu Ala Arg Arg Leu Glu Thr Pro Tyr Tyr Leu Val Gly Arg 400 405 410 agg cca gct gga ggg aac agc tcc ggc cag agt gac aac tgc agc agc 1538 Arg Pro Ala Gly Gly Asn Ser Ser Gly Gln Ser Asp Asn Cys Ser Ser 415 420 425 430 agc agc gag gcc aac ggg acg ggg ctg gag ctg ctg ggc ggc ccg tcg 1586 Ser Ser Glu Ala Asn Gly Thr Gly Leu Glu Leu Leu Gly Gly Pro Ser 435 440 445 ctg cgc agc gcc tac atc acc tcc ctc tac ttc gca ctc agc agc ctc 1634 Leu Arg Ser Ala Tyr Ile Thr Ser Leu Tyr Phe Ala Leu Ser Ser Leu 450 455 460 acc agc gtg ggc ttc ggc aac gtg tcc gcc aac acg gac acc gag aag 1682 Thr Ser Val Gly Phe Gly Asn Val Ser Ala Asn Thr Asp Thr Glu Lys 465 470 475 atc ttc tcc atc tgc acc atg ctc atc ggc gcc ctg atg cac gcg gtg 1730 Ile Phe Ser Ile Cys Thr Met Leu Ile Gly Ala Leu Met His Ala Val 480 485 490 gtg ttt ggg aac gtg acg gcc atc atc cag cgc atg tac gcc cgc cgc 1778 Val Phe Gly Asn Val Thr Ala Ile Ile Gln Arg Met Tyr Ala Arg Arg 495 500 505 510 ttt ctg tac cac agc cgc acg cgc gac cag cgc gac tac atc cgc atc 1826 Phe Leu Tyr His Ser Arg Thr Arg Asp Gln Arg Asp Tyr Ile Arg Ile 515 520 525 cac cgt atc ccc aag ccc ctc aag cag cgc atg ctg gag tac ttc cag 1874 His Arg Ile Pro Lys Pro Leu Lys Gln Arg Met Leu Glu Tyr Phe Gln 530 535 540 gcc acc tgg gcg gtg aac aat ggc atc gac acc acc gag ctg ctg cag 1922 Ala Thr Trp Ala Val Asn Asn Gly Ile Asp Thr Thr Glu Leu Leu Gln 545 550 555 agc ctc cct gac gag ctg cgc gca gac atc gcc atg cac ctg cac aag 1970 Ser Leu Pro Asp Glu Leu Arg Ala Asp Ile Ala Met His Leu His Lys 560 565 570 gag gtc ctg cag ctg cca ctg ttt gag gcg gcc agc cgc ggc tgc ctg 2018 Glu Val Leu Gln Leu Pro Leu Phe Glu Ala Ala Ser Arg Gly Cys Leu 575 580 585 590 cgg gca ctg tct ctg gcc ctg cgg ccc gcc ttc tgc acg ccg ggc gag 2066 Arg Ala Leu Ser Leu Ala Leu Arg Pro Ala Phe Cys Thr Pro Gly Glu 595 600 605 tac ctc atc cac caa ggc gat gcc ctg cag gcc ctc tac ttt gtc tgc 2114 Tyr Leu Ile His Gln Gly Asp Ala Leu Gln Ala Leu Tyr Phe Val Cys 610 615 620 tct ggc tcc atg gag gtg ctc aag ggt ggc acc gtg ctc gcc atc cta 2162 Ser Gly Ser Met Glu Val Leu Lys Gly Gly Thr Val Leu Ala Ile Leu 625 630 635 ggg aag ggc gac ctg atc ggc tgt gag ctg ccc cgg cgg gag cag gtg 2210 Gly Lys Gly Asp Leu Ile Gly Cys Glu Leu Pro Arg Arg Glu Gln Val 640 645 650 gta aag gcc aat gcc gac gtg aag ggg ctg acg tac tgc gtc ctg cag 2258 Val Lys Ala Asn Ala Asp Val Lys Gly Leu Thr Tyr Cys Val Leu Gln 655 660 665 670 tgt ctg cag ctg gct ggc ctg cac gac agc ctt gcg ctg tac ccc gag 2306 Cys Leu Gln Leu Ala Gly Leu His Asp Ser Leu Ala Leu Tyr Pro Glu 675 680 685 ttt gcc ccg cgc ttc agt cgt ggc ctc cga ggg gag ctc agc tac aac 2354 Phe Ala Pro Arg Phe Ser Arg Gly Leu Arg Gly Glu Leu Ser Tyr Asn 690 695 700 ctg ggt gct ggg gga ggc tct gca gag gtg gac acc agc tcc ctg agc 2402 Leu Gly Ala Gly Gly Gly Ser Ala Glu Val Asp Thr Ser Ser Leu Ser 705 710 715 ggc gac aat acc ctt atg tcc acg ctg gag gag aag gag aca gat ggg 2450 Gly Asp Asn Thr Leu Met Ser Thr Leu Glu Glu Lys Glu Thr Asp Gly 720 725 730 gag cag ggc ccc acg gtc tcc cca gcc cca gct gat gag ccc tcc agc 2498 Glu Gln Gly Pro Thr Val Ser Pro Ala Pro Ala Asp Glu Pro Ser Ser 735 740 745 750 ccc ctg ctg tcc cct ggc tgc acc tcc tca tcc tca gct gcc aag ctg 2546 Pro Leu Leu Ser Pro Gly Cys Thr Ser Ser Ser Ser Ala Ala Lys Leu 755 760 765 cta tcc cca cgt cga aca gca ccc cgg cct cgt cta ggt ggc aga ggg 2594 Leu Ser Pro Arg Arg Thr Ala Pro Arg Pro Arg Leu Gly Gly Arg Gly 770 775 780 agg cca ggc agg gca ggg gct ttg aag gct gag gct ggc ccc tct gct 2642 Arg Pro Gly Arg Ala Gly Ala Leu Lys Ala Glu Ala Gly Pro Ser Ala 785 790 795 ccc cca cgg gcc cta gag ggg cta cgg ctg ccc ccc atg cca tgg aat 2690 Pro Pro Arg Ala Leu Glu Gly Leu Arg Leu Pro Pro Met Pro Trp Asn 800 805 810 gtg ccc cca gat ctg agc ccc agg gta gta gat ggc att gaa gac ggc 2738 Val Pro Pro Asp Leu Ser Pro Arg Val Val Asp Gly Ile Glu Asp Gly 815 820 825 830 tgt ggc tcg gac cag ccc aag ttc tct ttc cgc gtg ggc cag tct ggc 2786 Cys Gly Ser Asp Gln Pro Lys Phe Ser Phe Arg Val Gly Gln Ser Gly 835 840 845 ccg gaa tgt agc agc agc ccc tcc cct gga cca gag agc ggc ctg ctc 2834 Pro Glu Cys Ser Ser Ser Pro Ser Pro Gly Pro Glu Ser Gly Leu Leu 850 855 860 act gtt ccc cat ggg ccc agc gag gca agg aac aca gac aca ctg gac 2882 Thr Val Pro His Gly Pro Ser Glu Ala Arg Asn Thr Asp Thr Leu Asp 865 870 875 aag ctt cgg cag gcg gtg aca gag ctg tca gag cag gtg ctg cag atg 2930 Lys Leu Arg Gln Ala Val Thr Glu Leu Ser Glu Gln Val Leu Gln Met 880 885 890 cgg gaa gga ctg cag tca ctt cgc cag gct gtg cag ctt gtc ctg gcg 2978 Arg Glu Gly Leu Gln Ser Leu Arg Gln Ala Val Gln Leu Val Leu Ala 895 900 905 910 ccc cac agg gag ggt ccg tgc cct cgg gca tcg gga gag ggg ccg tgc 3026 Pro His Arg Glu Gly Pro Cys Pro Arg Ala Ser Gly Glu Gly Pro Cys 915 920 925 cca gcc agc acc tcc ggg ctt ctg cag cct ctg tgt gtg gac act ggg 3074 Pro Ala Ser Thr Ser Gly Leu Leu Gln Pro Leu Cys Val Asp Thr Gly 930 935 940 gca tcc tcc tac tgc ctg cag ccc cca gct ggc tct gtc ttg agt ggg 3122 Ala Ser Ser Tyr Cys Leu Gln Pro Pro Ala Gly Ser Val Leu Ser Gly 945 950 955 act tgg ccc cac cct cgt ccg ggg cct cct ccc ctc atg gca ccc cgg 3170 Thr Trp Pro His Pro Arg Pro Gly Pro Pro Pro Leu Met Ala Pro Arg 960 965 970 ccc tgg ggt ccc cca gcg tct cag agc tcc ccc tgg cct cga gcc aca 3218 Pro Trp Gly Pro Pro Ala Ser Gln Ser Ser Pro Trp Pro Arg Ala Thr 975 980 985 990 gct ttc tgg acc tcc acc tca gac tca gag ccc cct gcc tca gga gac 3266 Ala Phe Trp Thr Ser Thr Ser Asp Ser Glu Pro Pro Ala Ser Gly Asp 995 1000 1005 ctc tgc tct gag ccc agc acc cct gcc tcc cct cct cct tct gag gaa 3314 Leu Cys Ser Glu Pro Ser Thr Pro Ala Ser Pro Pro Pro Ser Glu Glu 1010 1015 1020 ggg gct agg act ggg ccc gca gag cct gtg agc cag gct gag gct acc 3362 Gly Ala Arg Thr Gly Pro Ala Glu Pro Val Ser Gln Ala Glu Ala Thr 1025 1030 1035 agc act gga gag ccc cca cca ggg tca ggg ggc ctg gcc ttg ccc tgg 3410 Ser Thr Gly Glu Pro Pro Pro Gly Ser Gly Gly Leu Ala Leu Pro Trp 1040 1045 1050 gac ccc cac agc ctg gag atg gtg ctt att ggc tgc cat ggc tct ggc 3458 Asp Pro His Ser Leu Glu Met Val Leu Ile Gly Cys His Gly Ser Gly 1055 1060 1065 1070 aca gtc cag tgg acc cag gaa gaa ggc aca ggg gtc t gagtaccagc 3505 Thr Val Gln Trp Thr Gln Glu Glu Gly Thr Gly Val 1075 1080 cctagaactc agcgttgcca ggtgtgctgc catctgctgt tcggcccaac ctcagagtga 3565 aggcagggtg gcagcctccc cacggactcc atgcggcccg ctggctcagg gcagggagcc 3625 tggaagcaaa ggaggacctg gctcctgact ctcagagagg ataggctgga tccctggggc 3685 aggcctctcc tcggcctgct cctctgacct cccggtctcc ctctgcaggc tgggggcaga 3745 ggcctgagga caaggaagag ctttgccatc ccctgcatgt gcccctgcct ctacctgtcc 3805 ccaaattttt atattaaaaa aaaaaataaa ataaactaaa aaaaaaaaaa aa 3857 20 1082 PRT H. sapiens 20 Met Pro Ala Met Arg Gly Leu Leu Ala Pro Gln Asn Thr Phe Leu Asp 1 5 10 15 Thr Ile Ala Thr Arg Phe Asp Gly Thr His Ser Asn Phe Val Leu Gly 20 25 30 Asn Ala Ser Gly Gly Ala Leu Pro Val Val Tyr Cys Ser Asp Gly Phe 35 40 45 Cys Asp Leu Thr Gly Phe Ser Arg Ala Glu Val Met Gln Arg Gly Cys 50 55 60 Ala Cys Ser Phe Leu Tyr Gly Pro Asp Thr Ser Glu Leu Val Arg Gln 65 70 75 80 Gln Ile Arg Lys Ala Leu Asp Glu His Lys Glu Phe Lys Ala Glu Leu 85 90 95 Ile Leu Tyr Arg Lys Ser Gly Leu Pro Phe Trp Cys Leu Leu Asp Val 100 105 110 Ile Pro Ile Lys Asn Glu Lys Gly Glu Val Ala Leu Phe Leu Val Ser 115 120 125 His Lys Asp Ile Ser Glu Thr Lys Asn Arg Gly Gly Pro Asp Arg Trp 130 135 140 Lys Glu Thr Gly Gly Gly Arg Arg Arg Tyr Gly Arg Ala Arg Ser Lys 145 150 155 160 Gly Phe Asn Ala Asn Arg Arg Arg Ser Arg Ala Val Leu Tyr His Leu 165 170 175 Ser Gly His Leu Gln Lys Gln Pro Lys Gly Lys His Lys Leu Asn Lys 180 185 190 Gly Val Phe Gly Glu Lys Pro Asn Leu Pro Glu Tyr Lys Val Ala Ala 195 200 205 Ile Arg Lys Ser Pro Phe Ile Leu Leu His Cys Gly Ala Leu Arg Ala 210 215 220 Thr Trp Asp Gly Phe Ile Leu Leu Ala Thr Leu Tyr Val Ala Val Thr 225 230 235 240 Val Pro Tyr Ser Val Cys Val Ser Thr Ala Arg Glu Pro Ser Ala Ala 245 250 255 Arg Gly Pro Pro Ser Val Cys Asp Leu Ala Val Glu Val Leu Phe Ile 260 265 270 Leu Asp Ile Val Leu Asn Phe Arg Thr Thr Phe Val Ser Lys Ser Gly 275 280 285 Gln Val Val Phe Ala Pro Lys Ser Ile Cys Leu His Tyr Val Thr Thr 290 295 300 Trp Phe Leu Leu Asp Val Ile Ala Ala Leu Pro Phe Asp Leu Leu His 305 310 315 320 Ala Phe Lys Val Asn Val Tyr Phe Gly Ala His Leu Leu Lys Thr Val 325 330 335 Arg Leu Leu Arg Leu Leu Arg Leu Leu Pro Arg Leu Asp Arg Tyr Ser 340 345 350 Gln Tyr Ser Ala Val Val Leu Thr Leu Leu Met Ala Val Phe Ala Leu 355 360 365 Leu Ala His Trp Val Ala Cys Val Trp Phe Tyr Ile Gly Gln Arg Glu 370 375 380 Ile Glu Ser Ser Glu Ser Glu Leu Pro Glu Ile Gly Trp Leu Gln Glu 385 390 395 400 Leu Ala Arg Arg Leu Glu Thr Pro Tyr Tyr Leu Val Gly Arg Arg Pro 405 410 415 Ala Gly Gly Asn Ser Ser Gly Gln Ser Asp Asn Cys Ser Ser Ser Ser 420 425 430 Glu Ala Asn Gly Thr Gly Leu Glu Leu Leu Gly Gly Pro Ser Leu Arg 435 440 445 Ser Ala Tyr Ile Thr Ser Leu Tyr Phe Ala Leu Ser Ser Leu Thr Ser 450 455 460 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 Gln Arg Met Tyr Ala Arg Arg Phe Leu 500 505 510 Tyr His Ser Arg Thr Arg Asp Gln Arg Asp Tyr Ile Arg Ile His Arg 515 520 525 Ile Pro Lys Pro Leu Lys Gln Arg Met Leu Glu Tyr Phe Gln Ala Thr 530 535 540 Trp Ala Val Asn Asn Gly Ile Asp Thr Thr Glu Leu Leu Gln 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 Gln 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 Gln Gly Asp Ala Leu Gln 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 Gln Val Val Lys 645 650 655 Ala Asn Ala Asp Val Lys Gly Leu Thr Tyr Cys Val Leu Gln Cys Leu 660 665 670 Gln 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 Gln 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 Gln Pro Lys Phe Ser Phe Arg Val Gly Gln 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 Gln Ala Val Thr Glu Leu Ser Glu Gln Val Leu Gln Met Arg Glu 885 890 895 Gly Leu Gln Ser Leu Arg Gln Ala Val Gln 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 Gln Pro Leu Cys Val Asp Thr Gly Ala Ser 930 935 940 Ser Tyr Cys Leu Gln Pro Pro Ala Gly Ser Val Leu Ser Gly Thr Trp 945 950 955 960 Pro His Pro Arg Pro Gly Pro Pro Pro Leu Met Ala Pro Arg Pro Trp 965 970 975 Gly Pro Pro Ala Ser Gln Ser Ser Pro Trp Pro Arg Ala Thr Ala Phe 980 985 990 Trp Thr Ser Thr Ser Asp Ser Glu Pro Pro Ala Ser Gly Asp Leu Cys 995 1000 1005 Ser Glu Pro Ser Thr Pro Ala Ser Pro Pro Pro Ser Glu Glu Gly Ala 1010 1015 1020 Arg Thr Gly Pro Ala Glu Pro Val Ser Gln Ala Glu Ala Thr Ser Thr 1025 1030 1035 1040 Gly Glu Pro Pro Pro Gly Ser Gly Gly Leu Ala Leu Pro Trp Asp Pro 1045 1050 1055 His Ser Leu Glu Met Val Leu Ile Gly Cys His Gly Ser Gly Thr Val 1060 1065 1070 Gln Trp Thr Gln Glu Glu Gly Thr Gly Val 1075 1080 21 1800 DNA H. sapiens CDS (346)...(1057) K+Hnov28, splice 1 21 atttgaatga ctgggttact tcctagactc ttcctccttc tcttaagtac agtatagttc 60 tttctctgaa aatcttcagt ctcttagttc cagatgggtt ctctatggta ggaatacagg 120 acatgtagaa ggccctaggg gaatgctttc ttccccagat ctttgccctg tagtaggttt 180 cagctgagca aggacgagta gtttttctgg tgtttggcct cctctgttgg gtggaaaaag 240 actttcttct ctattttcct agttatatat gctatcatat gtctgttttt ctcctcttga 300 agtttccctg aaacctgggc tcttgaagac gcatcactgg agcag atg gat aat gga 357 Met Asp Asn Gly 1 gac tgg ggc tat atg atg act gac cca gtc aca tta aat gta ggt gga 405 Asp Trp Gly Tyr Met Met Thr Asp Pro Val Thr Leu Asn Val Gly Gly 5 10 15 20 cac ttg tat aca acg tct ctc acc aca ttg acg cgt tac ccg gat tcc 453 His Leu Tyr Thr Thr Ser Leu Thr Thr Leu Thr Arg Tyr Pro Asp Ser 25 30 35 atg ctt gga gct atg ttt ggg ggg gac ttc ccc aca gct cga gac cct 501 Met Leu Gly Ala Met Phe Gly Gly Asp Phe Pro Thr Ala Arg Asp Pro 40 45 50 caa ggc aat tac ttt att gat cga gat gga cct ctt ttc cga tat gtc 549 Gln Gly Asn Tyr Phe Ile Asp Arg Asp Gly Pro Leu Phe Arg Tyr Val 55 60 65 ctc aac ttc tta aga act tca gaa ttg acc tta ccg ttg gat ttt aag 597 Leu Asn Phe Leu Arg Thr Ser Glu Leu Thr Leu Pro Leu Asp Phe Lys 70 75 80 gaa ttt gat ctg ctt cgg aaa gaa gca gat ttt tac cag att gag ccc 645 Glu Phe Asp Leu Leu Arg Lys Glu Ala Asp Phe Tyr Gln Ile Glu Pro 85 90 95 100 ttg att cag tgt ctc aat gat cct aag cct ttg tat ccc atg gat act 693 Leu Ile Gln Cys Leu Asn Asp Pro Lys Pro Leu Tyr Pro Met Asp Thr 105 110 115 ttt gaa gaa gtt gtg gag ctg tct agt act cgg aag ctt tct aag tac 741 Phe Glu Glu Val Val Glu Leu Ser Ser Thr Arg Lys Leu Ser Lys Tyr 120 125 130 tcc aac cca gtg gct gtc atc ata acg caa cta acc atc acc act aag 789 Ser Asn Pro Val Ala Val Ile Ile Thr Gln Leu Thr Ile Thr Thr Lys 135 140 145 gtc cat tcc tta cta gaa ggc atc tca aat tat ttt acc aag tgg aat 837 Val His Ser Leu Leu Glu Gly Ile Ser Asn Tyr Phe Thr Lys Trp Asn 150 155 160 aag cac atg atg gac acc aga gac tgc cag gtt tcc ttt act ttt gga 885 Lys His Met Met Asp Thr Arg Asp Cys Gln Val Ser Phe Thr Phe Gly 165 170 175 180 ccc tgt gat tat cac cag gaa gtt tct ctt agg gtc cac ctg atg gaa 933 Pro Cys Asp Tyr His Gln Glu Val Ser Leu Arg Val His Leu Met Glu 185 190 195 tac att aca aaa caa ggt ttc acg atc cgc aac acc cgg gtg cat cac 981 Tyr Ile Thr Lys Gln Gly Phe Thr Ile Arg Asn Thr Arg Val His His 200 205 210 atg agt gag cgg gcc aat gaa aac aca gtg gag cac aac tgg act ttc 1029 Met Ser Glu Arg Ala Asn Glu Asn Thr Val Glu His Asn Trp Thr Phe 215 220 225 tgt agg cta gcc cgg aag aca gac gac t gatctccgac cctgccacag 1077 Cys Arg Leu Ala Arg Lys Thr Asp Asp 230 235 gttcctggaa agactctcca ggaaatggaa gatactgatt ttttttttta aatcacagtg 1137 tgagatattt tttttctttt aaatagttgt atttatttga aggcagtgag gaccagaagg 1197 aagttttgtg ctttggcaga ctcctccatg ttttgttccc ttccccctga gtatgcatgt 1257 gcctgttcag agtctccaga tacctttttt ataaaaagaa gtctgaaaat cattatggta 1317 tataatctac ccttaacaga gcttttctta ttacagtgct aaaatgattt ctgataaaat 1377 ggtccctaac tcaactagaa ggctaaaaat acaagaatga aagaataagc agagtactca 1437 tgatgccttt gagaaaaatc aaaacatcat gtagggtgac ctagtttcca aaccaataaa 1497 taagtagtat tgtaatatta aaggaaaact gttccaatca tttaaaagta cttattaagt 1557 actgcttttt acagttatga caactgtttc tttctatgca tataaatcaa ggaaccaaat 1617 atctgtagcc atggaaatgt ctgactagaa atatttatat tgaattctga atacaaaatg 1677 tccctgtggt agaaaactta ctctttatgc ctggtgcagt ataattccca agtgtactgt 1737 ctaccagaaa aaaaaaacaa aactaataaa aaatgaaata tgaaaaaaaa aaaaaaaaaa 1797 aaa 1800 22 1836 DNA H. sapiens CDS (382)...(1093) K+Hnov28 splice 2 22 gaggaatgtt atgattttgt gactatttgt gacagctttt taatattagg tcacttttaa 60 acctatagct tctctcttct agaccacatg gttgggaaag gagaaagaga aaatgattac 120 ttgtagagaa aaatccattt ctgcagtggt atggttaagg ataatctaac cataatcaca 180 ttatccttgt atgcctggct acttgtgctg gcctgtatgt gaatgttaac cccaaagact 240 cctttagatg tcgctgaact agttactata aaaagtattt cgctttcaaa ctcccacatt 300 tcaagaagag caaaactcaa tacaaggcaa ttttgaagtt tccctgaaac ctgggctctt 360 gaagacgcat cactggagca g atg gat aat gga gac tgg ggc tat atg atg 411 Met Asp Asn Gly Asp Trp Gly Tyr Met Met 1 5 10 act gac cca gtc aca tta aat gta ggt gga cac ttg tat aca acg tct 459 Thr Asp Pro Val Thr Leu Asn Val Gly Gly His Leu Tyr Thr Thr Ser 15 20 25 ctc acc aca ttg acg cgt tac ccg gat tcc atg ctt gga gct atg ttt 507 Leu Thr Thr Leu Thr Arg Tyr Pro Asp Ser Met Leu Gly Ala Met Phe 30 35 40 ggg ggg gac ttc ccc aca gct cga gac cct caa ggc aat tac ttt att 555 Gly Gly Asp Phe Pro Thr Ala Arg Asp Pro Gln Gly Asn Tyr Phe Ile 45 50 55 gat cga gat gga cct ctt ttc cga tat gtc ctc aac ttc tta aga act 603 Asp Arg Asp Gly Pro Leu Phe Arg Tyr Val Leu Asn Phe Leu Arg Thr 60 65 70 tca gaa ttg acc tta ccg ttg gat ttt aag gaa ttt gat ctg ctt cgg 651 Ser Glu Leu Thr Leu Pro Leu Asp Phe Lys Glu Phe Asp Leu Leu Arg 75 80 85 90 aaa gaa gca gat ttt tac cag att gag ccc ttg att cag tgt ctc aat 699 Lys Glu Ala Asp Phe Tyr Gln Ile Glu Pro Leu Ile Gln Cys Leu Asn 95 100 105 gat cct aag cct ttg tat ccc atg gat act ttt gaa gaa gtt gtg gag 747 Asp Pro Lys Pro Leu Tyr Pro Met Asp Thr Phe Glu Glu Val Val Glu 110 115 120 ctg tct agt act cgg aag ctt tct aag tac tcc aac cca gtg gct gtc 795 Leu Ser Ser Thr Arg Lys Leu Ser Lys Tyr Ser Asn Pro Val Ala Val 125 130 135 atc ata acg caa cta acc atc acc act aag gtc cat tcc tta cta gaa 843 Ile Ile Thr Gln Leu Thr Ile Thr Thr Lys Val His Ser Leu Leu Glu 140 145 150 ggc atc tca aat tat ttt acc aag tgg aat aag cac atg atg gac acc 891 Gly Ile Ser Asn Tyr Phe Thr Lys Trp Asn Lys His Met Met Asp Thr 155 160 165 170 aga gac tgc cag gtt tcc ttt act ttt gga ccc tgt gat tat cac cag 939 Arg Asp Cys Gln Val Ser Phe Thr Phe Gly Pro Cys Asp Tyr His Gln 175 180 185 gaa gtt tct ctt agg gtc cac ctg atg gaa tac att aca aaa caa ggt 987 Glu Val Ser Leu Arg Val His Leu Met Glu Tyr Ile Thr Lys Gln Gly 190 195 200 ttc acg atc cgc aac acc cgg gtg cat cac atg agt gag cgg gcc aat 1035 Phe Thr Ile Arg Asn Thr Arg Val His His Met Ser Glu Arg Ala Asn 205 210 215 gaa aac aca gtg gag cac aac tgg act ttc tgt agg cta gcc cgg aag 1083 Glu Asn Thr Val Glu His Asn Trp Thr Phe Cys Arg Leu Ala Arg Lys 220 225 230 aca gac gac t gatctccgac cctgccacag gttcctggaa agactctcca 1133 Thr Asp Asp 235 ggaaatggaa gatactgatt ttttttttta aatcacagtg tgagatattt tttttctttt 1193 aaatagttgt atttatttga aggcagtgag gaccagaagg aagttttgtg ctttggcaga 1253 ctcctccatg ttttgttccc ttccccctga gtatgcatgt gcctgttcag agtctccaga 1313 tacctttttt ataaaaagaa gtctgaaaat cattatggta tataatctac ccttaacaga 1373 gcttttctta ttacagtgct aaaatgattt ctgataaaat ggtccctaac tcaactagaa 1433 ggctaaaaat acaagaatga aagaataagc agagtactca tgatgccttt gagaaaaatc 1493 aaaacatcat gtagggtgac ctagtttcca aaccaataaa taagtagtat tgtaatatta 1553 aaggaaaact gttccaatca tttaaaagta cttattaagt actgcttttt acagttatga 1613 caactgtttc tttctatgca tataaatcaa ggaaccaaat atctgtagcc atggaaatgt 1673 ctgactagaa atatttatat tgaattctga atacaaaatg tccctgtggt agaaaactta 1733 ctctttatgc ctggtgcagt ataattccca agtgtactgt ctaccagaaa aaaaaaacaa 1793 aactaataaa aaatgaaata tgaaaaaaaa aaaaaaaaaa aaa 1836 23 1751 DNA H. sapiens CDS (297)...(1008) K+Hnov28 splice 3 23 ccatgtttct taccatgtct tgccagagct ttagaaattt gctctgcagt ttgctttaca 60 ggttgatttg ggattgaagt gtgtgagagg gaactgacta aggcagttca gtagctggga 120 aactgtttgt ttaaatgctt ttgaattgta gataaaaata aattcacatt ggcatcatta 180 gtatctgagc atttctcagt gtcttaaggc tggctctcca tgagtgctgg ctgattgact 240 ctcatctata tcgtttccct gaaacctggg ctcttgaaga cgcatcactg gagcag atg 299 Met 1 gat aat gga gac tgg ggc tat atg atg act gac cca gtc aca tta aat 347 Asp Asn Gly Asp Trp Gly Tyr Met Met Thr Asp Pro Val Thr Leu Asn 5 10 15 gta ggt gga cac ttg tat aca acg tct ctc acc aca ttg acg cgt tac 395 Val Gly Gly His Leu Tyr Thr Thr Ser Leu Thr Thr Leu Thr Arg Tyr 20 25 30 ccg gat tcc atg ctt gga gct atg ttt ggg ggg gac ttc ccc aca gct 443 Pro Asp Ser Met Leu Gly Ala Met Phe Gly Gly Asp Phe Pro Thr Ala 35 40 45 cga gac cct caa ggc aat tac ttt att gat cga gat gga cct ctt ttc 491 Arg Asp Pro Gln Gly Asn Tyr Phe Ile Asp Arg Asp Gly Pro Leu Phe 50 55 60 65 cga tat gtc ctc aac ttc tta aga act tca gaa ttg acc tta ccg ttg 539 Arg Tyr Val Leu Asn Phe Leu Arg Thr Ser Glu Leu Thr Leu Pro Leu 70 75 80 gat ttt aag gaa ttt gat ctg ctt cgg aaa gaa gca gat ttt tac cag 587 Asp Phe Lys Glu Phe Asp Leu Leu Arg Lys Glu Ala Asp Phe Tyr Gln 85 90 95 att gag ccc ttg att cag tgt ctc aat gat cct aag cct ttg tat ccc 635 Ile Glu Pro Leu Ile Gln Cys Leu Asn Asp Pro Lys Pro Leu Tyr Pro 100 105 110 atg gat act ttt gaa gaa gtt gtg gag ctg tct agt act cgg aag ctt 683 Met Asp Thr Phe Glu Glu Val Val Glu Leu Ser Ser Thr Arg Lys Leu 115 120 125 tct aag tac tcc aac cca gtg gct gtc atc ata acg caa cta acc atc 731 Ser Lys Tyr Ser Asn Pro Val Ala Val Ile Ile Thr Gln Leu Thr Ile 130 135 140 145 acc act aag gtc cat tcc tta cta gaa ggc atc tca aat tat ttt acc 779 Thr Thr Lys Val His Ser Leu Leu Glu Gly Ile Ser Asn Tyr Phe Thr 150 155 160 aag tgg aat aag cac atg atg gac acc aga gac tgc cag gtt tcc ttt 827 Lys Trp Asn Lys His Met Met Asp Thr Arg Asp Cys Gln Val Ser Phe 165 170 175 act ttt gga ccc tgt gat tat cac cag gaa gtt tct ctt agg gtc cac 875 Thr Phe Gly Pro Cys Asp Tyr His Gln Glu Val Ser Leu Arg Val His 180 185 190 ctg atg gaa tac att aca aaa caa ggt ttc acg atc cgc aac acc cgg 923 Leu Met Glu Tyr Ile Thr Lys Gln Gly Phe Thr Ile Arg Asn Thr Arg 195 200 205 gtg cat cac atg agt gag cgg gcc aat gaa aac aca gtg gag cac aac 971 Val His His Met Ser Glu Arg Ala Asn Glu Asn Thr Val Glu His Asn 210 215 220 225 tgg act ttc tgt agg cta gcc cgg aag aca gac gac t gatctccgac 1018 Trp Thr Phe Cys Arg Leu Ala Arg Lys Thr Asp Asp 230 235 cctgccacag gttcctggaa agactctcca ggaaatggaa gatactgatt ttttttttta 1078 aatcacagtg tgagatattt tttttctttt aaatagttgt atttatttga aggcagtgag 1138 gaccagaagg aagttttgtg ctttggcaga ctcctccatg ttttgttccc ttccccctga 1198 gtatgcatgt gcctgttcag agtctccaga tacctttttt ataaaaagaa gtctgaaaat 1258 cattatggta tataatctac ccttaacaga gcttttctta ttacagtgct aaaatgattt 1318 ctgataaaat ggtccctaac tcaactagaa ggctaaaaat acaagaatga aagaataagc 1378 agagtactca tgatgccttt gagaaaaatc aaaacatcat gtagggtgac ctagtttcca 1438 aaccaataaa taagtagtat tgtaatatta aaggaaaact gttccaatca tttaaaagta 1498 cttattaagt actgcttttt acagttatga caactgtttc tttctatgca tataaatcaa 1558 ggaaccaaat atctgtagcc atggaaatgt ctgactagaa atatttatat tgaattctga 1618 atacaaaatg tccctgtggt agaaaactta ctctttatgc ctggtgcagt ataattccca 1678 agtgtactgt ctaccagaaa aaaaaaacaa aactaataaa aaatgaaata tgaaaaaaaa 1738 aaaaaaaaaa aaa 1751 24 1542 DNA H. sapiens CDS (88)...(799) K+Hnov28, splice 4 24 cgggcatctc ccggcccggc cgcagcagcc gccgccgccg cgcatttccc tgaaacctgg 60 gctcttgaag acgcatcact ggagcag atg gat aat gga gac tgg ggc tat atg 114 Met Asp Asn Gly Asp Trp Gly Tyr Met 1 5 atg act gac cca gtc aca tta aat gta ggt gga cac ttg tat aca acg 162 Met Thr Asp Pro Val Thr Leu Asn Val Gly Gly His Leu Tyr Thr Thr 10 15 20 25 tct ctc acc aca ttg acg cgt tac ccg gat tcc atg ctt gga gct atg 210 Ser Leu Thr Thr Leu Thr Arg Tyr Pro Asp Ser Met Leu Gly Ala Met 30 35 40 ttt ggg ggg gac ttc ccc aca gct cga gac cct caa ggc aat tac ttt 258 Phe Gly Gly Asp Phe Pro Thr Ala Arg Asp Pro Gln Gly Asn Tyr Phe 45 50 55 att gat cga gat gga cct ctt ttc cga tat gtc ctc aac ttc tta aga 306 Ile Asp Arg Asp Gly Pro Leu Phe Arg Tyr Val Leu Asn Phe Leu Arg 60 65 70 act tca gaa ttg acc tta ccg ttg gat ttt aag gaa ttt gat ctg ctt 354 Thr Ser Glu Leu Thr Leu Pro Leu Asp Phe Lys Glu Phe Asp Leu Leu 75 80 85 cgg aaa gaa gca gat ttt tac cag att gag ccc ttg att cag tgt ctc 402 Arg Lys Glu Ala Asp Phe Tyr Gln Ile Glu Pro Leu Ile Gln Cys Leu 90 95 100 105 aat gat cct aag cct ttg tat ccc atg gat act ttt gaa gaa gtt gtg 450 Asn Asp Pro Lys Pro Leu Tyr Pro Met Asp Thr Phe Glu Glu Val Val 110 115 120 gag ctg tct agt act cgg aag ctt tct aag tac tcc aac cca gtg gct 498 Glu Leu Ser Ser Thr Arg Lys Leu Ser Lys Tyr Ser Asn Pro Val Ala 125 130 135 gtc atc ata acg caa cta acc atc acc act aag gtc cat tcc tta cta 546 Val Ile Ile Thr Gln Leu Thr Ile Thr Thr Lys Val His Ser Leu Leu 140 145 150 gaa ggc atc tca aat tat ttt acc aag tgg aat aag cac atg atg gac 594 Glu Gly Ile Ser Asn Tyr Phe Thr Lys Trp Asn Lys His Met Met Asp 155 160 165 acc aga gac tgc cag gtt tcc ttt act ttt gga ccc tgt gat tat cac 642 Thr Arg Asp Cys Gln Val Ser Phe Thr Phe Gly Pro Cys Asp Tyr His 170 175 180 185 cag gaa gtt tct ctt agg gtc cac ctg atg gaa tac att aca aaa caa 690 Gln Glu Val Ser Leu Arg Val His Leu Met Glu Tyr Ile Thr Lys Gln 190 195 200 ggt ttc acg atc cgc aac acc cgg gtg cat cac atg agt gag cgg gcc 738 Gly Phe Thr Ile Arg Asn Thr Arg Val His His Met Ser Glu Arg Ala 205 210 215 aat gaa aac aca gtg gag cac aac tgg act ttc tgt agg cta gcc cgg 786 Asn Glu Asn Thr Val Glu His Asn Trp Thr Phe Cys Arg Leu Ala Arg 220 225 230 aag aca gac gac t gatctccgac cctgccacag gttcctggaa agactctcca 839 Lys Thr Asp Asp 235 ggaaatggaa gatactgatt ttttttttta aatcacagtg tgagatattt tttttctttt 899 aaatagttgt atttatttga aggcagtgag gaccagaagg aagttttgtg ctttggcaga 959 ctcctccatg ttttgttccc ttccccctga gtatgcatgt gcctgttcag agtctccaga 1019 tacctttttt ataaaaagaa gtctgaaaat cattatggta tataatctac ccttaacaga 1079 gcttttctta ttacagtgct aaaatgattt ctgataaaat ggtccctaac tcaactagaa 1139 ggctaaaaat acaagaatga aagaataagc agagtactca tgatgccttt gagaaaaatc 1199 aaaacatcat gtagggtgac ctagtttcca aaccaataaa taagtagtat tgtaatatta 1259 aaggaaaact gttccaatca tttaaaagta cttattaagt actgcttttt acagttatga 1319 caactgtttc tttctatgca tataaatcaa ggaaccaaat atctgtagcc atggaaatgt 1379 ctgactagaa atatttatat tgaattctga atacaaaatg tccctgtggt agaaaactta 1439 ctctttatgc ctggtgcagt ataattccca agtgtactgt ctaccagaaa aaaaaaacaa 1499 aactaataaa aaatgaaata tgaaaaaaaa aaaaaaaaaa aaa 1542 25 237 PRT H. sapiens 25 Met Asp Asn Gly Asp Trp Gly Tyr Met Met Thr Asp Pro Val Thr Leu 1 5 10 15 Asn Val Gly Gly His Leu Tyr Thr Thr Ser Leu Thr Thr Leu Thr Arg 20 25 30 Tyr Pro Asp Ser Met Leu Gly Ala Met Phe Gly Gly Asp Phe Pro Thr 35 40 45 Ala Arg Asp Pro Gln Gly Asn Tyr Phe Ile Asp Arg Asp Gly Pro Leu 50 55 60 Phe Arg Tyr Val Leu Asn Phe Leu Arg Thr Ser Glu Leu Thr Leu Pro 65 70 75 80 Leu Asp Phe Lys Glu Phe Asp Leu Leu Arg Lys Glu Ala Asp Phe Tyr 85 90 95 Gln Ile Glu Pro Leu Ile Gln Cys Leu Asn Asp Pro Lys Pro Leu Tyr 100 105 110 Pro Met Asp Thr Phe Glu Glu Val Val Glu Leu Ser Ser Thr Arg Lys 115 120 125 Leu Ser Lys Tyr Ser Asn Pro Val Ala Val Ile Ile Thr Gln Leu Thr 130 135 140 Ile Thr Thr Lys Val His Ser Leu Leu Glu Gly Ile Ser Asn Tyr Phe 145 150 155 160 Thr Lys Trp Asn Lys His Met Met Asp Thr Arg Asp Cys Gln Val Ser 165 170 175 Phe Thr Phe Gly Pro Cys Asp Tyr His Gln Glu Val Ser Leu Arg Val 180 185 190 His Leu Met Glu Tyr Ile Thr Lys Gln Gly Phe Thr Ile Arg Asn Thr 195 200 205 Arg Val His His Met Ser Glu Arg Ala Asn Glu Asn Thr Val Glu His 210 215 220 Asn Trp Thr Phe Cys Arg Leu Ala Arg Lys Thr Asp Asp 225 230 235 26 3204 DNA H. sapiens CDS (182)...(1349) K+Hnov42 26 cggccgaacc ttgggtgtgg gacagagtgc gtgcgtgtgg tgtgtcccca agggcaggaa 60 ggtggcgaag ggaggcgaat ccgagtgggt ggagggaggg gaagggcggg aggagaaaaa 120 ggtgggagga ggaccaggtg ggagggtggc ggctcactca ggacccagcg ggggcagcgc 180 g atg agg cgg gtg acc ctg ttc ctg aac ggc agc ccc aag aac gga aag 229 Met Arg Arg Val Thr Leu Phe Leu Asn Gly Ser Pro Lys Asn Gly Lys 1 5 10 15 gtg gtt gct gta tat gga act tta tct gat ttg ctt tct gtg gcc agc 277 Val Val Ala Val Tyr Gly Thr Leu Ser Asp Leu Leu Ser Val Ala Ser 20 25 30 agt aaa ctc ggc ata aaa gcc acc agt gtg tat aat ggg aaa ggt gga 325 Ser Lys Leu Gly Ile Lys Ala Thr Ser Val Tyr Asn Gly Lys Gly Gly 35 40 45 ctg att gat gat att gct ttg atc agg gat gat gat gtt ttg ttt gtt 373 Leu Ile Asp Asp Ile Ala Leu Ile Arg Asp Asp Asp Val Leu Phe Val 50 55 60 tgt gaa gga gag cca ttt att gat cct cag aca gat tct aag cct cct 421 Cys Glu Gly Glu Pro Phe Ile Asp Pro Gln Thr Asp Ser Lys Pro Pro 65 70 75 80 gag gga ttg tta gga ttc cac aca gac tgg ctg aca tta aat gtt gga 469 Glu Gly Leu Leu Gly Phe His Thr Asp Trp Leu Thr Leu Asn Val Gly 85 90 95 ggg cgg tac ttt aca act aca cgg agc act tta gtg aat aaa gaa cct 517 Gly Arg Tyr Phe Thr Thr Thr Arg Ser Thr Leu Val Asn Lys Glu Pro 100 105 110 gac agt atg ctg gcc cac atg ttt aag gac aaa ggt gtc tgg gga aat 565 Asp Ser Met Leu Ala His Met Phe Lys Asp Lys Gly Val Trp Gly Asn 115 120 125 aag caa gat cat aga gga gct ttc tta att gac cga agt cct gag tac 613 Lys Gln Asp His Arg Gly Ala Phe Leu Ile Asp Arg Ser Pro Glu Tyr 130 135 140 ttc gaa ccc att ttg aac tac ttg cgt cat gga cag ctc att gta aat 661 Phe Glu Pro Ile Leu Asn Tyr Leu Arg His Gly Gln Leu Ile Val Asn 145 150 155 160 gat ggc att aat tta ttg ggt gtg tta gaa gaa gca aga ttt ttt ggt 709 Asp Gly Ile Asn Leu Leu Gly Val Leu Glu Glu Ala Arg Phe Phe Gly 165 170 175 att gac tca ttg att gaa cac cta gaa gtg gca ata aag aat tct caa 757 Ile Asp Ser Leu Ile Glu His Leu Glu Val Ala Ile Lys Asn Ser Gln 180 185 190 cca ccg gag gat cat tca cca ata tcc cga aag gaa ttt gtc cga ttt 805 Pro Pro Glu Asp His Ser Pro Ile Ser Arg Lys Glu Phe Val Arg Phe 195 200 205 ttg cta gca act cca acc aag tca gaa ctg cga tgc cag ggt ttg aac 853 Leu Leu Ala Thr Pro Thr Lys Ser Glu Leu Arg Cys Gln Gly Leu Asn 210 215 220 ttc agt ggt gct gat ctt tct cgt ttg gac ctt cga tac att aac ttc 901 Phe Ser Gly Ala Asp Leu Ser Arg Leu Asp Leu Arg Tyr Ile Asn Phe 225 230 235 240 aaa atg gcc aat tta agc cgc tgt aat ctt gca cat gca aat ctt tgc 949 Lys Met Ala Asn Leu Ser Arg Cys Asn Leu Ala His Ala Asn Leu Cys 245 250 255 tgt gca aat ctt gaa cga gct gat ctc tct gga tca gtg ctt gac tgt 997 Cys Ala Asn Leu Glu Arg Ala Asp Leu Ser Gly Ser Val Leu Asp Cys 260 265 270 gcg aat ctc cag gga gtc aag atg ctc tgt tct aat gca gaa gga gca 1045 Ala Asn Leu Gln Gly Val Lys Met Leu Cys Ser Asn Ala Glu Gly Ala 275 280 285 tcc ctg aaa ctg tgt aat ttt gag gat cct tct ggt ctt aaa gcc aat 1093 Ser Leu Lys Leu Cys Asn Phe Glu Asp Pro Ser Gly Leu Lys Ala Asn 290 295 300 tta gaa ggt gct aat ctg aaa ggt gtg gat atg gaa gga agt cag atg 1141 Leu Glu Gly Ala Asn Leu Lys Gly Val Asp Met Glu Gly Ser Gln Met 305 310 315 320 aca gga att aac ctg aga gtg gct acc tta aaa aat gca aag ttg aag 1189 Thr Gly Ile Asn Leu Arg Val Ala Thr Leu Lys Asn Ala Lys Leu Lys 325 330 335 aac tgt aac ctc aga gga gca act ctg gca gga act gat tta gag aat 1237 Asn Cys Asn Leu Arg Gly Ala Thr Leu Ala Gly Thr Asp Leu Glu Asn 340 345 350 tgt gat ctg tct ggg tgt gat ctt caa gaa gcc aac ctg aga ggg tcc 1285 Cys Asp Leu Ser Gly Cys Asp Leu Gln Glu Ala Asn Leu Arg Gly Ser 355 360 365 aac gtg aag gga gct ata ttt gaa gag atg ctg aca cca cta cac atg 1333 Asn Val Lys Gly Ala Ile Phe Glu Glu Met Leu Thr Pro Leu His Met 370 375 380 tca caa agt gtc aga t gagaatttta ggggctggag gaagatgtaa aagatgaaaa 1389 Ser Gln Ser Val Arg 385 tgttttcctt atcacttttc tttctccacc cactcagttg tctagaagaa ataacactgt 1449 aaggaaattt taaaaaaaaa catttagagg attatgcttg ttttgagtgg tgcataaggg 1509 aaaaaactga ctttttttcc atattctgat ttttaacaga aaagcactca tttaatagat 1569 gtagggaaac tagatattgc tgccttttga atggggtagg ggggtttacc tggttttatg 1629 accaggcata gtatctatta tatttgcttt taaataggca tgatgtggaa ataccatctt 1689 ggtttgagat gcatttgagg attttaattt atggaaagca caacatatgc aattatattt 1749 attgaattcc tagatgcagt atggatattt aaattgttaa aactttatga aaacttggaa 1809 aaggttgttc aggtttataa atagctttag tgatgcctcc cctctttaaa tacctgtcac 1869 accgtatgaa tatggtgaga tcagactccc taagactctt ttcaggttca tttttataat 1929 gtttactttt taggacagaa cagtagctaa attaaagtaa tatccagttc ttactgattg 1989 agacagagtg gaaagaaaga catcattgta catcactgtc attccaaagg tacagtgtaa 2049 ctctggatgg aggaataact tacctatcac tacaacactt acaaatgaga atttctcaga 2109 atttcattct aggcaagttc cactcaacac cagatcaagc aattctatct atttacacta 2169 ttagcctagt tttctcatac agtcatcaca agcataggaa gatacttcaa aaccaaaaaa 2229 accaaggtgc atcattaata ttcatttaat tcaaatacca aatagtttac atagggccag 2289 cttagaaata gatactaaat ccagagctac tgcaatcaaa gcttatatga gtgaatatgg 2349 tagagttgcc tgctaaaagg caatgtaata taattgcagc tagaacccta cagtggggaa 2409 tgaggaattt taaacacaca tttgattaca gccaccaaaa aaatagacgt aaaaataaag 2469 gcatttggct ggtccaagat gtaattttca atcagtcagc acctgtgatt cttttactta 2529 tttttttgtg gttttttttt tttaaacaaa ttttagccca attttcttga gtcattctct 2589 ctctgcagca gcagaggaag ggcctgtacc tccctaccaa tgacttggtg tccttatttt 2649 ctaccccaag agcagggata ttagctgtgt ccaaatgggt tctgaattct acagactcat 2709 caacatgagg caaggaatca ttgaaaacca cctgtgtctc ctttgggaga atgacatatc 2769 tttagtattt acgtagctta ttcttctata tctacatatg caaagctttc cttaacagta 2829 aagggtacat atgcatagtg ggaggagatc agacctttac aagtgaagga aagcaacttc 2889 agaaatgaat tattttcttt gctttattat ttttaccaag acagagaagt attgtattga 2949 gagataatct attttcataa tcaatatgtg cctaaattat atttaaatca tttcactctg 3009 tactatattt tcaggaatta cagaatgtgg tattcattca cttaaaggta cctctgtaga 3069 aataacctaa aactgcagaa ggatctgaaa gatctaaaca tggtgtgctt agaaactgca 3129 gattttagat ctaatgtata ctgcattaat aaatgatata aagtgtttgt tgaaaaaaaa 3189 aaaaaaaaaa aaaaa 3204 27 389 PRT H. sapiens 27 Met Arg Arg Val Thr Leu Phe Leu Asn Gly Ser Pro Lys Asn Gly Lys 1 5 10 15 Val Val Ala Val Tyr Gly Thr Leu Ser Asp Leu Leu Ser Val Ala Ser 20 25 30 Ser Lys Leu Gly Ile Lys Ala Thr Ser Val Tyr Asn Gly Lys Gly Gly 35 40 45 Leu Ile Asp Asp Ile Ala Leu Ile Arg Asp Asp Asp Val Leu Phe Val 50 55 60 Cys Glu Gly Glu Pro Phe Ile Asp Pro Gln Thr Asp Ser Lys Pro Pro 65 70 75 80 Glu Gly Leu Leu Gly Phe His Thr Asp Trp Leu Thr Leu Asn Val Gly 85 90 95 Gly Arg Tyr Phe Thr Thr Thr Arg Ser Thr Leu Val Asn Lys Glu Pro 100 105 110 Asp Ser Met Leu Ala His Met Phe Lys Asp Lys Gly Val Trp Gly Asn 115 120 125 Lys Gln Asp His Arg Gly Ala Phe Leu Ile Asp Arg Ser Pro Glu Tyr 130 135 140 Phe Glu Pro Ile Leu Asn Tyr Leu Arg His Gly Gln Leu Ile Val Asn 145 150 155 160 Asp Gly Ile Asn Leu Leu Gly Val Leu Glu Glu Ala Arg Phe Phe Gly 165 170 175 Ile Asp Ser Leu Ile Glu His Leu Glu Val Ala Ile Lys Asn Ser Gln 180 185 190 Pro Pro Glu Asp His Ser Pro Ile Ser Arg Lys Glu Phe Val Arg Phe 195 200 205 Leu Leu Ala Thr Pro Thr Lys Ser Glu Leu Arg Cys Gln Gly Leu Asn 210 215 220 Phe Ser Gly Ala Asp Leu Ser Arg Leu Asp Leu Arg Tyr Ile Asn Phe 225 230 235 240 Lys Met Ala Asn Leu Ser Arg Cys Asn Leu Ala His Ala Asn Leu Cys 245 250 255 Cys Ala Asn Leu Glu Arg Ala Asp Leu Ser Gly Ser Val Leu Asp Cys 260 265 270 Ala Asn Leu Gln Gly Val Lys Met Leu Cys Ser Asn Ala Glu Gly Ala 275 280 285 Ser Leu Lys Leu Cys Asn Phe Glu Asp Pro Ser Gly Leu Lys Ala Asn 290 295 300 Leu Glu Gly Ala Asn Leu Lys Gly Val Asp Met Glu Gly Ser Gln Met 305 310 315 320 Thr Gly Ile Asn Leu Arg Val Ala Thr Leu Lys Asn Ala Lys Leu Lys 325 330 335 Asn Cys Asn Leu Arg Gly Ala Thr Leu Ala Gly Thr Asp Leu Glu Asn 340 345 350 Cys Asp Leu Ser Gly Cys Asp Leu Gln Glu Ala Asn Leu Arg Gly Ser 355 360 365 Asn Val Lys Gly Ala Ile Phe Glu Glu Met Leu Thr Pro Leu His Met 370 375 380 Ser Gln Ser Val Arg 385 28 1246 DNA H. sapiens CDS (432)...(1092) K+Hnov44, splice 1 28 cagaaaacca cgcaggtcct tcttgatcat ctagaactga ccgctccgcc ttgccaggag 60 tctgcagaac cacgtggcta gcctgcctga agttctcacc tctccaggaa ggcggggggc 120 ttctaatggc tgcagctgcg ctgggggctg ggggctcccg ctgggactcc acttccgtgg 180 atgtctaagc ttcacctttc ttgcgcccgc aggggcatga ctcaggtgaa agggagccat 240 tttctcagac ccctggcctc atgcagccct tcagcatccc cgtgcaaatc acacttcagg 300 gcagccggag gcgccagggg aggacagcct ttcctgcctc agggaagaag agagagacag 360 actacagtga tggagaccca ctagatgtgc acaagaggct gccatccagt gctggagagg 420 accgagccgt g atg ctg ggg ttt gcc atg atg ggc ttc tca gtc cta atg 470 Met Leu Gly Phe Ala Met Met Gly Phe Ser Val Leu Met 1 5 10 ttc ttc ttg ctc gga aca acc att cta aag cct ttt atg ctc agc att 518 Phe Phe Leu Leu Gly Thr Thr Ile Leu Lys Pro Phe Met Leu Ser Ile 15 20 25 cag aga gaa gaa tcg acc tgc act gcc atc cac aca gat atc atg gac 566 Gln Arg Glu Glu Ser Thr Cys Thr Ala Ile His Thr Asp Ile Met Asp 30 35 40 45 gac tgg ctg gac tgt gcc ttc acc tgt ggt gtg cac tgc cac ggt cag 614 Asp Trp Leu Asp Cys Ala Phe Thr Cys Gly Val His Cys His Gly Gln 50 55 60 ggg aag tac ccg tgt ctt cag gtg ttt gtg aac ctc agc cat cca ggt 662 Gly Lys Tyr Pro Cys Leu Gln Val Phe Val Asn Leu Ser His Pro Gly 65 70 75 cag aaa gct ctc cta cat tat aat gaa gag gct gtc cag ata aat ccc 710 Gln Lys Ala Leu Leu His Tyr Asn Glu Glu Ala Val Gln Ile Asn Pro 80 85 90 aag tgc ttt tac aca cct aag tgc cac caa gat aga aat gat ttg ctc 758 Lys Cys Phe Tyr Thr Pro Lys Cys His Gln Asp Arg Asn Asp Leu Leu 95 100 105 aac agt gct ctg gac ata aaa gaa ttc ttc gat cac aaa aat gga act 806 Asn Ser Ala Leu Asp Ile Lys Glu Phe Phe Asp His Lys Asn Gly Thr 110 115 120 125 ccc ttt tca tgc ttc tac agt cca gcc agc caa tct gaa gat gtc att 854 Pro Phe Ser Cys Phe Tyr Ser Pro Ala Ser Gln Ser Glu Asp Val Ile 130 135 140 ctt ata aaa aag tat gac caa atg gct atc ttc cac tgt tta ttt tgg 902 Leu Ile Lys Lys Tyr Asp Gln Met Ala Ile Phe His Cys Leu Phe Trp 145 150 155 cct tca ctg act ctg cta ggt ggt gcc ctg att gtt ggc atg gtg aga 950 Pro Ser Leu Thr Leu Leu Gly Gly Ala Leu Ile Val Gly Met Val Arg 160 165 170 tta aca caa cac ctg tcc tta ctg tgt gaa aaa tat agc act gta gtc 998 Leu Thr Gln His Leu Ser Leu Leu Cys Glu Lys Tyr Ser Thr Val Val 175 180 185 aga gat gag gta ggt gga aaa gta cct tat ata gaa cag cat cag ttc 1046 Arg Asp Glu Val Gly Gly Lys Val Pro Tyr Ile Glu Gln His Gln Phe 190 195 200 205 aaa ctg tgc att atg agg agg agc aaa gga aga gca gag aaa tct t 1092 Lys Leu Cys Ile Met Arg Arg Ser Lys Gly Arg Ala Glu Lys Ser 210 215 220 aagacggtgg ccaaattaaa gtgctggcct tcagatgtct gtgatttctg caactgagga 1152 cctaattatg cctgtctgca aactaataat gtaaaaggta ataattaaag tatcatattt 1212 tcatgtggga aaaaaaaaaa aaaaaaaaaa aaaa 1246 29 1111 DNA H. sapiens CDS (297)...(957) K+Hnov44, splice 2 29 aaaaaccatg acttgtggca ccagaagaga gccggggact tcaatccaag aaagcagaga 60 agataccaaa gaaggaccga gaagggcaaa gcaaagaaga ctgtaccatg tcctaagctg 120 aggcaggcgg caggcgtggt gcacaagaag tctgagtgtg aggggctctt ttctctccac 180 tgccaatgac agcctttcct gcctcaggga agaagagaga gacagactac agtgatggag 240 acccactaga tgtgcacaag aggctgccat ccagtgctgg agaggaccga gccgtg atg 299 Met 1 ctg ggg ttt gcc atg atg ggc ttc tca gtc cta atg ttc ttc ttg ctc 347 Leu Gly Phe Ala Met Met Gly Phe Ser Val Leu Met Phe Phe Leu Leu 5 10 15 gga aca acc att cta aag cct ttt atg ctc agc att cag aga gaa gaa 395 Gly Thr Thr Ile Leu Lys Pro Phe Met Leu Ser Ile Gln Arg Glu Glu 20 25 30 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 35 40 45 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 Gln Gly Lys Tyr Pro 50 55 60 65 tgt ctt cag gtg ttt gtg aac ctc agc cat cca ggt cag aaa gct ctc 539 Cys Leu Gln Val Phe Val Asn Leu Ser His Pro Gly Gln Lys Ala Leu 70 75 80 cta cat tat aat gaa gag gct gtc cag ata aat ccc aag tgc ttt tac 587 Leu His Tyr Asn Glu Glu Ala Val Gln Ile Asn Pro Lys Cys Phe Tyr 85 90 95 aca cct aag tgc cac caa gat aga aat gat ttg ctc aac agt gct ctg 635 Thr Pro Lys Cys His Gln 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 tca tgc 683 Asp Ile Lys Glu Phe Phe Asp His Lys Asn Gly Thr Pro Phe Ser Cys 115 120 125 ttc tac agt cca gcc agc caa tct gaa gat gtc att ctt ata aaa aag 731 Phe Tyr Ser Pro Ala Ser Gln Ser Glu Asp Val Ile Leu Ile Lys Lys 130 135 140 145 tat gac caa atg gct atc ttc cac tgt tta ttt tgg cct tca ctg act 779 Tyr Asp Gln Met Ala Ile Phe His Cys Leu Phe Trp Pro Ser Leu Thr 150 155 160 ctg cta ggt ggt gcc ctg att gtt ggc atg gtg aga tta aca caa cac 827 Leu Leu Gly Gly Ala Leu Ile Val Gly Met Val Arg Leu Thr Gln His 165 170 175 ctg tcc tta ctg tgt gaa aaa tat agc act gta gtc aga gat gag gta 875 Leu Ser Leu Leu Cys Glu Lys Tyr Ser Thr Val Val Arg Asp Glu Val 180 185 190 ggt gga aaa gta cct tat ata gaa cag cat cag ttc aaa ctg tgc att 923 Gly Gly Lys Val Pro Tyr Ile Glu Gln His Gln Phe Lys Leu Cys Ile 195 200 205 atg agg agg agc aaa gga aga gca gag aaa tct t aagacggtgg 967 Met Arg Arg Ser Lys Gly Arg Ala Glu Lys Ser 210 215 220 ccaaattaaa gtgctggcct tcagatgtct gtgatttctg caactgagga cctaattatg 1027 cctgtctgca aactaataat gtaaaaggta ataattaaag tatcatattt tcatgtggga 1087 aaaaaaaaaa aaaaaaaaaa aaaa 1111 30 220 PRT H. sapiens 30 Met Leu Gly Phe Ala Met Met Gly Phe Ser Val Leu Met Phe Phe Leu 1 5 10 15 Leu Gly Thr Thr Ile Leu Lys Pro Phe Met Leu Ser Ile Gln Arg Glu 20 25 30 Glu Ser Thr Cys Thr Ala Ile His Thr Asp Ile Met Asp Asp Trp Leu 35 40 45 Asp Cys Ala Phe Thr Cys Gly Val His Cys His Gly Gln Gly Lys Tyr 50 55 60 Pro Cys Leu Gln Val Phe Val Asn Leu Ser His Pro Gly Gln Lys Ala 65 70 75 80 Leu Leu His Tyr Asn Glu Glu Ala Val Gln Ile Asn Pro Lys Cys Phe 85 90 95 Tyr Thr Pro Lys Cys His Gln 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 Gln Ser Glu Asp Val Ile Leu Ile Lys 130 135 140 Lys Tyr Asp Gln 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 Gln 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 Gln His Gln Phe Lys Leu Cys 195 200 205 Ile Met Arg Arg Ser Lys Gly Arg Ala Glu Lys Ser 210 215 220 31 22 DNA Artificial Sequence Primer 31 tatccacatc aatggacaaa gc 22 32 20 DNA Artificial Sequence Primer 32 tgcataactg gctgggtgta 20 33 22 DNA Artificial Sequence Primer 33 tgacatcact ggatgaactt ga 22 34 20 DNA Artificial Sequence Primer 34 tgcctgcaaa gtttgaacat 20 35 22 DNA Artificial Sequence Primer 35 tgacatcact ggatgaactt ga 22 36 20 DNA Artificial Sequence Primer 36 tgcctgcaaa gtttgaacat 20 37 20 DNA Artificial Sequence Primer 37 acctggtggt atggaagcat 20 38 19 DNA Artificial Sequence Primer 38 tttctcctgg cctctaccc 19 39 19 DNA Artificial Sequence Primer 39 tccctcttgg gtgaccttc 19 40 20 DNA Artificial Sequence Primer 40 atctttgtca gccaccagct 20 41 24 DNA Artificial Sequence Primer 41 aggtgtgctg ccatctgctg ttcg 24 42 24 DNA Artificial Sequence Primer 42 agcctatcct ctctgagagt cagg 24 43 21 DNA Artificial Sequence Primer 43 aagcagagta ctcatgatgc c 21 44 20 DNA Artificial Sequence Primer 44 tctggtagac agtacagtgg 20 45 20 DNA Artificial Sequence Primer 45 catttggctg gtccaagatg 20 46 20 DNA Artificial Sequence Primer 46 agtcattggt agggaggtac 20 47 20 DNA Artificial Sequence Primer 47 catgcttcta cagtccagcc 20 48 20 DNA Artificial Sequence Primer 48 ggtcctcagt tgcagaaatc 20 49 45 DNA Artificial Sequence Primer 49 tggtgggctg tggtgaccat gacaactgtg ggctatgggg acatg 45 50 45 DNA Artificial Sequence Primer 50 tggtgggcag tggtcaccat gaccactgtg ggctacgggg acatg 45 51 45 DNA Artificial Sequence Primer 51 tggtgggcag tcgtctccat gacaactgta ggctatggag acatg 45 52 45 DNA Artificial Sequence Primer 52 tggtgggcag tggtaaccat gacaacagtg ggttacggcg atatg 45 53 45 DNA Artificial Sequence Primer 53 tggtgggctg tggtcaccat gacgaccctg ggctatggag acatg 45 54 45 DNA Artificial Sequence Primer 54 tggtgggggg tggtcacagt caccaccatc ggctatgggg acaag 45 55 45 DNA Artificial Sequence Primer 55 tggtgggcag tggtcaccat gaccacggtt ggctatgggg acatg 45 56 45 DNA Artificial Sequence Primer 56 tggtgggccg tggtcaccat gacgaccctg ggctatggag acatg 45 57 45 DNA Artificial Sequence Primer 57 tggtgggctg tggtcaccat gacgacactg ggctacggag acatg 45 58 45 DNA Artificial Sequence Primer 58 tggtgggctg tggtgaccat gacaactgtg ggctatgggg acatg 45 59 47 DNA Artificial Sequence Primer 59 ttcctgttct ccattgagac cgaaacaacc attgggtatg gcttccg 47 60 47 DNA Artificial Sequence Primer 60 tttttattct caatagagac agaaaccacc attggttatg gctaccg 47 61 47 DNA Artificial Sequence Primer 61 ttcctcttct ccattgagac ccagacaacc ataggctatg gtttcag 47 62 47 DNA Artificial Sequence Primer 62 ttcctgttct cggtggagac gcagacgacc atcggctatg ggttccg 47 63 47 DNA Artificial Sequence Primer 63 ttcctcttct cccttgaatc ccaaaccacc attggctatg gcttccg 47 64 47 DNA Artificial Sequence Primer 64 tttctctttt ccctggaatc ccagacaacc attggctatg gagtccg 47 65 47 DNA Artificial Sequence Primer 65 ttccttttct ccattgaggt ccaagtgact attggctttg gggggcg 47 66 47 DNA Artificial Sequence Primer 66 tttctcttct ccattgaagt tcaagttacc attgggtttg gagggag 47 67 50 DNA Artificial Sequence Primer 67 gcgctctact tcaccttcag cagcctcacc agtgtgggct tcggcaacgt 50 68 15 PRT Artificial Sequence consensus sequences 68 Trp Trp Ala Val Val Ser Met Thr Thr Val Gly Tyr Gly Asp Met 1 5 10 15 69 15 PRT Artificial Sequence Primer 69 Trp Trp Ala Val Val Thr Met Thr Thr Leu Gly Tyr Gly Asp Met 1 5 10 15 70 15 PRT Artificial Sequence Primer 70 Trp Trp Gly Val Val Thr Val Thr Thr Ile Gly Tyr Gly Asp Lys 1 5 10 15 71 15 PRT Artificial Sequence Primer 71 Trp Trp Ala Val Val Thr Met Thr Thr Val Gly Tyr Gly Asp Met 1 5 10 15 72 15 PRT Artificial Sequence Primer 72 Phe Leu Phe Ser Ile Glu Val Gln Val Thr Ile Gly Phe Gly Gly 1 5 10 15 73 15 PRT Artificial Sequence Primer 73 Phe Leu Phe Ser Leu Glu Ser Gln Thr Thr Ile Gly Tyr Gly Val 1 5 10 15 74 15 PRT Artificial Sequence Primer 74 Phe Leu Phe Ser Ile Glu Thr Glu Thr Thr Ile Gly Tyr Gly Tyr 1 5 10 15 75 15 PRT Artificial Sequence Primer 75 Phe Leu Phe Ser Ile Glu Thr Gln Thr Thr Ile Gly Tyr Gly Phe 1 5 10 15 76 15 PRT Artificial Sequence Primer 76 Phe Leu Phe Ser Val Glu Thr Gln Thr Thr Ile Gly Tyr Gly Phe 1 5 10 15 77 15 PRT Artificial Sequence Primer 77 Phe Leu Phe Ser Leu Glu Ser Gln Thr Thr Ile Gly Tyr Gly Phe 1 5 10 15 78 15 PRT Artificial Sequence Primer 78 Phe Leu Phe Ser Ile Glu Thr Glu Thr Thr Ile Gly Tyr Gly Phe 1 5 10 15 79 16 PRT Artificial Sequence Primer 79 Ala Leu Tyr Phe Thr Phe Ser Ser Leu Thr Ser Val Gly Phe Gly Asn 1 5 10 15 80 2571 DNA H. sapiens CDS (110)...(1051) 80 gctgccgcgc ctgtagcact cccggaactg gaactaggtg ccagacggtc cggaggcggg 60 ggccacgtca gcggggccac ccagggctcg cggggtcccg gtgggtgcc atg cgg agg 118 Met Arg Arg 1 ggc gcg ctt ctg gcg ggc gcc ttg gcc gcg tac gcc gcg tac ctg gtg 166 Gly Ala Leu Leu Ala Gly Ala Leu Ala Ala Tyr Ala Ala Tyr Leu Val 5 10 15 ctg ggc gcg ctg ttg gtg gcg cgg ctg gag ggg ccg cac gaa gcc agg 214 Leu Gly Ala Leu Leu Val Ala Arg Leu Glu Gly Pro His Glu Ala Arg 20 25 30 35 ctc cga gcc gag ctg gag acg ctg cgg gcg cag ctg ctt cag cgc agc 262 Leu Arg Ala Glu Leu Glu Thr Leu Arg Ala Gln Leu Leu Gln Arg Ser 40 45 50 ccg tgt gtg gct gcc ccc gcc ctg gac gcc ttc gtg gag cga gtg ctg 310 Pro Cys Val Ala Ala Pro Ala Leu Asp Ala Phe Val Glu Arg Val Leu 55 60 65 gcg gcc gga cgg ctg ggg cgg gtc gtg ctt gct aac gct tcg ggg tcc 358 Ala Ala Gly Arg Leu Gly Arg Val Val Leu Ala Asn Ala Ser Gly Ser 70 75 80 gcc aac gcc tcg gac ccc gcc tgg gac ttc gcc tct gct ctc ttc ttc 406 Ala Asn Ala Ser Asp Pro Ala Trp Asp Phe Ala Ser Ala Leu Phe Phe 85 90 95 gcc agc acg ctg atc acc acc gtg ggc tat ggg tac aca acg cca ctg 454 Ala Ser Thr Leu Ile Thr Thr Val Gly Tyr Gly Tyr Thr Thr Pro Leu 100 105 110 115 act gat gcg ggc aag gcc ttc tcc atc gcc ttt gcg ctc ctg ggc gtg 502 Thr Asp Ala Gly Lys Ala Phe Ser Ile Ala Phe Ala Leu Leu Gly Val 120 125 130 ccg acc acc atg ctg ctg ctg acc gcc tca gcc cag cgc ctg tca ctg 550 Pro Thr Thr Met Leu Leu Leu Thr Ala Ser Ala Gln Arg Leu Ser Leu 135 140 145 ctg ctg act cac gtg ccc ctg tct tgg ctg agc atg cgt tgg ggc tgg 598 Leu Leu Thr His Val Pro Leu Ser Trp Leu Ser Met Arg Trp Gly Trp 150 155 160 gac ccc cgg cgg gcg gcc tgc tgg cac ttg gtg gcc ctg ttg ggg gtc 646 Asp Pro Arg Arg Ala Ala Cys Trp His Leu Val Ala Leu Leu Gly Val 165 170 175 gta gtg acc gtc tgc ttt ctg gtg ccg gct gtg atc ttt gcc cac ctc 694 Val Val Thr Val Cys Phe Leu Val Pro Ala Val Ile Phe Ala His Leu 180 185 190 195 gag gag gcc tgg agc ttc ttg gat gcc ttc tac ttc tgc ttt atc tct 742 Glu Glu Ala Trp Ser Phe Leu Asp Ala Phe Tyr Phe Cys Phe Ile Ser 200 205 210 ctg tcc acc atc ggc ctg ggc gac tac gtg ccc ggg gag gcc cct ggc 790 Leu Ser Thr Ile Gly Leu Gly Asp Tyr Val Pro Gly Glu Ala Pro Gly 215 220 225 cag ccc tac cgg gcc ctc tac aag gtg ctg gtc aca gtc tac ctc ttc 838 Gln Pro Tyr Arg Ala Leu Tyr Lys Val Leu Val Thr Val Tyr Leu Phe 230 235 240 ctg ggc ctg gtg gcc atg gtg ctg gtg ctg cag acc ttc cgc cac gtg 886 Leu Gly Leu Val Ala Met Val Leu Val Leu Gln Thr Phe Arg His Val 245 250 255 tcc gac ctc cac ggc ctc acg gag ctc atc ctg ctg ccc cct ccg tgc 934 Ser Asp Leu His Gly Leu Thr Glu Leu Ile Leu Leu Pro Pro Pro Cys 260 265 270 275 cct gcc agt ttc aat gcg gat gag gac gat cgg gtg gac atc ctg ggc 982 Pro Ala Ser Phe Asn Ala Asp Glu Asp Asp Arg Val Asp Ile Leu Gly 280 285 290 ccc cag ccg gag tcg cac cag caa ctc tct gcc agc tcc cac acc gac 1030 Pro Gln Pro Glu Ser His Gln Gln Leu Ser Ala Ser Ser His Thr Asp 295 300 305 tac gct tcc atc ccc agg tag ctggggcagc ctctgccagg cttgggtgtg 1081 Tyr Ala Ser Ile Pro Arg 310 cctggcctgg gactgagggg tccaggcgac cagagctggc tgtacaggaa tgtccacgag 1141 cacagcaggt gatcttgagg ccttgccgtc caccgtctct cctttgtttc ccagcatctg 1201 gctgggatgt gaagggcagc actccctgtc cccatgtccc gggctccact gggcaccaac 1261 ataaccttgt tctctgtcct ttctctcatc ctctttacac tgtgtctctc tggctctctg 1321 gcattctcgc tgcctctgtc tttccctctt gctgtctctg tttctcattc tctttcatgt 1381 tccgtctgtg tctctcaatt aaccactcgt caactgctga ttctactggg ctgtgggctc 1441 agacctcatt tcaggcacca gattggtcgc tacaccctgg acaagtgact gcccgtctct 1501 gagccttgat ttcctcagct gccaaatggg aagaatagaa gaatttgccc ctaaacccct 1561 cctgtgtgct ggccctgtgc tagacagtgc tggagacata gttgggggtg gagaactgcc 1621 cttatggagc ttgcagtcca gtgaggtgga cagacctgtc cccagacagt gatggcccaa 1681 aatggtcagg actttaatgg aggaggtgag gtgttgaaag cacaggcaga gtggtcaggg 1741 ctgaagtcgg agaagcatag ggactaggcc caatccagcc tggaaagtca gggaggactt 1801 cctagaggaa gggacatcga actaagacct gaactatgag aaataggcag gaagaagttg 1861 tacctgactc atttttctca ggtgtctcca gggagcagga cccatggagg gacccctggt 1921 gtaggcctgg gcgatagact cttcctcagc agcctggcag gcaggaaaca gacataggac 1981 cccagcccag atctgaatgg catgggaggt gctgccctta accatgacac cattgtaaga 2041 gctgtccaca tttgtatgtt gtgccctgga atcagcctgg ttgagctcaa atcccaactt 2101 agccacgtct ggcctgtgtc cttgggcagt cacactacct ctctgatttt gtttccttat 2161 ctgtaaaatg gtgatcatca taatacaact tcaaaaggat ttcaggctga gtgtggtggc 2221 tcacgcctat acacccagca ctttggaagg ctgaggaagg aggatcgctt gaggccagga 2281 gtttgagact agcctaggca acacagtgag gccttatctc aacaacaacc acaaaatcta 2341 aaaattagct gggtgtggtg gtgcatgcct gtgatcctgg ctacttcaga ggctgaggtg 2401 gaaggatcac ttgaggccag gagtttgagg ctgcagtgag ttatgatggc actgctgcac 2461 tccagcctgc gggacagagt gagaccctgt ctgaaagaaa gagagaaaga aagaaagaaa 2521 gagagagaaa gaaagaaaga aagaaaggga aagatggaag gaaggaagga 2571 81 313 PRT H. sapiens 81 Met Arg Arg Gly Ala Leu Leu Ala Gly Ala Leu Ala Ala Tyr Ala Ala 1 5 10 15 Tyr Leu Val Leu Gly Ala Leu Leu Val Ala Arg Leu Glu Gly Pro His 20 25 30 Glu Ala Arg Leu Arg Ala Glu Leu Glu Thr Leu Arg Ala Gln Leu Leu 35 40 45 Gln Arg Ser Pro Cys Val Ala Ala Pro Ala Leu Asp Ala Phe Val Glu 50 55 60 Arg Val Leu Ala Ala Gly Arg Leu Gly Arg Val Val Leu Ala Asn Ala 65 70 75 80 Ser Gly Ser Ala Asn Ala Ser Asp Pro Ala Trp Asp Phe Ala Ser Ala 85 90 95 Leu Phe Phe Ala Ser Thr Leu Ile Thr Thr Val Gly Tyr Gly Tyr Thr 100 105 110 Thr Pro Leu Thr Asp Ala Gly Lys Ala Phe Ser Ile Ala Phe Ala Leu 115 120 125 Leu Gly Val Pro Thr Thr Met Leu Leu Leu Thr Ala Ser Ala Gln Arg 130 135 140 Leu Ser Leu Leu Leu Thr His Val Pro Leu Ser Trp Leu Ser Met Arg 145 150 155 160 Trp Gly Trp Asp Pro Arg Arg Ala Ala Cys Trp His Leu Val Ala Leu 165 170 175 Leu Gly Val Val Val Thr Val Cys Phe Leu Val Pro Ala Val Ile Phe 180 185 190 Ala His Leu Glu Glu Ala Trp Ser Phe Leu Asp Ala Phe Tyr Phe Cys 195 200 205 Phe Ile Ser Leu Ser Thr Ile Gly Leu Gly Asp Tyr Val Pro Gly Glu 210 215 220 Ala Pro Gly Gln Pro Tyr Arg Ala Leu Tyr Lys Val Leu Val Thr Val 225 230 235 240 Tyr Leu Phe Leu Gly Leu Val Ala Met Val Leu Val Leu Gln Thr Phe 245 250 255 Arg His Val Ser Asp Leu His Gly Leu Thr Glu Leu Ile Leu Leu Pro 260 265 270 Pro Pro Cys Pro Ala Ser Phe Asn Ala Asp Glu Asp Asp Arg Val Asp 275 280 285 Ile Leu Gly Pro Gln Pro Glu Ser His Gln Gln Leu Ser Ala Ser Ser 290 295 300 His Thr Asp Tyr Ala Ser Ile Pro Arg 305 310 82 3300 DNA H. sapiens CDS (50)...(1285) 82 aaatgcctgc ccgtgcagct cggagcgcgc agcccgtctc tgaataaga atg gcg gca 58 Met Ala Ala 1 cct gac ttg ctg gat cct aaa tct gcc gct cag aac tcc aaa ccg agg 106 Pro Asp Leu Leu Asp Pro Lys Ser Ala Ala Gln Asn Ser Lys Pro Arg 5 10 15 ctc tcg ttt tcc acg aaa ccc aca gtg ctt gct tcc cgg gtg gag agt 154 Leu Ser Phe Ser Thr Lys Pro Thr Val Leu Ala Ser Arg Val Glu Ser 20 25 30 35 gac acg acc att aat gtt atg aaa tgg aag acg gtc tcc acg ata ttc 202 Asp Thr Thr Ile Asn Val Met Lys Trp Lys Thr Val Ser Thr Ile Phe 40 45 50 ctg gtg gtt gtc ctc tat ctg atc atc gga gcc acc gtg ttc aaa gca 250 Leu Val Val Val Leu Tyr Leu Ile Ile Gly Ala Thr Val Phe Lys Ala 55 60 65 ttg gag cag cct cat gag att tca cag agg acc acc att gtg atc cag 298 Leu Glu Gln Pro His Glu Ile Ser Gln Arg Thr Thr Ile Val Ile Gln 70 75 80 aag caa aca ttc ata tcc caa cat tcc tgt gtc aat tcg acg gag ctg 346 Lys Gln Thr Phe Ile Ser Gln His Ser Cys Val Asn Ser Thr Glu Leu 85 90 95 gat gaa ctc att cag caa ata gtg gca gca ata aat gca ggg att ata 394 Asp Glu Leu Ile Gln Gln Ile Val Ala Ala Ile Asn Ala Gly Ile Ile 100 105 110 115 ccg tta gga aac acc tcc aat caa atc agt cac tgg gat ttg gga agt 442 Pro Leu Gly Asn Thr Ser Asn Gln Ile Ser His Trp Asp Leu Gly Ser 120 125 130 tcc ttc ttc ttt gct ggc act gtt att aca acc ata gga ttt gga aac 490 Ser Phe Phe Phe Ala Gly Thr Val Ile Thr Thr Ile Gly Phe Gly Asn 135 140 145 atc tca cca cgc aca gaa ggc ggc aaa ata ttc tgt atc atc tat gcc 538 Ile Ser Pro Arg Thr Glu Gly Gly Lys Ile Phe Cys Ile Ile Tyr Ala 150 155 160 tta ctg gga att ccc ctc ttt ggt ttt ctc ttg gct gga gtt gga gat 586 Leu Leu Gly Ile Pro Leu Phe Gly Phe Leu Leu Ala Gly Val Gly Asp 165 170 175 cag cta ggc acc ata ttt gga aaa gga att gcc aaa gtg gaa gat acg 634 Gln Leu Gly Thr Ile Phe Gly Lys Gly Ile Ala Lys Val Glu Asp Thr 180 185 190 195 ttt att aag tgg aat gtt agt cag acc aag att cgc atc atc tca aca 682 Phe Ile Lys Trp Asn Val Ser Gln Thr Lys Ile Arg Ile Ile Ser Thr 200 205 210 atc ata ttt ata cta ttt ggc tgt gta ctc ttt gtg gct ctg cct gcg 730 Ile Ile Phe Ile Leu Phe Gly Cys Val Leu Phe Val Ala Leu Pro Ala 215 220 225 atc ata ttc aaa cac ata gaa ggc tgg agt gcc ctg gac gcc att tat 778 Ile Ile Phe Lys His Ile Glu Gly Trp Ser Ala Leu Asp Ala Ile Tyr 230 235 240 ttt gtg gtt atc act cta aca act att gga ttt ggt gac tac gtt gca 826 Phe Val Val Ile Thr Leu Thr Thr Ile Gly Phe Gly Asp Tyr Val Ala 245 250 255 ggt gga tcc gat att gaa tat ctg gac ttc tat aag cct gtc gtg tgg 874 Gly Gly Ser Asp Ile Glu Tyr Leu Asp Phe Tyr Lys Pro Val Val Trp 260 265 270 275 ttc tgg atc ctt gta ggg ctt gct tac ttt gct gct gtc ctg agc atg 922 Phe Trp Ile Leu Val Gly Leu Ala Tyr Phe Ala Ala Val Leu Ser Met 280 285 290 att gga gat tgg ctc cga gtg ata tct aaa aag aca aaa gaa gag gtg 970 Ile Gly Asp Trp Leu Arg Val Ile Ser Lys Lys Thr Lys Glu Glu Val 295 300 305 gga gag ttc aga gca cac gct gct gag tgg aca gcc aac gtc aca gcc 1018 Gly Glu Phe Arg Ala His Ala Ala Glu Trp Thr Ala Asn Val Thr Ala 310 315 320 gaa ttc aaa gaa acc agg agg cga ctg agt gtg gag att tat gac aag 1066 Glu Phe Lys Glu Thr Arg Arg Arg Leu Ser Val Glu Ile Tyr Asp Lys 325 330 335 ttc cag cgg gcc acc tcc atc aag cgg aag ctc tcg gca gaa ctg gct 1114 Phe Gln Arg Ala Thr Ser Ile Lys Arg Lys Leu Ser Ala Glu Leu Ala 340 345 350 355 gga aac cac aat cag gag ctg act cct tgt agg agg acc ctg tca gtg 1162 Gly Asn His Asn Gln Glu 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 1210 Asn His Leu Thr Ser Glu Arg Asp Val Leu Pro Pro Leu Leu Lys Thr 375 380 385 gag agt atc tat ctg aat ggt ttg acg cca cac tgt gct ggt gaa gag 1258 Glu Ser Ile Tyr Leu Asn Gly Leu Thr Pro His Cys Ala Gly Glu Glu 390 395 400 att gct gtg att gag aac atc aaa tag ccctctcttt aaataacctt 1305 Ile Ala Val Ile Glu Asn Ile Lys 405 410 aggcatagcc ataggtgagg acttctctat gctctttatg actgttgctg gtagcatttt 1365 ttaaattgtg catgagctca aagggggaac aaaatagata cacccatcat ggtcatctat 1425 catcaagaga atttggaatt ctgagccagc actttctttc tgatgatgct tgttgaacgg 1485 tccactttct ttgatgagtg gaatgacaag caatgtctga tgcctttttg tgcccagact 1545 gttttcctct ctctttccct aatgtgccat aaggcctcag aatgaatgag aattgtttct 1605 ggtaacaatg tagctttgag ggatcagttc ttaacttttc agggtctacc taactgagcc 1665 tagatatgga ccatttatgg atgacaacaa tttttttttt gtaaatgaca agaaattctt 1725 atgcagcctt ttacctaaga aattttctgt cagtgcctta tcttatgaag aaacagaacc 1785 tctctagcta atgtgtggtt tctccttccc tgcccccacc cctaggctca cctctgcagt 1845 cttttacccc agttctccca tttgaatacc ataccttgct ggaaacagtg tgtaaaatga 1905 ctgaagtgat gatgcccgaa gatgaaatag atgccaaatt agatggacat tgaagcaaca 1965 ctcagcgttg cctagcgtta aaggcactgc agagaaatga ggtgcagagg tggcccctct 2025 gagtatttat ttgactcagg taccagtggt acatatatac agtgtaatta tgaccaggct 2085 ggtaaaattg gctgctcgca aacaatcccc ttttttcctg gcagtatttg gaatttatca 2145 tttattaata actatacatt tttaaaggca gaagaagaaa atctatctat catctatcta 2205 tctatctatc tatctatcta tctatctatc tatctatcta tctatctaaa tgacctgaca 2265 gaagaaaact gttaaaaatg gatattattg gaggggattt aaaacagtgg gtgtgaatta 2325 tcattctgat ggaaagaaaa tagcaaaaca atgtgttaca agtatttgct aataaacagt 2385 atactgccag cttctaattg ctttttgatg tatgaaaggc ttatataatt ttcttttcgt 2445 tgggtgactt ttgccagatg agaggaggtg gcacagtggt gagtgcaggg cacagtccta 2505 gccttctgtg ggtatacttt tggagttgtg acttggctgt gagggcagaa gttgaagttg 2565 ggatcactgt gactttgcac atggaaaaat gcagattgca ggcataattc atctctgaca 2625 ttagagaaaa agctgttata gcacaattta aattttgaga gtttgctgtg tttttttttc 2685 acataaaaga ggctgattat tctttttagt ttaattttat atcctgtaat tctttggatg 2745 gttccaagat tcagaaaaaa ttcagtaaat gcaccccgta aattgctacc ctttccttta 2805 ttttcatact tagatctgct gtacattgta tatatatata atttttaaaa tgcagaaaga 2865 aaataatttc cctaaatata attgcaaact gatttctttt acttttttgt gtctgggggt 2925 gggagctgta tctgaataag tggcattcag attagggtct tgaaaaataa acccagaatc 2985 tttaaaagaa gcaaataaac taatagacgc ttattttcca aaatttaaat ttaagctaga 3045 aatgtaaata ttcaattaat ttgttaaaag tacttttata aagttaaaaa aaatccaacc 3105 aaaattttag aaagtcaggc tcttttagaa agaaagctac acccatttcc tcaaataact 3165 gttccgaaaa tttatatggt ggaatgcgcc atgtataaac tgtgaattgt attgacaaat 3225 aaagtttgta attaaagtca aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 3285 aaaaaaaaaa aaaaa 3300 83 411 PRT H. sapiens 83 Met Ala Ala Pro Asp Leu Leu Asp Pro Lys Ser Ala Ala Gln Asn Ser 1 5 10 15 Lys Pro Arg Leu Ser Phe Ser Thr Lys Pro Thr Val Leu Ala Ser Arg 20 25 30 Val Glu Ser Asp Thr Thr Ile Asn Val Met Lys Trp Lys Thr Val Ser 35 40 45 Thr Ile Phe Leu Val Val Val Leu Tyr Leu Ile Ile Gly Ala Thr Val 50 55 60 Phe Lys Ala Leu Glu Gln Pro His Glu Ile Ser Gln Arg Thr Thr Ile 65 70 75 80 Val Ile Gln Lys Gln Thr Phe Ile Ser Gln His Ser Cys Val Asn Ser 85 90 95 Thr Glu Leu Asp Glu Leu Ile Gln Gln Ile Val Ala Ala Ile Asn Ala 100 105 110 Gly Ile Ile Pro Leu Gly Asn Thr Ser Asn Gln Ile Ser His Trp Asp 115 120 125 Leu Gly Ser Ser Phe Phe Phe Ala Gly Thr Val Ile Thr Thr Ile Gly 130 135 140 Phe Gly Asn Ile Ser Pro Arg Thr Glu Gly Gly Lys Ile Phe Cys Ile 145 150 155 160 Ile Tyr Ala Leu Leu Gly Ile Pro Leu Phe Gly Phe Leu Leu Ala Gly 165 170 175 Val Gly Asp Gln Leu Gly Thr Ile Phe Gly Lys Gly Ile Ala Lys Val 180 185 190 Glu Asp Thr Phe Ile Lys Trp Asn Val Ser Gln Thr Lys Ile Arg Ile 195 200 205 Ile Ser Thr Ile Ile Phe Ile Leu Phe Gly Cys Val Leu Phe Val Ala 210 215 220 Leu Pro Ala Ile Ile Phe Lys His Ile Glu Gly Trp Ser Ala Leu Asp 225 230 235 240 Ala Ile Tyr Phe Val Val Ile Thr Leu Thr Thr Ile Gly Phe Gly Asp 245 250 255 Tyr Val Ala Gly Gly Ser Asp Ile Glu Tyr Leu Asp Phe Tyr Lys Pro 260 265 270 Val Val Trp Phe Trp Ile Leu Val Gly Leu Ala Tyr Phe Ala Ala Val 275 280 285 Leu Ser Met Ile Gly Asp Trp Leu Arg Val Ile Ser Lys Lys Thr Lys 290 295 300 Glu Glu Val Gly Glu Phe Arg Ala His Ala Ala Glu Trp Thr Ala Asn 305 310 315 320 Val Thr Ala Glu Phe Lys Glu Thr Arg Arg Arg Leu Ser Val Glu Ile 325 330 335 Tyr Asp Lys Phe Gln Arg Ala Thr Ser Ile Lys Arg Lys Leu Ser Ala 340 345 350 Glu Leu Ala Gly Asn His Asn Gln Glu Leu Thr Pro Cys Arg Arg Thr 355 360 365 Leu Ser Val Asn His Leu Thr Ser Glu Arg Asp Val Leu Pro Pro Leu 370 375 380 Leu Lys Thr Glu Ser Ile Tyr Leu Asn Gly Leu Thr Pro His Cys Ala 385 390 395 400 Gly Glu Glu Ile Ala Val Ile Glu Asn Ile Lys 405 410 84 20 DNA H. sapiens 84 catagccata ggtgaggact 20 85 20 DNA H. sapiens 85 gagaggaaaa cagtctgggc 20 86 20 DNA H. sapiens 86 ggacatcgaa ctaagacctg 20 87 20 DNA H. sapiens 87 tcccatgcca ttcagatctg 20

Claims

What is claimed is:

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, 30, 81 or 83.

3. An isolated nucleic acid according to claim 1, wherein said K+Hnov protein has an 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 sequence of said nucleic acid is SEQ ID NO:l, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 22, 23, 24, 26, 28, 29, 80 or 82.

5. An isolated nucleic acid that hybridizes under stringent conditions to a nucleic acid sequence of claim 4.

6. 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 claim 1 under the transcriptional regulation of said transcriptional initiation region, and a transcriptional termination region functional in said expression host.

7. A cell comprising an expression cassette according to claim 6 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 host cell.

8. A method for producing mammalian K+Hnov protein, said method comprising:

growing a cell according to claim 7, whereby said mammalian K+Hnov protein is expressed; and

isolating said K+Hnov protein free of other proteins.

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

10. A monoclonal antibody binding specifically to a K+Hnov protein.

11. A non-human transgenic animal model for K+Hnov gene function wherein said transgenic animal comprises an introduced alteration in a K+Hnov gene.

12. The animal model of claim 11, wherein said animal is heterozygous for said introduced alteration.

13. The animal model of claim 12, wherein said animal is homozygous for said introduced alteration.

14. The animal model of claim 12, wherein said introduced alteration is a knockout of endogenous K+Hnov gene expression.