CA2321194A1 - Human potassium channel genes - Google Patents

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

HUMAN POTASSIUM CHANNEL GENES
INTRODUCTION
Background Ion channels are mufti-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 1o 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 (Cf), calcium (Caf') 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 congenita, episodic ataxia) and congenital neural deafness (Jervell-Lange-Nielson syndrome), amongst others.
The potassium channel gene family is believed to be the largest and most diverse ion channel family. K' channels have critical roles in multiple cell types andpathways, and are the focus of significant investigation. Four human conditions, episodic ataxia with myokymia, long QT syndrome, epilepsy and Bartter's syndrome have been shown to be caused by defective K' ion channels.
As the K~ channel family is very diverse, and given that these proteins are critical components of virtually all cells, it is likely that abnormal K+ channels will be involved in the etiology of additional renal, cardiovascular and central nervous 3o 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 minx (IsK) gene contains a single TMD, and although not a channel by itself, minx 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
~5 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 4TI2P channels all have distinct characteristics, but are all thought to be involved in maintaining the steady-state K' potentials across 2o 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 25 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 aI. (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
30 273(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 10z-103 individual genes. Despite the large number of potential genes, an analysis of public sequence databases and the scientific I~erature 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 mu~iple different processes and are important regulators of homeostasis in nearly al! cell types. Their relevance to ~o 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 Biotechnolo4v 9:565-572). The ~5 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.
2o 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.
25 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. Grammar, 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), 30 and voltage gated channels (ISBN: 0121844536). Hille, B. (1992) "Ionic Channels of Excitable Membranes", 2"~ Ed. Sunderland MA: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. Enal. 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 aG (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 ef al. (1989) Arch.
Neurol. 46405-408). Electromyography demonstrated that mechanical stimulation ~o provoked electrically silent contractions. The responsible gene was localized to the distal end of the long arm of chromosome 1, in a 12-cM region near D1S235.
Type II pseudohypoaldosteronism is the designation used for a syndrome of chronic mineralocorticoid-resistant hyperkalemia with hypertension. The primary abnormality in type II PHA is thought to be a specific defect of the renal ~5 secretory mechanism for potassium, which limits the kaliuretic response to, but not the sodium and chloride reabsorptive effect of, mineraiocorticoid. 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.
2o 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
25 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 18(3):868-77.
The electrophysiological properties of Task channels are of interest, ao (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 ~o 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.
2o 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
3o 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 poiymorphisms. 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 ~o 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 ~s 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 2o profiles elicited by depolarization and hyperpolarization, current-voltage (I-1~
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 25 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 channets.
In many cases the functional ion channel formed by K+Hnov polypeptides will be heteromultimers. Heteromultimers are known to form between different 3o voltage gated, outward rectifying potassium channel a subunits, generally comprising four subunits, and frequently associated with auxiliary, ~
subunits.
Typically such a 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 s 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 ~o channel may have decreased or increased conductance relative to a homomultimer, and may be altered in response to beta subunits or other modulatory molecules.
Known voltage gated K+ channel a subunits include Kv1.1-1.8 (Gutman et al. (1993) Sem. Neurosci. 5:101-106); Kv2.1-2.2; Kv3.1-3.4; Kv4.1-4.3; Kv5.1;
~ 5 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.

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K+Hf110V 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 poiypeptides, 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 1o 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
1s 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 2o 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, 2s 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 3o proper tissue and stage specfic 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 speck 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 traps acting factors that regulate or mediate K+Hnov expression.
Such transcription or translational control regions may be operably linked to a 2o 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.
3o 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 s 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, 1o 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 15 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 2o 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 2s 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 3o 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.
o 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 speck mutagenesis can be found in Sambrook et aL, Molecular ~5 Cloning: A Laboratory Manual, CSH Press 1989, pp. 15.3-15.108; Weiner et al., Gene 126:35-41 (1993); Sayers et aL, Biotechniques 13:592-6 (1992); Jones and Winistorfer, 8iotechniques 12:528-30 (1992); Barton et al., Nucleic Acids Res 18:7349-55 (1990); Marotti and Tomich, Gene Anal Tech 6:67-70 (1989); and Zhu, Anal Biochem 177:120-4 (1989). Such mutated genes may be used to study 2o 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, 25 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 6XSSC (0.9 M sodium chloridel0.09 M sodium citrate) and remain bound when subjected to washing at 55°C in 1XSSC (0.15 M sodium 3o chloridel0.015 M sodium citrate). Sequence identity may be determined by hybridization under stringent conditions, for example, at 50°C or higher and 0.1XSSC (15 mM sodium chloride101.5 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, efc., 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 1o 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 3o 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, to 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 2o 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 mod~ed 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 3o host and the lysate purified using HPLC, exclusion chromatography, gel electrophoresis, affinity chromatography, or other purification technique. The WO 99/43696 PC1'/US99/038Z6 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 welt 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 ~o 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 ~s 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 Laborator)r Manual, Harlow 2o and Lane eds., Cold Spring Harbor Laboratories, Cold Spring Harbor, New York, 1988. If desired, the mRNA encoding the heavy and light chains may be isolated and mutagenized by cloning in E. 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, 25 usually in conjunction with in vitro affinity maturation.
K+HNOV GENOTYPING
The subject nucleic acid andlor polypeptide compositions may be used to genotyping and other analysis for the presence of polymorphisms in the 3o sequence, or variation in the expression of the subject genes. Genotyping may be performed to determine whether a particular poiymorphisms is associated with ~s a disease state or genetic predisposition to a disease state, particularly diseases associated with defects in excitatory properties of cells, e.g. cardiac, muscle, renal and neural cells. Disease of interest include rippling muscle disease, and type II
psuedohypoaldosteronism.
Clinical disorders associated with K+ channel defects include long-QT
syndrome; a congenital disorder affecting 1 in 10,000-15,000. Affected individuals have a prolonged QT interval in the electrocardiogram due to a delayed repolarization of the ventricle. Genetic linkage analyses identified two loci for long QT syndrome, LQT1, in 11p15.5 and LQT2, in 7q35-36. Positional ~o 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 ~5 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 (~rpll 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
2o 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 25 toxicity or therapeutic failure. Relationships between polymorphisms in channel expression or specificity can be used to optimize therapeutic dose administration.
Genetic poiymorphisms 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 30 reactivity and adverse side effects in response to drugs that act on K+
channels.

K+Hnov genotyping is performed by DNA or RNA sequence andlor 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 1o 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 2o 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, ei'c.
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 ampl~ed 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 3o current techniques may be found in Sambrook et' al. Molecular Cloning: A
Laboratory Manual, CSH Press 1989, pp.14.2-14.33. Amplification may be used WO 99/43696 PC"T/US99/03826 to determine whether a polymorphism is present, by using a primer that is specific for the polymorphism. Alternatively, various methods are known in the art that utilize oligonucleotide ligation as a means of detecting polymorphisms, for examples see Riley et al. (1990) N.A.R. 18:2887-2890; and Delahunty ef 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',T-dimethoxy-4',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'-tetramethyi~- 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 2o sequenced by dideoxy or other methods. Hybridization with the variant sequence may also be used to determine its presence, by Southern blots, dot blots, efc.
The hybridization pattern of a control and variant sequence to an array of oligonucleotide probes immobilised on a solid support, as described in U.S.
5,445,934, or in 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 3o 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 polyrnorphic 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 oligonucieotides, each of which can spec~cally hybridize to a different polymorphism. For examples of arrays, see Hacia et al.
(1996) Nature Genetics 14:441-447; Lockhart et al. (1996) Nature Biotechnol.
14:1675-1680; and De Risi et al. (1996) Nature Genetics 14:457-460.
Screening for polymorphisms in K+Hnov may be based on the functional or ~5 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 2o 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;
25 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 pertormed by a number of methods to determine the 3o 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 histoiogical 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.
1o 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 2o 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 3o by any number of routes, including viral infection, microinjection, or fusion of vesicles. Jet injection may also be used for intramuscutar 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 ef 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.
~a 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, ~5 where a combination may comprise multiple different sequences.
Antisense molecules may be produced by expression of alt 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 20 ~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 25 oiigonucleotides, of from 7 to 8 bases in length, can be strong and selective inhibitors of gene expression (see Wagner et al. (1996) Nature Biotechnoloav 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 30 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 ef 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-~5 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 stabilityr and affinity. The a-anomer of deoxyribose may be used, where the base is inverted with respect to the natural ~i-anomer. The 2'-OH of the ribose sugar may be 2o altered to form 2'-O-methyl or 2'-O-allyl sugars, which provides resistance to degradation without comprising affinity. Modification of the heterocyctic 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'-25 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 3o 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 Beigeiman et al. (1995) Nucl. Acids Res 23:4434-42).
Examples of oligonucleotides with catalytic activity are described in WO
9506764.
Conjugates of anti-sense ODN with a metal complex, e.g. terpyridylCu{II), capable of mediating mRNA hydrolysis are described in Bashkin et al. (1995) Ap~l 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 ~ o 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 ~ 5 and regulation. For example, a series of small deletions andlor 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 2o 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.
25 DNA constructs for homologous recombination will comprise at least a portion of the K+Nnov 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, marker; for positive and negative selection are included. Methods for generating so 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, s 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.
~o 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 ~5 blastocoel of the blastocyst. After injection, the blastocysts are returned to each uterine hom of pseudopregnant females. Females are then allowed to go to temp 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.
2o The chimeric animals are screened for the presence of the mod~ed gene and males and females having the mod~cation 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 25 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 ~5 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 2o 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 dele~on, substitution, etc.
to determine the functional role of specific domains.
25 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 hetermuitimers. 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 3o 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 ~5 agents comprise functional groups necessary for structural interaction with proteins, particularly hydrogen bonding, and typically include at least an amine, c~rbonyi, hydroxyl or carboxyl group, preferably at least two of the functional chemical groups. The candidate agents often comprise cyclical carbon or heterocyclic structures andlor aromatic or polyaromatic structures substituted with 20 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 25 available for random and directed synthesis of a wide variety of organic compounds and biomolecules, including expression of randomized oligonucleotides and oiigopeptides. 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 3o 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, amid~cation, 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. Speciftc. binding molecules include pairs, such as biotin and streptavidin, digoxin and antidigoxin etc. For the specific binding members, ~o 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 andlor reduce non-specific or ~5 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, typicaAy between 4 and 40°C. Incubation periods are selected for optimum 2o 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 25 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, 3o salves, lotions and the like. Pharmaceutical grade organic or inorganic carriers andlor 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 s 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, ~s 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.
20 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 25 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 descrybed in the publications which might be used in connection with the presently described invention. The publications discussed 3o 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 WO 99/43696 PC"f/I1S99/03826 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 n:garded as the invention. Efforts have been made to ensure accuracy with respect to the numbers used (e.g. amounts, temperature, concentrations, etc.) but some ~o experimental errors and deviations should be allowed for. Unless othervvise indicated, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees centigrade; and pressure is at or near atmospheric.
~5 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 2o channel. Eleven variant peptide sequences corresponding to the pore domain were used in TBLASTN searches against the EST division of Genbank.
Significant matches were ident~ed, 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.

a C~ C9 ~ O ~ ~ ~ ~ U V O U U U U
a a v ~ ~ ~ a c~
v a v ~ ~ ~ ~ ~ ~ ~ ~ a ~ a ra- ~
a a v v ~ a ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ v a ~~~~~~"~''~c~~~a~4~a~c~
1-C'!- !C!- 10-, C'i V U CO's V U C~'J U U U U V
U~~Ca'lU~~(~U~V ~~UU~
a Ua U U a U U U ~ ta'~ a Ca'! O O U
c~ c~ ~ c~ c~
c~' aaaaa~a~c~c~aaUUUUU
U U U U U a U U a U U ~"' ~ U
V V ~ U
OC?(~(9UO~U' U~' (~'~i,~'~~~ H OO
~ a a a ~ I-I-O- i~-. ~ ~ V ~ V CO'! V U U U U
C'~ O C'J C9 (' (' U U U U U U U U
~tV?~~CU'!t0'!(~.9~~~UUVUV UUa t0,9 ~ O C9 t9 (9 t,9 C9 ~ C'! ~ ~ V ~U' U
!- i- 1-O- ice- t~0- 10- H !~O- !O-. FO- V a V V ~ I~U- ~ ~ U
C'l ~? C9 ~ t9 C'~ C! C! G C9 ~ ~ U U V U V
H H 1-O- f- 10- 1~0- 1~0- !~O- H 10- ~ ~ ~ ~ ~ ~ C9 x H ~ ~ M
C9 J ~ ~ ~ N
X H ~ > > ~ ~ ~ 7 O
Z
D_ D
cui .°'r ~°n ~i h ~ i~ ~ °~ n irk h ~ e~'o ~ m i~ ~ ~ m The unique pore peptides sequences are shown ~n Table 3 1 s 68 VWVAVVSMTTVGYG'DM

69 ~ WINAVVTMTTLGYGOM

70 i WV'JGWXVTTIGYGD~K

77 FLFSLES~TTIGYGF

The second set of experiments was based on a complex, reiterative process.
Annotated protein and DNA sequences were obtained from GenBank for all knovm K+
channels from all species. The TBLASTN and 8LA:3TN programs were used to identify homologous ESTs, which were then analyzed using the BLASTX and BLASTN
algorithms to identify ESTs which were related to h:+ 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.
t 5 Isolation of full length cDNA sequence. E:ST clones were picked from the IMAGE consortium cONA library and end-sequenced with vector primers. Gap closure was achieved either by primer walking ar 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 ND:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21-24, 26 and 28-29.
Polymorphisms, chromosome ~cations and family assignments are shown in Table 1.
ESTs that had top human hits with X95% 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 tie variation from the known related probe sequence was a result of poor database sequence. Poor database sequence was usually ident~ed as a number of 'N' nuGeotides 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 Gsnbank K+Hnov clone tD Tracs IMAGE Plate Resd 5'/3' Accessioa* Coordlnatss N39619 K+Hnov2 277113 yy51 h05. 611 p10 3' s1 N46T6T K+Hnov2 277113 yy51h05.r1811p10 5' _ ,-, 819352 K+Hnovll 33144 yg24f12.r1155024 5' 844828 K+Hnovll 33144 yg24f12.s1155024 3' 835526 K+Hnovl4 37299 yg64s08.r1165015 5' 873353 K+Hnovl4 157854 y110e04.r1251807 5' AA397616 K+Hnovl4 728558 zt79c08.r11787j15 5' AA286692 K+Hnov28 700757 zs48h03.r11715d6 5' AA150494 K+Hnov42 491748 z108e07.s11170013 3' AA156697 K+Hnov42 491748 z108e07.r11170013 5' AA191752 K+Hnov42 626699 zp82d06.r11522f12 5' AA216446 K+Hnov42 626699 zp82d06.s11522f12 3' AA430591 K+Hnov42 773611 zw51f10.r11904020 5' AA236930 K+Hnov44 683888 zs01 a05.s11671 e9 3' AA236968 K+Hnov44 683888 zs01 a05.r11671 e9 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 GB4 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 G84 (SEQ ID N0:31 ) F: 5' TATCCACATCAATGGACAAAGC 3' (SEQ ID N0:32) 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 G84 (SEQ ID N0:33) F: 5' TGACATCACTGGATGAACTTGA 3' (SEQ ID N0:34) R: 5' TGCCTGCAAAGTTTGAACAT 3' Results: 5.23 cR from WI-5509, Cytogenetic location of 2p23 K+Hnov9 on G84 (SEQ ID N0:35) F: 5' TGACATCACTGGATGAACTTGA 3' (SEGI ID N0:36) R: 5' TGCCTGCAAAGTTTGAACAT 3' WO 99I43b96 PCTIUS99103826 Results: 1.21 cR from AFMZOOVC7, Cytogenetic location of 8q23 K+Hnovll on G64 (SEA ID N0:37) F: 5' ACCTGGTGGTATGGAAGCAT 3' (SEQ ID N0:38) R: 5' TTTCTCCTGGCCTCTACCC 3' Results: 2.43 cR from WI-6756, Cytogenetic location of 8q23 K+Hnovl2 on G3 (SEQ ID N0:39) F: 5' TCCCTCTTGGGTGACCTTC 3' (SEQ ID N0:40) R: 5' ATCTTTGTCAGCCACCAGCT 3' Results: 7.45 cR from SHGC-32925, Cytogenetic location of Xp21 K+Hnovl4 on G84 (SEQ ID N0:41 ) F: 5' AGGTGTGCTGCCATCTGCTGTTCG3' (SEQ ID N0:42) R: 5' AGCCTATCCTCTCTGAGAGTCAGG
Results: 7.69 cR from WI-7107, Cytogenetic location of 12q14 K+Hnov28 on GB4 (SEA ID N0:43) F: 5' AAGCAGAGTACTCATGATGCC 3' (SEQ !0 N0:44) R: 5' TCTGGTAGACAGTACAGTGG 3' Results: 35.38 cR from WI-9695, Cytogenetic location of 3q29 K+Hnov42 on G3 (SEQ ID N0:45) F: 5' CATTTGGCTGGTCCAAGATG 3' (SEQ ID N0:46) R: 5' AGTCATTGGTAGGGAGGTAC 3' Results: 7.45 cR from SHGC-32925, Cytogenetic location of Xp21 K+Hnov44 on G3 (SEQ ID N0:47) F: 5' CATGCTTCTACAGTCCAGCC 3' (SEQ ID N0:48) R: 5' GGTCCTCAGTTGCAGAAATC 3' Results: 7.45 cR from SHGC-32925, Cytogenetic location of Xp21 Map positions for K+HnovlS and K+Hnov27 were obtained from public databases.
K+Hnov2 and K+Hnov4 have not been mapped.
EXAMPLE 3: EXPRESSION ANALYSIS
RT-PCR was utilized to characterize the expression pattern of the novel ion channels. This approach used RNA from 30 different tissues to generate fast strand cDNA. Total RNA was purchased (Ctontech, Invitrogen) and used to synthesize first strand cDNA using M-MLV reverse transcriptase and the supplied buffer (Gibco-8RL).
The 20 NI reaction contained 5 Ng total RNA, 100 ng of random primers, 10 mM
OTT, 0.5 mM each dNTP, and an RNAse inhibitor (Gibco-8RL). Identical reactions were set up without reverse transcxiptase to control far 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 cDNA synthesis reactions without reverse transcriptase, were diluted 1:5 and 2 NI of each sample were arrayed into 96-well trays, dried, and resuspended in PCR buffer prior to PCR ampl~cation. The cDNAs were tested with primers with defined expression patterns to verify the presence of ampi~able cDNA from each tissue. Gene-speck primers were used to amplify the cDNAs in 20 NI PCR reactions with standard conditions, 2.5 mM MgCI=, 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. Modfications can be employed, such as the use of internal control primers, limited cycling parameters, and dilution series to convert this to a quantitative experiment.
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WO 99/43696 PCTIUS99l03826 K+Hnov49 on Whitehead GB4 RH mapping panel:
Primer 1 (SEQ ID N0:5): 5' - CATAGCCATAGGTGAGGACT - 3' Primer 2: (SEQ ID N:6) 5' - GAGAGGAAAACAGTCTGGGC - 3' Results: Cytogenetic location 1 q41, 4.6cR from framework marker D15217 K+Hnov59 on Whitehead GB4 RH mapping panel Primer 1 (SEQ ID N0:7): 5' - GGACATCGAACTAAGACCTG - 3' Primer 2 (SEQ ID NO:8): 5' - TCCCATGCCATTCAGATCTG - 3' Results: Cytogenetic location 19q13.2, 8.34cr from framework marker D19S425 EXPRESSION ANALYSIS OF K+HNOV49 A probe was created from a fragment corresponding to nucleotides 50 to 1284 of SEQ ID N0:83 (K+Hnov49) and purified DNA fragment was labeled with t5 [32PjdCTP (Amersham) by the random primer method. Adult human Multiple Tissue Northern (MTMT"") Blots (Clontech) were hybridized with the [~P]-labeled fragment in ExpressHybTM solution {Clontech) for four hours, washed to a final stringency of 0.lxSSC, 0.1% SDS at 65°C and subjected to autoradiography for 24 hours.
2o 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 25 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.

Tabie 4 b _~ b ;~ ai "°
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a b ~ ~ c~ n~ ° d ~ ~ d T~ > ~ '° ~ ~ ° d ~iu x ~ ~ a 8 n~
aac4a4UJt~wt~.tc.==x3..-Wa.a,~oGcncwn:ncntn:
#49 + + + + + + - + + _ + + + - + + - - + . + + - + - + + + _ - - - - + - + - + + - - + + + + - + + + - - + + + + + + +

SEQUENCE LISTING
<110> Miller, Andrew Curran, Mark Buckler, Alan <120> Novel Human Potassium Channels <130> SEQ-15PCT
<150> 60/076,687 <151> 1998-02-25 <150> 60/095,836 <151> 1998-08-07 <150> 60/116,448 <151> 1999-O1-19 <160> 87 <170> FastSEQ for Windows Version 3.0 <210> 1 <211> 2932 <212> DNA
<213> H. Sapiens <220>
<221> CDS
<222> (103)...(1180) <223> K+Hnovi <400> 1 attaaaatta tctgatcaaa ccttaagacctaccttggca 60 aaggcagact ctgtaaattt taaaggctga cccagcaaaa ag atg agcagt 114 gaactgagaa gac atacagcctg Met SerSer Asp aattgcaaagtt attgetcct cta caaagatac aggatg 162 ctc agt cgg AsnCysLysVal IleAlaPro Leu GlnArgTyr ArgMet Leu Ser Arg gtcaccaaggat ggccacagc ctt atggatggc caaaga 210 aca caa get ValThrLysAsp GlyHisSer Leu MetAspGly GlnArg Thr Gln Ala ggtcttgcatat cttcgagat tgg atcctaatg atgcgc 258 get gga gac GlyLeuAlaTyr LeuArgAsp Trp IleLeuMet MetArg Ala Gly Asp tggcgttggatg atgttggtc tct tcttttgtt cactgg 306 ttt get gtc TrpArgTrpMet MetLeuVal Ser SerPheVal HisTrp Phe Ala Val cttgtctttgca gtgctctgg gtt getgagatg ggtgat 354 tat ctg aat LeuValPheAla ValLeuTrp Val AlaGluMet GlyAsp Tyr Leu Asn ctggaacta gatcatgatgcccca cctgaaaaccacact atctgtgtc 402 LeuGluLeu AspHisAspAlaPro ProGluAsnHisThr IleCyaVal aagtatatc accagtttcacaget gcattctccttctcc ctggagaca 450 LysTyrile ThrSerPheThrAla AlaPheSerPheSer LeuGluThr caactcaca attggttatggtacc atgttccccagtggt gactgtcca 498 GlnLeuThr IleGlyTyrGlyThr MetPheProSerGly AspCysPro agtgcaatc gccttacttgccata caaatgctcctaggc ctcatgcta 546 SerAlaIle AlaLeuLeuAlaIle GlnMetLeuLeuGly LeuMetLeu gaggetttt atcacaggtgetttt gtggcgaagattgcc cggccaaaa 594 GluAlaPhe IleThrGlyAlaPhe ValAlaLysIleAla ArgProLys aatcgaget ttttcaattcgcttt actgacacagcagta gtagetcac 642 AsnArgAla PheSerIleArgPhe ThrAspThrAlaVal ValAlaHis atggatggc aaacctaatcttatc ttccaagtggccaac acccgacct 690 MetAspGly LysProAsnLeuIle PheGlnValAlaAsn ThrArgPro agccctcta accagtgtccgggtc tcagetgtactctat caggaaaga 738 SerProLeu ThrSerValArgVal SerAlaValLeuTyr GlnGluArg gaaaatggc aaactctaccagacc agtgtggatttccac cttgatggc 786 GluAsnGly LysLeuTyrGlnThr SerValAspPheHis LeuAspGly atcagttct gacgaatgtccattc ttcatctttccacta acgtactat 834 IleSerSer AspGluCysProPhe PheIlePheProLeu ThrTyrTyr cactccatt acaccatcaagtcct ctggetactctgctc cagcatgaa 882 HisSerIle ThrProSerSerPro LeuAlaThrLeuLeu GlnHisGlu aatccttct cactttgaattagtt gtattcctttcagca atgcaggag 930 AsnProSer HisPheGluLeuVal ValPheLeu5erAla MetGlnGlu 265 2?0 275 ggcactgga gaaatatgccaaagg aggacatcctaccta ccgtctgaa 978 GlyThrGly GluIleCysGlnArg ArgThrSerTyrLeu ProSerGlu atcatgtta catcactgttttgca tctctgttgacccga ggttccaaa 1026 IleMetLeu HisHisCysPheAla SerLeuLeuThrArg GlySerLys ggtgaatat caaatcaagatggag aattttgacaagact gtccctgaa 1074 GlyGluTyr GlnIleLysMetGlu AsnPheAspLysThr ValProGlu tttccaact cctctggtttctaaa agcccaaacaggact gacctggat 1122 Phe Pro Thr Pro Leu Val Ser Lys Ser Pro Asn Arg Thr Asp Leu Asp 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 gga ctg aca g aataagactt atccattttt taatgtatta aatacaccca 1220 Gly Leu Thr gccagttatgcagctactttttctttactgtatctcatgttttcttttttcaatgctaat1280 tatagctctctacatcacggtaatcatgcctatgcctacataagaatggctgagctaaca1340 atacacattctggaaacataacactctacattacaaagtttgttacctgctgaaatcaat1400 gtaactcaacttgacagacacttatacagaaatgttgctggtgaatttataagaatgtgg1460 tatgatactagtaatgaaggcaaaatggacagtgaagtttaacacaactgaactctaaga1520 aaatcaaccattaatctctcattttcatctgcaaattgaagcaacagtttagtttcaaac1580 ctagctccctgggtggaatgacgacttcactatacttagtgaatatcctttaagagctgg1640 gatttttttcaagacaacaaagatcattcatttggttctttatactatgaaacttgagta1700 agtattacctccttaatttttaacaactaagaacaaaaattaacgagaaaaacaacaaag1760 tacagatttatacataaacctaaaagcatttgaacatgacacccgaacacatacatatat1820 gttcacttatttgtggcagaaggtgatcagataagctccagcccaaatggaacctgtggg1880 gtggtattttgcattgcaaggagacgcaaaattttattttaaaactgtcctccataataa1940 tcaaacggtgattcatctaaatgacttctagcaacctaagtaaaaacattcccctcctat2000 gtatgattcatttgatcatataaaacatcatgatggctctaattcataaatacaaaaata2060 tatttaagtctttatagatataaagctttacttagatataacttgagtgagtagggaaaa2120 aaatctacagtagataaagcaaaagataattaggcaacaaagcattttcaaactcaaatt2180 cctgtttccaacttcaaatagttttttctataaacacaaaatcagtgtttattcaccagt2240 aggaggttggactagatgaactctattatttctttctaaatctaatagtctataaaaatt2300 atgtttcctctgttttttattttatctatgctaaaatgagccctttcccttatgtccagt2360 ttaagatgatcatttgcatgattttcatttcaataaaaaaaagagaaactgtccttaaaa2420 caaaacaaaaaccaaaaaagtcaccctatcaggtttcaaacagatttgtggctgttcttt2480 tctgaaatttcccttattcaggtttctgtgggaaaaatgaaagattaaccttccccactg2540 gtgatgacctaggcaggaatcatctcttgaaataaatactagctgagtaaaggcaagcag2600 gtgtgaagagcagggctcagcagcaagtcacatttttctactatttgaccaaaaggaaaa2660 gaaaataaagaagaactctggagtggtctaagactgataatagcagaagaatatcaagaa2720 cacagaaacttaattattgtgaacttttgctgtttgaaaatcttagacattcattcttaa2780 gtagaaatcagaccaacagattttcccaacccaagactattgtaacacataaagacagca2840 agaattcttatttctataataaattaacaagattcacctaacctttgaaaataaagtagt2900 attgaagacttaaaaaaaaaaaaaaaaaaaas 2932 <210> 2 <211> 359 <212> PRT
<213> H. sapiens <400> 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 Gly Ala Gln Arg Gly Leu Ala Tyr Leu Arg Asp Ala Trp Gly Ile Leu Met Asp Met Arg Trp Arg Trp Met Met Leu Val Phe Ser Ala Ser Phe Val Val His Trp Leu Vai Phe Ala Val Leu Trp Tyr Val Leu Ala Glu Met Asn Gly Asp Leu Glu Leu Asp His Asp Ala Pro Pro Glu Asn His Thr Ile Cys Val Lys Tyr Ile Thr Ser Phe Thr Ala Ala Phe Ser Phe WO 99143696 PG"TIUS99I03826 Ser Leu Glu Thr Gln Leu Thr Ile Gly Tyr Gly Thr Met Phe Pro Ser Gly Asp Cys Pro Ser Ala Ile Ala Leu Leu Ala Ile Gln Met Leu Leu Gly Leu Met Leu Glu Ala Phe Ile Thr Gly Ala Phe Val Ala Lys Ile Ala Arg Pro Lys Asn Arg Ala Phe Ser Ile Arg Phe Thr Asp Thr Ala Val Val Ala His Met Asp Gly Lys Pro Asn Leu Ile Phe Gln Val Ala Asn Thr Arg Pro Ser Pro Leu Thr Ser Val Arg Val Ser Ala Val Leu Tyr Gln Glu Arg Glu Asn Gly Lys Leu Tyr Gln Thr Ser Val Asp Phe His Leu Asp Gly Ile Ser Ser Asp Glu Cys Pro Phe Phe Ile Phe Pro Leu Thr Tyr Tyr His Ser Ile Thr Pro Ser Ser Pro Leu Ala Thr Leu Leu Gln His Glu Asn Pro Ser His Phe Glu Leu Val Val Phe Leu Ser Ala Met Gln Glu Gly Thr Gly Glu Ile Cys Gln Arg Arg Thr Ser Tyr Leu Pro Ser Glu Ile Met Leu His His Cys Phe Ala Ser Leu Leu Thr Arg Gly Ser Lys Gly Glu Tyr Gln Ile Lys Met Glu Asn Phe Asp Lys Thr Val Pro Glu Phe Pro Thr Pro Leu Val Ser Lys Ser Pro Asn Arg Thr Asp Leu Asp Ile His Ile Asn Gly Gln Ser Ile Asp Asn Phe Gln Ile Ser Glu Thr Gly Leu Thr <210> 3 <211> 1927 <212> DNA
<213> H. sapiens <220>
<221> CDS
<222> (105)...(1908}
<223> K+Hnov4 <400> 3 ggagccccgcagcgcttctt ctcctcctaccgcgggcgca 60 atgatcagct cggtgtgtgt agtcggggaacaagcctccg ggag atg 116 tccaaaacat gcc aag gtctgaagga ggc Met Ala Lys Gly gag gcg gag aagatc atc gtgggcggc acg catgag 164 tcg atc aac cga Glu Ala Glu LysIle Ile ValGlyGly Thr HisGlu Ser Ile Asn Arg acc tac agc accctg acc ccgggaacc cgc gcctgg 212 cgc cgc cta ctc Thr Tyr Ser ThrLeu Thr ProGlyThr Rrg AlaTrp Arg Arg Leu Leu ctg gcc ccc gacggc ggc cccgagacc gat ggcggt 260 gac ggg cgg ggc Leu Ala Pro AspGly Gly ProGluThr Asp GlyGly Asp Gly Arg Gly gtgggtagc agcggcagcagc ggcggcgggggc tgcgagttcttc ttc 308 ValGlySer SerGlySerSer GlyGlyGlyGly CysGluPhePhe Phe gacaggcac ccgggcgtcttc gcctacgtgctc aactactaccgc acc 356 AspArgHis ProGlyValPhe AlaTyrValLeu AsnTyrTyrArg Thr ggcaagctg cactgccccgca gacgtgtgcggg ccgctcttcgag gag 404 GlyLysLeu HisCysProAla AspValCysGly ProLeuPheGlu Glu gagctggcc ttctggggcatc gacgagaccgac gtggagccctgc tgc 452 GluLeuAla PheTrpGlyIle AspGluThrAsp ValGluProCys Cys 105 110 lI5 tggatgacc taccggcagcac cgcgacgccgag gaggcgctggac atc 500 TrpMetThr TyrArgGlnHis ArgAspAlaGlu GluAlaLeuAsp Ile ttcgagacc cccgacctcatt ggcggcgacccc ggcgacgacgag gac 548 PheGluThr ProAspLeuIle GlyGlyAspPro GlyAspAspGlu Asp ctggcggcc aagaggctgggc atcgaggacgcg gcggggctcggg ggc 596 LeuAlaAla LysArgLeuGly IleGluAspAla AlaGlyLeuGly Gly cccgacggc aaatctggccgc tggaggaggctg cagccccgcatg tgg 644 ProAspGly LysSerGlyArg TrpArgArgLeu GlnProArgMet _ Trp gccctcttc gaagacccctac tcgtccagagcc gccaggtttatt get 692 AlaLeuPhe GluAspProTyr SerSerArgAla AlaArgPheIle Ala tttgettct ttattcttcatc ctggtttcaatt acaactttttgc ctg 740 PheAlaSer LeuPhePheIle LeuValSerIle ThrThrPheCys Leu gaaacacat gaagetttcaat attgttaaaaac aagacagaacca gtc 788 GluThrHis GluAlaPheAsn IleValLysAsn LysThrGluPro Val atcaatggc acaagtgttgtt ctacagtatgaa attgaaacggat cct 836 IleAsnGly ThrSerValVal LeuGlnTyrGlu IleGluThrAsp Pro gccttgacg tatgtagaagga gtgtgtgtggtg tggtttactttt gaa 884 AlaLeuThr TyrValGluGly ValCysValVal TrpPheThrPhe Glu tttttagtc cgtattgttttt tcacccaaraaa cttgaattcatc aaa 932 PheLeuVal ArgIleValPhe SerProAsnLys LeuGluPheIle Lys aatctcttg aatatcattgac tttgtggccatc ctacctttctac tta 980 AsnLeuLeu AsnIleIleAsp PheValAlaIle LeuProPheTyr Leu gaggtggga ctcagtgggctg tcatccaaaget getaaagatgtg ctt 1028 Glu VaI Gly Leu Ser Gly Leu Ser Ser Lys Ala Ala Lys Asp Val Leu ggcttcctcagg gtggtaagg tttgtgaggatcctg agaattttcaag 1076 GlyPheLeuArg ValValArg PheValArgIleLeu ArgIlePheLys ctcacccgccat tttgtaggt ctgagggtgcttgga catactcttcga 1124 LeuThrArgHis PheValGly LeuArgValLeuGly HisThrLeuArg getagtactaat gaatttttg ctgctgataattttc ctggetctagga 1172 AlaSerThrAsn GluPheLeu LeuLeuIleIlePhe LeuAlaLeuGly gttttgatattt getaccatg atctactatgccgag agagtgggaget 1220 ValLeuIlePhe AlaThrMet IleTyrTyrAlaGlu ArgValGlyAla caacctaacgac ccttcaget agtgagcacacacag ttcaaaaacatt 1268 GlnProAsnAsp ProSerAla SerGluHisThrGln PheLysAsnIle cccattgggttc tggtggget gtagtgaccatgact accctgggttat 1316 ProIleGlyPhe TrpTrpAla ValValThrMetThr ThrLeuGlyTyr ggggatatgtac ccccaaaca tggtcaggcatgctg gtgggagccctg 1364 GlyAspMetTyr ProGlnThr TrpSerGlyMetLeu ValGlyAlaLeu tgtgetctgget ggagtgctg acaatagccatgcca gtgcctgtcatt 1412 CysAlaLeuAla GlyValLeu ThrIleAlaMetPro ValProValIle gtcaataatttt ggaatgtac tactccttggcaatg gcaasgcagaaa 1460 ValAsnAanPhe GlyMetTyr TyrSerLeuAlaMet AlaLysGlnLys cttccaaggaaa agaaagaag cacatccctcctget cetcaggcaagc 1508 LeuProArgLys ArgLysLys HisIleProProAla ProGlnAlaSer tcacctactttt tgcaagaca gaattaaatatggcc tgcaatagtaca 1556 SerProThrPhe CysLysThr GluLeuAsnMetAla CysAsnSerThr cagagtgacaca tgtctgggc aaagacaatcgactt ctggaacataac 1604 GlnSerAspThr CysLeuGly LysAspAsnArgLeu LeuGluHisAsn agatcagtgtta tcaggtgac gacagtacaggaagt gagccgccacta 1652 ArgSerValLeu SerGlyAsp AspSerThrGlySer GluProProLeu tcacccccagaa aggctcccc atcagacgctctagt accagagacaaa 1700 SerProProGlu ArgLeuPro IleArgArgSerSer ThrArgAspLys aac aga aga ggg gaa aca tgt ttc cta ctg acg aca ggt gat tac acg 1748 Aan Arg Arg Gly Glu Thr Cys Phe Leu Leu Thr Thr Gly Asp Tyr Thr tgtgettct gatggagggatcagg aaaggatatgaa aaatcccgaagc 1796 CysAlaSer AspGlyGlyIleArg LysGlyTyrGlu LysSerArgSer ttaaacaac atagcgggcttggca ggcaatgetctg aggctctctcca 1844 LeuAsnAsn IleAlaGlyLeuAla GlyAsnAlaLeu ArgLeuSerPro gtaacatca ccctacaactctcct tgtcctctgagg cgctctcgatct 1892 ValThrSer ProTyrAsnSerPro CysProLeuArg ArgSerArgSer cccatccca tctatct accctcgtg 1927 tgtaaaccaa ProIlePro SerIle <210> 4 <211> 601 <212> PRT
<213> H. Sapiens <400> 4 Met Ala Lys Gly Glu Ala Ser Glu Lys Ile Ile Ile Asn Val Gly Gly Thr Arg His Glu Thr Tyr Arg Ser Thr Leu Arg Thr Leu Pro Gly Thr 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 Glu Phe Phe Phe Asp Arg His Pro Gly Val Phe Ala Tyr Val Leu Asn Tyr Tyr Arg Thr Gly Lys Leu His Cys Pro Ala Asp Val Cys Gly Pro Leu Phe Glu Glu Glu Leu Ala Phe Trp Gly Ile Asp Glu Thr Asp val Glu Pro Cys Cys Trp Met Thr Tyr Arg Gln His Arg Asp Ala Glu Glu Ala Leu Asp Ile Phe Glu Thr Pro Asp Leu Ile Gly Gly Asp Pro Gly Asp Asp Glu Asp Leu Ala Ala Lys Arg Leu Gly Ile Glu Asp Ala Ala Gly Leu Gly Gly Pro Asp Gly Lys Ser Gly Arg Txp Arg Arg Leu Gln Pro Arg Met Trp Ala Leu Phe Glu Asp Pro Tyr Ser Ser Arg Ala Ala Arg Phe Ile Ala Phe Ala Ser Leu Phe Phe Ile Leu Val Ser Ile Thr Thr Phe Cys Leu Glu Thr His Glu Ala Phe Asn Ile Val Lys Asn Lys Thr Glu Pro Val Ile Asn Gly Thr Ser Val Val Leu Gln Tyr Glu Ile Glu Thr Asp Pro Ala Leu Thr Tyr Val Glu Gly Val Cys Val Val Trp Phe Thr Phe Glu Phe Leu Val Arg Ile Val Phe Ser Pro Asn Lys Leu Glu Phe Ile Lys Asn Leu Leu Asn Ile Ile Asp Phe Val Ala Ile Leu Pro Phe Tyr Leu Glu Val Gly Leu Ser Gly Leu Ser Ser Lys Ala Ala 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 His Thr Leu Arg Ala Ser Thr Asn Glu Phe Leu Leu Leu Ile Ile Phe Leu Ala Leu Gly Val Leu Ile Phe Ala Thr Met Ile Tyr Tyr Ala Glu Arg Val Gly Ala Gln Pro Asn Asp Pro Ser Ala Ser Glu His Thr Gln Phe Lys Asn Ile Pro Ile Gly Phe Trp Trp Ala Val Val Thr Met Thr Thr Leu Gly Tyr Gly Asp Met Tyr Pro Gln Thr Trp Ser Gly Met Leu Val Gly Ala Leu Cys Ala Leu Ala Gly Val Leu Thr Ile Ala Met Pro Val Pro Val Ile Val Asn Asn Phe Gly Met Tyr Tyr Ser Leu Ala Met Ala Lys Gln Lys Leu Pro Arg Lys Arg Lys Lys His Ile Pro Pro Ala Pro Gln Ala Ser Ser Pro Thr Phe Cys Lys Thr Glu Leu Asn Met Ala Cys Asn Ser Thr Gln Ser Asp Thr Cys Leu Gly Lys Asp Asn Arg Leu Leu Glu His Asn Arg Ser Val Leu Ser Gly Asp Asp Ser Thr Gly Ser Glu Pro Pro Leu Ser Pro Pro Glu Arg Leu Pro Ile Arg Arg Ser Ser Thr Arg Asp Lys Asn Arg Arg Gly Glu Thr Cys Phe Leu Leu Thr Thr Gly Asp Tyr Thr Cys Ala Ser Asp Gly Gly Ile Arg Lys Gly Tyr Glu Lys Ser Arg Ser Leu Asn Asn Ile Ala Gly Leu Ala Gly Asn Ala Leu Arg Leu Ser Pro Val Thr Ser Pro Tyr Asn Ser Pro Cys Pro Leu Arg Arg Ser Arg Ser Pro Ile Pro Ser Ile <210> 5 <211> 2293 <212> DNA
<213> H. sapiens <220>
<221> CDS
<222> (330)...(1800) <223> K+Hnov6 <400>

gggaagagcgaacccagggcccttgctctcgtgcagcgctgcgccctgggtggggacggc60 gtgaggcttgcagcgcaggtgagagtgattttccagtgattgctttggcctgtacaacca120 gagaacaggattcttcccttctttttggccaccaaatgcctatgtgcaccacacattcca180 gtgtgctgagaagggcagagcttcttggatgatgatggacgtcccaccgggcaggatgaa240 ggcagagcgtgtggcatctccacctcaagggtgcagcctgatcttcctcttctcccttgc300 cagccagcactctgccttctgtatccacc ggt gag ttc cat 353 atg gtg ttt ttt Met Val Gly GIu Phe His Phe Phe cgccctggacaa gacgaggaacttgtc aacctgaatgtg gggggcttt 401 ArgProGlyGln AspGluGiuLeuVal AsnLeuAsnVal GlyGlyPhe aagcagtctgtt gaccaaagcaccctc ctgcggtttcct cacaccaga 449 LysGlnSerVal AspGlnSerThrLeu LeuArgPhePro HisThrArg ctggggaagctg cttacttgccattct gaagaggccatt ctggagctg 497 LeuGlyLysLeu LeuThrCysHisSer GluGluAlaIle LeuGluLeu tgtgatgattac agtgtggccgataag gaatactacttt gatcggaat 545 CysAspAspTyr SerValAlaAspLys GluTyrTyrPhe AspArgAsn ccctccttgttc agatatgttttgaat ttttattacacg gggaagctg 593 ProSerLeuPhe ArgTyrValLeuAsn PheTyrTyrThr GlyLysLeu catgtcatggag gagctgtgcgtattc tcattctgccag gagatcgag 691 HisValMetGlu GluLeuCysValPhe SerPheCysGln GluIleGlu tactggggcatc aacgagctcttcatt gattcttgctgc agcaatcgc 689 TyrTrpGlyIle AsnGluLeuPheIle AspSerCysCys SerAsnArg taccaggaacgc aaggaggaaaaccac gagaaggactgg gaccagaaa 737 TyrGlnGluArg LysGluGluAsnHis GluLysAspTrp AspGlnLys agccatgatgtg agtaccgactcctcg tttgaagagtcg tctctgttt 785 SerHisAspVal SerThrAspSerSer PheGluGluSer SerLeuPhe gagaaagagctg gagaagtttgacaca ctgcgatttggt cagctccgg 833 GluLysGluLeu GluLysPheAspThr LeuArgPheGly GlnLeuArg aagaaaatctgg attagaatggagaat ccagcgtactgc ctgtccget 881 LysLysIleTrp IleArgMetGluAsn ProAlaTyrCys LeuSerAla aagcttatcget atctcctccttgagc gtggtgctggcc tccatcgtg 929 LysLeuIleAla IleSerSerLeuSer ValValLeuAla SerIleVal gccatgtgcgtt cacagcatgtcggag ttccagaatgag gatggagaa 977 AlaMetCysVal HisSerMetSerGlu PheGlnAsnGiu AspGlyGlu gtggatgatccg gtgctggaaggagtg gagatcgcgtgc attgcctgg 1025 ValAspAspPro ValLeuGluGlyVal GluIleAlaCys IleAlaTrp ttcaccggggag cttgccgtccggctg getgccgetcct tgtcaaaag 1073 PheThrGlyGlu LeuAlaValArgLeu AlaAlaAlaPro CysGlnLys aaattctggaaa aaccctctgaacatc attgactttgtc tctattatt 1121 Lys Phe Trp Lys Asn Pro Leu Asn Ile Ile Asp Phe Val Ser Ile Ile cccttctatgccacg ttggetgtagacacc aaggaggaagag agtgag 1169 ProPheTyrAlaThr LeuAlaValAspThr LysGluGluGlu SerGlu gatattgagaacatg ggcaaggtggtccag atcctacggctt atgagg 1217 AspIleGluAsnMet GlyLysValValGln IleLeuArgLeu MetArg attttccgaattcta aagcttgcccggcac tcggtaggactt cggtct 1265 IlePheArgIleLeu LysLeuAlaArgHis SerValGlyLeu ArgSer ctaggtgccacactg agacacagctaccat gaagttgggctt ctgctt 1313 LeuGlyAlaThrLeu ArgHisSerTyrHis GluValGlyLeu LeuLeu ctcttcctctctgtg ggcatttccattttc tctgtgcttatc tactcc 1361 LeuPheLeuSerVal GlyIleSerIlePhe SerValLeuIle TyrSer gtggagaaagatgac cacacatccagcctc accagcatcccc atctgc 1409 ValGluLyaAspAsp HisThrSerSerLeu ThrSerIlePro IleCys tggtggtgggccacc atcagcatgacaact gtgggctatgga gacacc 1457 TrpTrpTrpAlaThr IleSerMetThrThr ValGlyTyrGly AspThr cacccggtcaccttg gcgggaaagctcatc gccagcacatgc atcatc 1505 HisProValThrLeu AlaGlyLysLeuIle AlaSerThrCys IleIle tgtggcatcttggtg gtggcccttcccatc accatcatcttc aacaag 1553 CysGlyIleLeuVal ValAlaLeuProIle ThrIleIlePhe AsnLys ttttccaagtactac cagaagcaaaaggac attgatgtggac cagtgc 1601 PheSerLysTyrTyr GlnLysGlnLysAsp IleAspValAsp GlnCys agtgaggatgcacca gagaagtgtcatgag ctaccttacttt aacatt 1649 SerGluAspAlaPro GluLysCysHisGlu LeuProTyrPhe AsnIle agggatatatatgca cagcggatgcacgcc ttcattaccagt ctctct 1697 ArgAspIleTyrAla GlnArgMetHisAla PheIleThrSer LeuSer tctgtaggcattgtg gtgagcgatcctgac tccacagatget tcaagc 1745 SerValGlyIleVal ValSerAspProAsp SerThrAspAla SerSer attgaagacaatgag gacatttgtaacacc acctccttggag aattgc 1793 IleGluAspAsnGlu AspIleCysAsnThr ThrSerLeuGlu AsnCys acagcaa cctgtttctc 1850 aatgagcggg ttatcctttc ggtgtttgtg ccaacattag ThrAla gttaacacagctttataaacctcagtgggttcgttaaaatcatttaattctcagggtgta1910 cctttcagccatagttggacattcattgctgaattctgaaatgatagaattgtctttatt1970 tttctctgtgaggtcaattaaatgccttgttctgaaatttattttttacaagagagagtt2030 gtgatagagtttggaatataagataaatggtattgggtggggtttgtggctacagcttat2090 gcatcattctgtgtttgtcatttactcacattgagctaactttaaattactgacaagtag2150 aatcaaaggtgcagctgactgagacgacatgcatgtaagatccacaaaatgagacaatgc2210 atgtaaatccatgctcatgttctaaacatggaaactaggagcctaataaacttcctaatt2270 cagaaaaaaaaaaaaaaaaaaaa 2293 <210> 6 <211> 490 <212> PRT
<213> H. sapiens <400> 6 Met Val Phe Gly Glu Phe Phe His Arg Pro Gly Gln Asp Glu Glu Leu Val Asn Leu Asn Val Gly Gly Phe Lys Gln Ser Val Asp Gln Ser Thr Leu Leu Arg Phe Pro His Thr Arg Leu Gly Lys Leu Leu Thr Cys His Ser Glu Glu Ala Ile Leu Glu Leu Cys Asp Asp Tyr Ser Val Ala Asp Lys Glu Tyr Tyr Phe Asp Arg Asn Pro Ser Leu Phe Arg Tyr Val Leu Asn Phe Tyr Tyr Thr Gly Lys Leu His Val Met Glu Glu Leu Cys Val 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 His Glu Lys Asp Trp Asp Gln Lys Ser His Asp Val Ser Thr Asp Ser Ser Phe Glu Glu Ser Ser Leu Phe Glu Lys Glu Leu Glu Lys Phe Asp Thr Leu Arg Phe Gly Gln Leu Arg Lys Lys Ile Trp Ile Arg Met Glu Asn Pro Ala Tyr Cys Leu Ser Ala Lys Leu Ile Ala Ile Ser Ser Leu Ser Val Val Leu Ala Ser Ile Val Ala Met Cys VaI His Ser Met Ser Glu Phe Gln Asn Glu Asp Gly Glu Val Asp Asp Pro Val Leu Glu Gly Val Glu Ile Ala Cys Ile Ala Trp Phe Thr Gly Glu Leu Ala Val Arg Leu Ala AIa Ala Pro Cys Gln Lys Lys Phe Trp Lys Asn Pro Leu Asn Ile Ile Asp Phe val Ser Ile Ile Pro Phe Tyr Ala Thr Leu Ala Val Asp Thr Lys Glu Glu Glu Ser Glu Asp Ile Glu Asn Met Gly Lys Val Val Gln Ile Leu Arg Leu Met Arg Ile Phe Arg Ile Leu Lys Leu Ala Arg His Ser Val Gly Leu Arg Ser Leu Gly Ala Thr Leu Arg His Ser Tyr His Glu Val Gly Leu Leu Leu Leu Phe Leu Ser Val Gly Ile Ser Ile Phe Ser Val Leu Ile Tyr Ser Val Glu Lys Asp Asp His Thr Ser Ser Leu Thr Ser Ile Pro Ile Cys Trp Trp Trp Ala Thr Ile Ser Met Thr Thr Val Gly Tyr Gly Aap Thr His Pro Val Thr Leu Ala Gly Lys Leu Ile Ala Ser Thr Cys Ile Ile Cys Gly Ile Leu Val Val Ala Leu Pro Ile Thr Ile Ile Phe Asn Lys Phe Ser Lys Tyr Tyr Gln Lys Gln Lys Asp Ile Asp Val Asp Gln Cys Ser Glu Asp Ala Pro Glu Lys Cys His Glu Leu Pro Tyr Phe Asn Ile Arg Asp Ile Tyr Ala Gln Arg Met His Ala Phe Ile Thr Ser Leu Ser Ser Val Gly Ile Val Val Ser Asp 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 <210> 7 <211> 3080 <212> DNA
<213> H. sapiens <220>
<221> CDS
<222> (480)...(1977) <223> K+Hnov9 <400> 7 gtctctcctcttcctcctcc tccgccccac atctccctccttcctcccttccccaacccc60 tccacccaccaagtagcgag tcattcaatc tgtacacctcctgggctgggaatcgcaatt120 gcgaagttgggaggcggggt gacaacgttt gggaagggccagggcgaccggcagtgtgca180 cagggactgtgtcgggcttg gacctcacct gatcctctctcttagcgcgacccttcctct240 gctccctgtctectctttct gccacttgtg cgctgcttccgcgcactcccggctccctag300 cggcaggaggaggaaggcgc acagcgggtg gagagggtgcgccaaggagaggtaacccct360 tcgggagcccggggaatccc ggccgccacc aggggccgtgccaccgccctcgcgggacca420 aagcttccggcgtgtcccca actttgtggc gccctcaggccgcggcgactgggttagag 479 atg cct agc ggc aga gcg ctg ctg ccg ctg agc ggc 527 tcc gac tcg gac Met Pro Ser Gly Arg Ala Leu Leu Pro Leu Ser Gly Ser Asp Ser Asp tcc ctg tcc ctg gac tct agt gtc agc gag gaa ggg 575 acc ttc tgc ggt Ser Leu Ser Leu Asp Ser Ser Val Ser Glu Glu Gly Thr Phe Cys Gly gag ccc gcg ctc ggg gac tgc ttc aac gtg ggc agc 623 ttg acg gtc ggc Glu Pro Ala Leu Gly Asp Cys Phe Asn Val Gly Ser Leu Thr Val Gly cgc ttc ctc tcg cag cag gcg ctg ttc ccg acg cgc 671 gtg tcc tgc cac Arg Phe Leu Ser Gln Gln Ala Leu Phe Pro Thr Arg Val Ser Cys His ctt ggc ctg gcc gtg gtg gtg get cgc cgc ggg gcc 719 aag tcc tac ccc Leu Gly Leu Ala Val Val Val Ala Arg Arg Gly Ala Lys Ser Tyr pro ctg gcc gtg ccc agc cct ctg gag gac gat aac ccc 767 gcc ctt tgc gcc Leu Ala Val Pro Ser Pro Leu Glu Asp Asp Asn Pro Ala Leu Cys Ala WO 99/43b9b PCT/US99/03826 gtggacaacgagtac ttcttcgaccgc agctcgcaggcg ttccgatat 815 ValAspAsnGluTyr PhePheAspArg 5erSerGlnAla PheArgTyr gtcctgcactactac cgcaccggccgc ctgcatgtcatg gagcagctg 863 ValLeuHisTyrTyr ArgThrGlyArg LeuHisValMet GluGlnLeu tgcgcgctctccttc ctgcaggagatc cagtactggggc atcgatgag 911 CyaAlaLeuSerPhe LeuGlnGluIle GlnTyrTrpGly IleAspGlu ctcagcatcgattcc tgctgcagggac agatacttcaga aggaaagag 959 LeuSerIIeAspSer CysCysArgAsp ArgTyrPheArg ArgLysGlu ctgagtgaaacttta gacttcaagaag gacacagaagac caggaaagt 1007 LeuSerGluThrLeu AspPheLysLys AspThrGluAsp GlnGluSer caacatgagagtgaa caggacttctcc caaggaccttgt cccactgtt 1055 GlnHisGluSerGlu GlnAsgPheSer GlnGlyProCys ProThrVal cgccagaagctctgg aatatcctggag aaacctggatct tccacaget 1103 ArgGlnLysLeuTrp AsnIleLeuGlu LysProGlySer SerThrAla gcccgtatctttggc gtcatctccatt atcttcgtggtg gtgtccatc 1151 AlaArgIlePheGly ValIleSerIle IlePheValVal ValSerIle attaacatggccctg atgtcagetgag ttaagctggctg gacctgcag 1199 IleAsnMetAlaLeu MetSerAlaGlu LeuSerTrpLeu AspLeuGln ctgctggaaatcctg gagtatgtgtgc attagctggttc accggggag 1247 LeuLeuGluIleLeu GluTyrValCys IleSerTrpPhe ThrGlyGlu tttgtcctccgcttc ctgtgtgtgcgg gacaggtgtcgc ttcctaaga 1295 PheVa1LeuArgPhe LeuCysValArg AspArgCysArg PheLeuArg aaggtgccaaacatc atagacctcctt gccatcttgccc ttctacatc 1343 LysValProAsnIle IleAspLeuLeu AlaIleLeuPro PheTyrIle actcttctggtagag agcctaagtggg agccagaccacg caggagctg 1391 ThrLeuLeuValGlu SerLeuSerGly SerGlnThrThr GlnGluLeu gagaacgtggggcgc attgtccaggtg ttgaggctgctc agggetctg 1439 GluAsnValGlyArg IleValGlnVal LeuArgLeuLeu ArgAlaLeu cgcatgctaaagctg ggcagacattcc acaggattacgc tcccttggg 1487 ArgMetLeuLysLeu GlyArgHiaSer ThrGlyLeuArg SerLeuGly atgacaatc acccagtgttac gaagaagtcggc ctactgctcctattt 1535 MetThrIle ThrGlnCysTyr GluGluValGly LeuLeuLeuLeuPhe ctatccgtg ggaatctctata ttttcaactgta gaatactttgetgag 1583 LeuSerVal GlyIleSerIle PheSerThrVal GluTyrPheAlaGlu caaagcatt cctgacacaacc ttcacaagtgtc ccttgtgcatggtgg 1631 GlnSerIle ProAspThrThr PheThrSerVal ProCysAlaTrpTrp tgggccacc acctctatgact actgtgggatat ggggacattagacca 1679 TrpAlaThr ThrSerMetThr ThrValGlyTyr GlyAspIleArgPro gacaccacc acaggcaaaatc gtggccttcatg tgtatattatcggga 1727 AspThrThr ThrGlyLysIle ValAlaPheMet CysIleLeuSerGly attcttgtc ttggccttgcct attgetattatt aacgatcgcttctct 1775 IleLeuVal LeuAlaLeuPro IleAlaIleIle AsnAspArgPheSer gettgctac ttcaccttgaaa ctcaaggaagca getgttagacagcgt 1823 AlaCysTyr PheThrLeuLys LeuLysGluAla AlaValArgGlnArg gaagcccta aagaagcttacc aagaatatagcc actgactcatatatc 1871 GluAlaLeu LysLysLeuThr LysAsnIleAla ThrAspSerTyrIle agtgttaac ttgagagatgtc tatgcccggagt atcatggagatgctg 1919 SerValAsn LeuArgAspVal TyrAlaArgSer IleMetGluMetLeu cgactgaaa ggcagagaaaga gcaagtactagg agcagcgggggagat 1967 ArgLeuLys GlyArgGluArg AlaSerThrArg SerSerGlyGlyAsp gat ttc tgg t tttgaattaa ttttcaattt atttacaaaa gctatgtaca 2017 Asp Phe Trp attaactaaaatgataaagcagtgatgtggatttctgtattctgatgatgagtctcttca2077 gagtactgctcatcttaattaatttttgctgatatattgcttcatctactagaatatttc2137 acatcacctataacaactgcacagtgttctgacacatttgagtgtccaaaatagccaatt2197 aacacaaccaaatacaactgggccaatataaacatgtttgaattgtcaaatataaaataa2257 tgttattgcaatacatacaaaaaagttaaagattttatgtatcactaacattagaagttt2317 tttgcaccactaattttttaaaaatggaaggtaaactgcatagcccagagaaagataagt2377 aaatatttaagaacatattgaacaactttgctatttaaagatattatccaagtacataaa2437 ttactccgttctctatcagttaaagctattgaatataatacttagctttacaagagaaaa2497 cccatatttgatgggcagagattatatccctatcttctttttcatgtaaaccactggtca2557 caaatgaactgatctctgtatcccattattactataagaggtgggaatcccaaaactgct2617 tagattgcagtacatgagtctacacaaagacttcaacaattgcacatcttcattctccca2677 actgagtgtagtatgtggagcataaaacagcatatttcttagtatttcatgaatatcaga2737 tggtctttaaatgtctctttatggatgtattgttcacattatggctttaaaataatgaat2797 atgtaaaagtgaggtagtgaacatcctaaatttctacactggaattactaaataatctta2857 tttcataaatgggaaatatatgttaaatgacatcactggatgaacttgaagatcttttac2917 ttgttaacaaaaaaatactatggacagctttctgattgttggggtaaatagcaaatgttc2977 aaactttgcaggcattttgacattcatcataacaacacaattcctagacattgtattata3037 taattaaagc caaaacctct aaagctaaaa aaaaaaaaaa aaa 3080 <210> 8 <211> 499 <212> PRT
<213> H. Sapiens <400> 8 Met Pro Ser Ser Gly Arg Ala Leu Leu Aap Ser Pro Leu Asp Ser Gly Ser Leu Thr Ser Leu Asp Ser Ser Val Phe Cys Ser Glu Gly Glu Gly Glu Pro Leu Ala Leu Gly Asp Cys Phe Thr Val Asn Val Gly Gly Ser Arg Phe Val .Leu Ser Gln Gln Ala Leu Ser Cys Phe Pro His Thr Arg Leu Gly Lys Leu Ala Val Val Val Ala Ser Tyr Arg Arg Pro Gly Ala Leu Ala Ala Val Pro Ser Pro Leu Glu Leu Cys Asp Asp Ala Asn Pro Val Asp Asn Glu Tyr Phe Phe Asp Arg Ser Ser Gln Ala Phe Arg Tyr Val Leu His Tyr Tyr Arg Thr Gly Arg Leu His Val Met Glu Gln Leu Cys Ala Leu Ser Phe Leu Gln Glu Ile Gln Tyr Trp Gly Ile Asp Glu Leu Ser Ile Asp Ser Cys Cys Arg Asp Arg Tyr phe Arg Arg Lys Glu Leu Ser Glu Thr Leu Asp Phe Lys Lys Asp Thr Glu Asp Gln Glu Ser Gl_n His Glu Ser Glu Gln Asp Phe Ser Gln Gly Pro Cys Pro Thr Val Arg Gln Lys Leu Trp Asn Ile Leu Glu Lya Pro Gly Ser Ser Thr Ala Ala Arg Ile Phe Gly Val Ile Ser Ile Ile Phe Val Val Val Ser Ile Ile Asn Met Ala Leu Met Ser Ala Glu Leu Ser Trp Leu Asp Leu Gln Leu Leu Glu Ile Leu Glu Tyr Val Cys Ile Ser Trp Phe Thr Gly Glu Phe Val Leu Arg Phe Leu Cys Val Arg Asp Arg Cys Arg Phe Leu Arg Lys Val Pro Asn Ile Ile Asp Leu Leu Ala Ile Leu Pro Phe Tyr Ile Thr Leu Leu Val Glu Ser Leu Ser Gly Ser Gln Thr Thr Gln Glu Leu Glu Asn Val Gly Arg Ile Val Gln Val Leu Arg Leu Leu Arg Ala Leu Arg Met Leu Lys Leu Gly Arg His Ser Thr Gly Leu Arg Ser Leu Gly Met Thr Ile Thr Gln Cys Tyr Glu Glu Val Gly Leu Leu Leu Leu Phe Leu Ser Val Gly Ile Ser Ile Phe Ser Thr Val Glu Tyr Phe Ala Glu Gln Ser Ile Pro Asp Thr Thr Phe Thr Ser Val Pro Cys Ala Trp Trp Trp Ala Thr Thr Ser Met Thr Thr Val Gly Tyr Gly Asp Ile Arg Pro Asp Thr Thr Thr Gly Lys Ile Val Ala Phe Met Cys Ile Leu Ser Gly Ile Leu Val Leu Ala Leu Pro Ile Ala Ile Ile Asn Asp Arg Phe Ser Ala Cys Tyr Phe Thr Leu Lys Leu Lys Glu Ala Ala Val Arg Gln Arg Glu Ala Leu Lys Lys Leu Thr Lys Asn Ile Ala Thr Asp Ser Tyr Ile Ser Val Asn Leu Arg Asp Val Tyr Ala Arg Ser Ile Met Glu Met Leu Arg Leu Lys Gly Arg Glu Arg Ala Ser Thr Arg Ser Ser Gly Gly Asp Asp Phe Trp <210> 9 <211> 3424 <212> DNA
<213> H. sapiens <220>
<221> CDS
<222> (257)...(2195) <223> K+Hnovl2 <400> 9 ctcttctcca tgtcccca ag gcccttctca acattgcccaggcccctcct 60 gtccctcaga aggttctgta aatgtccc cc agactccttc agttcttcctcctggttcct ccatctcttt cttggcctct ctagacac cc ccagtttcct gctcaaggtgtctccaagcc tgtttgggtg cccaccatcc tggagacagc cctcactaagtctccctggg 240 cacattctcc taaacgccac cttggggagt ggcacg tg gcg ct ~
a gca ttt 292 ggc get ctg gcc acg tgg ctg c Met ro Ala Phe Ala Ala Gly Leu Ala Thr Trp Leu P

cgg gcagca gtgggc ctgccc ccg cag caa ctg ccc 340 gca tgg gcc ccc Arg AlaAla ValGly LeuPro Pro Gln Gln Leu Pro Ala Trp Ala Pro ccg ccgggg gtgaag tctcga gga grg gtt gtg gtg 388 gca gca gat ctg Pro ProGly ValLys SerArg Gly Xaa Val Val Val Ala Ala Asp Leu aac agcgga cggcgc gagact tgg aat acg gac cgc 436 gtg ttt aag ctg Asn SerGly ArgArg GluThr Trp Asn Thr Asp Arg Val Phe Lys Leu tac gacacc ttgctg agctcg gag gaa ttc tac gat 484 cca ggc aag ttc Tyr AspThr LeuLeu SerSer Glu Glu Phe Tyr Asp Pro Gly Lys Phe get tcaggc gagtac ttcgat cgc cct gac ttc cgc 532 gac ttc gac atg Ala SerGly GluTyr PheAsp Arg Pro Asp Phe Arg Asp Phe Asp Met BO 85 gp cat ctgaac ttctac acgggg cgg cat tgc cgg cag 580 gtg cga ctg cca His LeuAsn PheTyr ThrGly Arg His Cys Arg Gln Val Arg Leu Pro gag atccag gccttc gaagag ctg ttc tac ctg gtt 628 tgc gac get ggc Glu IleGln AlaPhe GluGlu Leu Phe Tyr Leu Val Cys Asp Ala Gly ccc ctagtc ggtgac tgcctt gaa tat cgg cga aag 676 gag tgc gag gac Pro LeuVal GlyAsp CysLeu Glu Tyr Arg Arg Lys Glu Cys Glu Asp aaggagaat gccgagcgcctg gcagaggatgaggag gcagagcaggcc 724 LysGluAsn AlaGluArgLeu AlaGluAspGluGlu AlaGluGlnAla ggggacggc ccagccctgcca gcaggcagctccctg cggcagcgg~ctc 772 GlyAspGly ProAlaLeuPro AlaGlySerSerLeu ArgGlnArgLeu tggcgggcc ttcgagaatcca cacacgagcaccgca gccctcgttttc 820 TrpArgAla PheGluAsnPro HisThrSerThrAla AlaLeuValPhe tactatgtg accggcttcttc atcgccgtgtcggtc atcgccaatgtg 868 TyrTyrVal ThrGlyPhePhe IleAlaValSerVal IleAlaAsnVal gtggagacc atcccatgccgc ggctctgcacgcagg tcctcaagggag 916 ValGluThr IleProCysArg GlySerAlaArgArg SerSerArgGlu 205 2i0 215 220 cagccctgt ggcgaacgcttc ccacaggcctttttc tgcatggacaca 964 GlnProCys GlyGluArgPhe ProGlnAlaPhePhe CysMetAspThr gcctgtgta ctcatattcaca ggtgaatacctcctg cggctgtttgcc 1012 AlaCysVal LeuIlePheThr GlyGluTyrLeuLeu ArgLeuPheAla gcccccagc cgttgccgcttc ctgcggagtgtcatg agcctcatcgac 1060 AlaProSer ArgCysArgPhe LeuArgSerValMet SerLeuIleAsp gtggtggcc atcctgccctac tacattgggcttttg gtgcccaagaac 1108 ValValAla IleLeuProTyr TyrIleGlyLeuLeu ValProLysAsn gacgatgtc tctggcgccttt gtcaccctgcgtgtg ttccgggtgttt 1156 AspAspVal SerGlyAlaPhe ValThrLeuArgVal PheArgValPhe cgcatcttc aagttctccagg cactcacagggcttg aggattctgggc 1204 ArgIlePhe LysPheSerArg HieSerGlnGlyLeu ArgIleLeuGly tacacactc aagagctgtgcc tctgagctgggcttt ctcctcttttcc 1252 TyrThrLeu LysSerCysAla SerGluLeuGlyPhe LeuLeuPheSer ctaaccatg gccatcatcatc tttgccactgtcatg ttttatgetgag 1300 LeuThrMet AlaIleIleIle PheAlaThrValMet PheTyrAlaGlu aagggcaca aacaagaccaac tttacaagcatccct gcggccttctgg 1348 LysGlyThr AsnLysThrAsn PheThrSerIlePro AlaAlaPheTrp tataccatt gtcaccatgacc acgcttggctacgga gacatggtgccc 1396 TyrThrIle ValThrMetThr ThrLeuGlyTyrGly AspMetValPro agcaccattgetggc aagattttcggg tccatctgctcactc agtggc 1444 SerThrIleAlaGly LysIlePheGly SerIleCysSerLeu SerGly gtcttggtcattgcc ctgcctgtgcca gtcattgtgtccaac tttagc 1492 ValLeuValIleAla LeuProValPro ValIleValSerAsn PheSer cgcatctaccaccag aaccagcggget gacaagcgccgagca cagcag 1540 ArgIleTyrHisGln AsnGlnArgAla AspLysArgArgAla GlnGln aaggtgcgcttggca aggatccgattg gcaaagagtggtacc accaat 1588 LysValArgLeuAla ArgIleArgLeu AlaLysSerGlyThr ThrAsn gccttcctgcagtac aagcagaatggg ggccttgaggacagc ggcagt 1636 AlaPheLeuGlnTyr LysGlnAsnGly GlyLeuGluAspSer GlySer ggcgaggaacagget ctttgtgtcagg aaccgttctgccttt gaacag 1684 GlyGluGluGlnAla LeuCysValArg AsnArgSerAlaPhe GluGln caacatcaccacttg ctgcactgtcta gagaagacaacgtgc catgag 1732 GlnHisHisHisLeu LeuHisCysLeu GluLysThrThrCys HisGlu ttcacagatgagctc accttcagtgaa gccctgggagccgtc tcgccg 1780 PheThrAspGluLeu ThrPheSerGlu AlaLeuGlyAlaVal SerPro ggtggccgcaccagc cgtagcacctct gtgtcttcccagcca gtggga 1828 GlyGlyArgThrSer ArgSerThrSer ValSerSerGlnPro ValGly cccggaagcctgctg tcttcttgctgc cctcgcagggccaag cgccgc 1876 ProGlySerLeuLeu SerSerCysCys ProArgArgAlaLys ArgArg gccatccgccttgcc aactccactgcc tcagtcagccgtggc agcatg 1924 AlaIleArgLeuAla AsnSerThrAla SerValSerArgGly SerMet caggagctggacatg ctggcagggctg cgcaggagccatgcc cctcag 1972 GlnGluLeuAspMet LeuAlaGlyLeu ArgArgSerHisAla ProGln agccgctccagcctc aatgccaagccc catgacagccttgac ctgaac 2020 SerArgSerSerLeu AsnAlaLysPro HisAspSerLeuAsp LeuAsn tgcgacagccgggac ttcgtggetgcc attatcagcatccct acccct 2068 CysAspSerArgAsp PheValAlaAla IleIleSerIlePro ThrPro cctgccaacacccca gatgagagccaa ccttcctcccctggc ggcggt 2116 ProAlaAsnThrPro AspGluSerGln ProSerSerProGly GlyGly WO 99/4369b PCTNS99I03826 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 ctc ttc ccc gag act gtc aag atc tca tcc c tgtgaggggt aggcctgctg 2215 Leu Phe Pro Glu Thr Val Lys Ile Ser Ser attcagagggtcctcttcatttttgggaactcctttccaaagccatatttttgggaggca2275 gagaggggcaggcttgggcaccccttctgccccccccactgagaactatgcaatggagtt2335 tcatgaaatggtccacatagtggggaagtagccaggaaatgagaaacttcctcccacccc2395 agacatttttcctggtgggagctgaagcactgggcttccacaggcccctggcctccttgc2455 cctagcacactgggactggccccactctcccagctggactcctgcatgctcctccccttg2515 ggctctcagatgaaggcaaagctttgatccgacatctgagctctagcctaagaaggagag2575 ttgagatttcctcctccctctggctgggatatggagctttggaggttcagagaagagaac2635 cctcacctctgatctggcctctacgagaggtcctcatctccatctggcccaacaattccc2695 agattctgaagcttggaatgcaaacacaggcttcatgggctgtggcctctgcagcgacct2755 gccatccccaggccttgcctgaggggtcaggctgcctctcccaacacacactcagatagc2815 acaaattctaccatccccttccctggctgctggaaatggaccccgcaaccctgtcctctg2875 ctgggcccccagcaaactctagcaatagcagctgctgccgtgtcattatgcaaagcctct2935 gaccagtttgctgcagcatttacatctgccctaatcagaggggccacctctaactcctcc2995 tcctcctctcttctcctctggtttgcgtccttcctgggttgggctggagtctggactggc3055 tgagataagagcctggcaaccagcaagagctgggctgtatttggagatcatgggctgatt3115 ccatgttcttgggcaacagtccagaagcatcaggggctccggcctgggatgtttctgaac3175 tttgggagttataggagacaggaggaacttctcctcctcctcctcccctacaattccttt3235 tcacatattcctttcttctccctcttgggtgaccttccaaaactctgctctcaggctgaa3295 atctggcatcatctcaggttccctgtccccagcactgtccccatggagctggtggctgac3355 aaagatgtagtttccatcagtcaataaaacctgagaggagagatgaggaaaaaaaaaaaa3415 aaaaaaaaa 3424 <210> 10 <211> 646 <212> PRT
<213> H. sapiens <220>
<221> VARIANT
<222> (1)...(646) <223> Xaa = Any Amino Acid <400> 10 Met Ala Ala Gly Leu Ala Thr Trp Leu Pro Phe Ala Arg Ala Ala Ala Val Gly Trp Leu Pro Pro Ala Gln Gln Pro Leu Pro Pro Ala Pro Gly Val Lys Ala Ser Arg Gly Aap Xaa Val Leu Val Val Asn Val Ser Gly Arg Arg Phe Glu Thr Trp Lys Asn Thr Leu Asp Arg Tyr Pro Asp Thr Leu Leu Gly Ser Ser Glu Lys Glu Phe Phe Tyr Asp Ala Asp Ser Gly Glu Tyr Phe Phe Asp Arg Asp Pro Asp Met Phe Arg His Val Leu Asn Phe Tyr Arg Thr Gly Arg Leu His Cya Pro Arg Gln Glu Cys Ile Gln Ala Phe Asp Glu Glu Leu Ala Phe Tyr Gly Leu Val Pro GIu Leu Val Gly Asp Cys Cys Leu Glu Glu Tyr Arg Asp Arg Lys Lys Glu Asn Ala Glu Arg Leu Ala Glu Asp Glu Glu Ala Glu Gln Ala Gly Asp Gly Pro Ala Leu Pro Ala Gly Ser Ser Leu Arg Gln Arg Leu Trp Arg Ala Phe Glu Asn Pro His Thr Ser Thr Ala Ala Leu Val Phe Tyr Tyr Val Thr Gly Phe Phe Ile Ala Val Ser Val Ile Ala Asn Val Val Glu Thr Ile Pro Cys Arg Gly Ser Ala Arg Arg Ser Ser Arg Glu Gln Pro Cys Gly Glu Arg Phe Pro Gln Ala Phe Phe Cys Met Asp Thr Ala Cys Val Leu Ile Phe Thr Gly Glu Tyr Leu Leu Arg Leu Phe Ala Ala Pro Ser Arg Cys Arg Phe Leu Arg Ser Val Met Ser Leu Ile Asp Val Val Ala Ile Leu Pro Tyr Tyr Ile Gly Leu Leu Val Pro Lys Asn Asp Asp Val Ser Gly Ala Phe Val Thr Leu Arg Val Phe Arg Val Phe Arg Ile Phe Lys Phe Ser Arg His Ser Gln Gly Leu Arg Ile Leu Gly Tyr Thr Leu Lys Ser Cys Ala Ser Glu Leu Gly Phe Leu Leu Phe Ser Leu Thr Met Ala Ile Ile Ile Phe Ala Thr Val Met Phe Tyr Ala Glu Lys Gly Thr Asn Lys Thr Asn Phe Thr Ser Ile Pro Ala Ala Phe Trp Tyr Thr Ile Val Thr Met Thr Thr Leu Gly Tyr Gly Asp Met Val Pro Ser Thr Ile Ala Gly Lys Ile Phe Gly Ser Ile Cys Ser Leu Ser Gly Val Leu Val Ile Ala Leu Pro Val Pro Val Ile Val Ser Asn Phe Ser Arg Ile Tyr His Gln Asn Gln Arg Ala Asp Lys Arg Arg Ala Gln Gln Lys Val Arg Leu Ala Arg Ile Arg Leu Ala Lys Ser Gly Thr Thr Asn Ala Phe Leu Gln Tyr Lys Gln Asn Gly Gly Leu Glu Asp Ser Gly Ser Gly Glu Glu Gln Ala Leu Cys Val Arg Asn Arg Ser Ala Phe Glu Gln Gln His His His Leu Leu His Cys Leu Glu Lys Thr Thr Cys His Glu Phe Thr Asp Glu Leu Thr Phe Ser Glu Ala Leu Gly Ala Val Ser Pro Gly Gly Arg Thr Ser Arg Ser Thr Ser Val Sex Ser Gln Pro Val Gly Pro Gly Sex Leu Leu Ser Ser Cys Cys Pro Arg Arg Ala Lys Arg Arg Ala Ile Arg Leu Ala Asn Ser Thr Ala Ser Val Ser Arg Gly Ser Met Gln Glu Leu Asp Met Leu Ala Gly Leu Arg Arg Ser His Ala Pro Gln Ser Arg Ser Ser Leu Asn Ala Lys Pro His Asp Ser Leu Asp Leu Asn Cys Asp Ser Arg Asp Phe Val Ala Ala Ile Ile Ser Ile Pro Thr Pro Pro Ala Asn Thr Pro Asp Glu Ser Gln Pro Ser Ser Pro Gly Gly Gly Gly Arg Ala Gly Ser Thr Leu Arg Asn Ser Ser Leu Gly Thr Pro Cys Leu Phe Pro Glu Thr Val Lys Ile Ser Ser <210> 11 <211> 1862 <212> DNA
<213> H. sapiens <220>
<221> CDS
<222> (383)...(1157) <223> K+HnovlS
<400> 11 cagctgaatgtggaggcctttaagagaact tccagctcctgtaaaaacccagaccagagg60 actactgaccaacatttcaggctgatcctc cagacctcgaagttactctccttactctcc120 tgactcttaattacatcacacctgtgtcga cactctctgggaaaagactgaagaaataat180 cttttcaagaagcagaaagctcctgcatac ataggctgatacgccacctactgcaaaacc240 gagctgacagcgcaggcgatgctgccagcg tttccattccatcaccaggctggggctgaa300 taaaggcgtgcttgtgtggtagtgtctctt tttaaaaaatctcaaagccaagaagaacaa360 gctgaaatagcatcttcaaaas atg gag cgt a gaa aaa 412 aaa ata aac aga ag Met Glu Arg Lys Ile Asn Arg Arg Glu Lys gaa aag tat gaa gaa gat gat caa 460 gag ggg act aaa cac aac agc ctg Glu Lys Tyr Glu Glu Asp Asp Gln Glu Gly Thr Lys His Asn Ser Leu gga aag tgc aaa aac gtt gga tat 508 aac tcc ggt aca ctg atg acc ctc Gly Lys Cys Lys Asn Val Gly Tyr Asn Ser Gly Thr Leu Met Thr Leu tta tac act caaaaa caa ctgaccaagtaccca gacactttc 556 att aca Leu Tyr Thr GlnLys Gln LeuThrLysTyrPro AspThrPhe Ile Thr ctt gaa ata gtaaat gga atcctctgcccgttt gatgetgat 604 ggt aaa Leu Glu Ile ValAsn Gly IleLeuCysProPhe AspAlaAsp Gly Lys 60 65 7p ggt cat ttc atagac agg ggtctcctcttcagg catgtccta 652 tat gat Gly His Phe IleAsp Arg GlyLeuLeuPheArg HisValLeu Tyr Asp aac ttc cga aatgga gaa ctattgcccgaaggg tttcgagaa 700 cta ctt Asn Phe Arg AsnGly Glu LeuLeuProGluGly PheArgGlu Leu Leu aat caa ctt gcacaa gaa gaattctttcagctc aagggactg 748 ctt gca Asn Gln Leu AlaGln Glu GluPhePheGlnLeu LysGlyLeu Leu Ala gca gag gtg aaatcc agg gagaaagaacagcta acacccaga 796 gaa tgg Ala Glu Val LysSer Arg GluLysGluGlnLeu ThrProArg Glu Trp gag act ttc ttggaa ata gataaccacgatcgt tcacaagga 844 act aca Glu Thr Phe LeuGlu Ile AspAsnHisAspArg SerGlnGly Thr Thr tta aga ttc tgtaat get gatttcatatcaaaa ataaagtct 892 atc cct Leu Arg Phe CysAsn Ala AspPheIleSerLys IleLysSer Ile Pro cgcatt gttctggtgtcc aaaagcaggctggat ggatttccagag gag 940 ArgIle ValLeuValSer LysSerArgLeuAsp GlyPheProGlu Glu ttttca atatcgtcaaat atcatccaatttaaa tacttcataaag tct 988 PheSer IleSerSerAsn IleIleGlnPheLys TyrPheIleLys Ser gaaaat ggcactcgactt gtactaaaggaagac aacacctttgtc tgt 1036 GluAsn GlyThrArgLeu ValLeuLysGluAsp AsnThrPheVal Cys accttg gaaactcttaag tttgaggetatcatg atggetttaaag tgt 1084 ThrLeu GluThrLeuLys PheGluAlaIleMet MetAlaLeuLys Cys ggcttt agactgctgacc agcctggattgttcc aaagggtcaatt gtt 1132 GlyPhe ArgLeuLeuThr SerLeuAspCysSer LysGlySerIle Vai cacagc gatgcacttcat tttatca 1177 agtaattacc tgtgtcacga HisSer AspAlaLeuHis PheIle acaaaggcaacaagcatgcagccagcaagcttcggaaaaccacagcatcaaagacatccc1237 aaataacatgcccagctagctctgtactacagagccctgctactaatcaattactgtgag1297 ctaacggtatgtaaattctatcgctaaagatgtccttcctctggggtgttcctactgatc1357 agactcttccacctaaaatgaaaacagtaaccttctatatactgtaaataaagactgaaa1417 gcttttgctatttatttgtccttaagctgtctttcaattcagattgtcttgggtatttgc1477 acaaaaagaagcatgtacattatctatcgttcatttaagtaaatggtaataaaatatttt1537 aaggggctattaatatttaaaatccttttctactatggcaaaaatctacagagaaactga1597 actggcaaaattaactacctggagcaaaacagatgtgcagatctaactaaaacagagcta1657 tagtgaaacaaaatgagattgtaagaagacattaaagctattgatttgatttttccatag1717 caagcaccaaaagcttatattcacagttcctgtgtttcatattagacttatagctgaatt1777 ggtattttgctgaaaattcctagaaaactgcttgatgacaataaaaagtaaataaaagca1837 ctgctaccttcaaaaaaaaaaaaaa 1862 <210> 12 <211> 258 <212> PRT

<213> H. sapiens <400> 12 Met Glu Arg Lys Ile Asn Arg Arg Glu Lys Glu Lys Glu Tyr Glu Gly Lys His Asn Ser Leu Glu Asp Thr Asp Gln Gly Lys Asn Cys Lys Ser Thr Leu Met Thr Leu Asn Val Gly Gly Tyr Leu Tyr Ile Thr Gln Lys Gln Thr Leu Thr Lys Tyr Pro Asp Thr Phe Leu Glu Gly Ile Val Asn Gly Lys Ile Leu Cys Pro Phe Asp Ala Asp Gly His Tyr Phe Ile Asp Arg Asp Gly Leu Leu Phe Arg His Val Leu Asn Phe Leu Arg Asn Gly Glu Leu Leu Leu Pro Glu Gly Phe Arg Glu Asn Gln Leu Leu Ala Gln 100 105 lI0 Glu Ala Glu Phe Phe Gln Leu Lys Gly Leu Ala Glu Glu Val Lys Ser Arg Trp Glu Lys Glu Gln Leu Thr Pro Arg Glu Thr Thr Phe Leu Glu Ile Thr Asp Asn His Asp Arg Ser Gln Gly Leu Arg Ile Phe Cys Asn Ala Pro Asp Phe Ile Ser Lys Ile Lys Ser Arg Ile Val Leu Val Ser Lys Ser Arg Leu Asp Gly Phe Pro Glu Glu Phe Ser Ile Ser Ser Asn Ile Ile Gln Phe Lys Tyr Phe Ile Lys Ser Glu Asn Gly Thr Arg Leu Val Leu Lys Glu Asp Asn Thr Phe Val Cys Thr Leu Glu Thr Leu Lys Phe Glu Ala Ile Met Met Ala Leu Lys Cys Gly Phe Arg Leu Leu Thr Ser Leu Asp Cys Ser Lys Gly Ser Ile Val His Ser Asp Ala Leu His Phe Ile <210> 13 <211> 1877 <212> DNA
<213> H. Sapiens <22U>
<221> CDS
<222> (322)...(1090) <223> K+Hnov27 <400> 13 caccaccgcccccagccgcc tcctccccaaagacagccag60 ctcgctgggg aacacttaca gtcgggcccgacgtgaaatc ccctgtacgagtctgtgttc120 cgaggctgcg cccaagcgcg gggtcgggggaaatctgcgg tttgtatccgcccctcggag180 ccccacttcc cccaaaagac cctgtggatgcggtggtggt ccctgcctcttcttccagaa240 ggtttccgtg aaacacgacc gccaatgggcacagaagcac cacctgctattgtttccccc300 caattctccc acaatagttt acccaggacagtcggcccaaatgtca agacct atc act tcc cct 351 t ctg aga MetSer ArgPro Ile Thr Ser Pro Leu Arg gca tct ctg awc caaggc atccct cca gca ctc aca 399 cca aac act caa Ala Ser Leu Xaa GlnGly IlePro Pro Ala Leu Thr Pro Asn Thr Gln aaa tcc gcg cct cacatt gatgtg ggc cac tac acc 447 aat gtc ggc atg Lys Ser Ala Pro HisIle AspVal Gly His Tyr Thr Asn Val Gly Met agc agc gcc acc accaaa taccct tcc aga gga aga 495 ctg ctc gaa atc Ser Ser Ala Thr ThrLys TyrPro Ser Arg Gly Arg Leu Leu Glu Ile ctt ttt ggt aca cccatt gttttg agt ctc cag cac 543 gat gag gac aaa Leu Phe Gly Thr ProIle ValLeu Ser Leu Gln His Asp Glu Asp Lys tat ttc gac aga ggacag atgttc tat atc aat ttt 591 att gat aga ttg Tyr Phe Asp Arg GlyGln MetPhe Tyr Ile Asn Phe Ile Asp Arg Leu cta cga tcc aaa ctcatt cctgat ttc aag tac act 639 aca ctc gat gac Leu Arg Ser Lys LeuIle ProAsp Phe Lys Tyr Thr Thr Leu Asp Asp ttgttatatgaa gaggcaaaatat tttcagcttcagccc atgttgttg 687 LeuLeuTyrGlu GluAlaLysTyr PheGlnLeuGlnPro MetLeuLeu gagatggaaaga tggaagcaggac agagaaactggtcga ttttcaagg 735 GluMetGluArg TrpLysGlnAsp ArgGluThrGlyArg PheSerArg ccctgtgagtgc ctcgtcgtgcgt gtggccccagacctc ggagaaagg 783 ProCysGluCys LeuValValArg ValAlaProAspLeu GlyGluArg atcacgctaagc ggtgacaaatcc ttgatagaagaagta tttccagag 831 IleThrLeuSer GlyAspLysSer LeuIleGluGluVal PheProGlu 155 160 165 1?0 atcggcgacgtg atgtgtaactct gtcaatgcaggctgg aatcacgac 879 IleGlyAspVal MetCysAsnSer ValAsnAlaGlyTrp AsnHisAsp tcgacgcacgtc atcaggtttcca ctaaatggctactgt cacctcaac 927 SerThrHisVal IleArgPhePro LeuAsnGlyTyrCys HisLeuAsn tcagtccaggtc ctcgagaggttg cagcaaagaggattt gaaatcgtg 975 SerValGlnVal LeuGluArgLeu GlnGlnArgGlyPhe GluIleVal ggctcctgtggg ggaggagtagac tcgtcccagttcagc gaatacgtc 1023 GlySerCysGly GlyGlyValAsp SerSerGlnPheSer GluTyrVal cttcggcgggaa ctgaggcggacg ccccgtgtaccctcc gtcatccgg 1071 LeuArgArgGlu LeuArgArgThr ProArgValProSer ValIleArg ataaagcaagag cctctgg catatttctt atgcaaaaag 1120 actaaatgga IleLysGlnGlu ProLeu gaaaacacacacaaccaataactcaaacaaaaaagggacatttatgtgcagttgggacag1180 caaaccaagtcctggacgtaaaattgaataaaagacacatttatatccaatagagaccac1240 acctgtattcatatgggaacaattggaatagtgatatcctcaaggtgtaaaaaatatata1300 aatatatatatatatgtcaaaaggtaggaaatgcaaaaaagaaaaaaaaaaaaggtgaca1360 gccgcagttggtgctgtgatggccgtgaagtgtcctgggcctcccgaggcctctgacaaa1420 taaacaagccatgagtggtgaggacacagtctccttacagtttccattgccaacaacagc1480 catccatatttcttttttcctttgtctttctttttcctttttttttaaaaaaacaaaaca1540 aacaaaacaccttgaatcaagtttgtttgtatatggaggttccacgtctttctttaggca1600 gggaccaggcaggacttcagaaaaaccctcatgagcacattgcaaagatgttagacatga1660 aattttaaatgtagtttgtacagaagtcacacttttttgtccacctcacagatgtgaact1720 ttactttgttttaaaactgatcagttttgccaaggggccagaattattccttgttagaat1780 tgctccagttcaagtctgctgctttcctacaatttttcaaattttataatgtattaaata1840 caataaactctgtttaaaaaataaaaaaaaaaaaaaa 1877 <210> 14 <211> 256 <212> PRT

<213> H. sapiens <220>
<221> VARIANT
<222> (1)...(256) <223> Xaa = Any Amino Acid <400> 14 Met Ser Arg Pro Leu Ile Thr Arg Ser Pro Ala Ser Pro Leu Xaa Asn Gln Gly Ile Pro Thr Pro Ala Gln Leu Thr Lys Ser Asn Ala Pro Val His Ile Asp Val Gly Gly His Met Tyr Thr Ser Ser Leu Ala Thr Leu Thr Lys Tyr Pro Glu Ser Arg Ile Gly Arg Leu Phe Asp Gly Thr Glu Pro Ile Val Leu Asp Ser Leu Lys Gln His Tyr Phe Ile Asp Arg Asp Gly Gln Met Phe Arg Tyr Ile Leu Asn Phe Leu Arg Thr Ser Lys Leu Leu Ile Pro Asp Asp Phe Lys Asp Tyr Thr Leu Leu Tyr Glu Glu Ala 100 lOS 110 Lys Tyr Phe Gln Leu Gln Pro Met Leu Leu Glu Met Glu Arg Trp Lys Gln Asp Arg Glu Thr Gly Arg Phe Ser Arg Pro Cys Glu Cys Leu Val Val Arg Val Ala Pro Asp Leu Gly Glu Arg Ile Thr Leu Ser Gly Asp Lys Ser Leu Ile Glu Glu Val Phe Pro Glu Ile Gly Asp Val Met Cys Asn Ser Val Asn Ala Gly Trp Asn His Asp Ser Thr His Val Ile Arg Phe Pro Leu Asn Gly Tyr Cys His Leu Asn Ser Val Gln Val Leu Glu Arg Leu Gln Gln Arg Gly Phe Glu Ile Val Gly Ser Cys Gly Gly Gly Val Asp Ser Ser Gln Phe Ser Glu Tyr Val Leu Arg Arg Glu Leu Arg Arg Thr Pro Arg Val Pro Ser Val Ile Arg Ile Lys Gln Glu Pro Leu <210> 15 <211> 923 <212> DNA
<213> H. sapiena <220>
<221> CDS
<222> (165)...(756) <223> K+Hnov2 <400> 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 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 cca gcc tcc tta get 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 gtgctcagccgccca cgtgcctgg gtagcggtccactgg cagctgtca 320 ValLeuSerArgPro ArgAlaTrp ValAlaValHisTrp GlnLeuSer ccggccagggetgcg ctgctgcag gcagttgcactggga ctgctggtg 368 ProAlaArgAlaAla LeuLeuGln AlaValAlaLeuGly LeuLeuVal gccagcagctttgtg ctgctgcca gcgctggtgctgtgg ggccttcag 416 AlaSerSerPheVal LeuLeuPro AlaLeuValLeuTrp GlyLeuGln ?0 75 gp ggcgactgcagcctg ctgggggcc gtctacttctgcttc agctcgctc 464 GlyAspCysSerLeu LeuGlyAla ValTyrPheCysPhe SerSerLeu agcaccattggcctg gaggacttg ctgcccggccgcggc cgcagcctg 512 SerThrIleGlyLeu GluAspLeu LeuProGlyArgGly ArgSerLeu caccccgtgatttac cacctgggc cagctcgcacttctt ggttacttg 560 HisProValIleTyr HisLeuGly GlnLeuAlaLeuLeu GlyTyrLeu cttctaggactcttg gccatgctg ctggcagtggagacc ttctctgag 608 LeuLeuGlyLeuLeu AlaMetLeu LeuAlaValGluThr PheSerGlu ctgccgcaggtccgt gccatgggg aagttcttcagaccc agtggtcct 656 LeuProGlnValArg AlaMetGly LysPhePheArgPro SerGlyPro gtgactgetgaggac caaggtggc atcctagggcaggat gaactgget 704 ValThrAlaGluAsp GlnGlyGly IleLeuGlyGlnAsp GluLeuAla ctgagcaccctgccg cccgcggcc ccagettcaggacaa gcccctget 752 LeuSerThrLeuPro ProAlaAla ProAlaSerGlyGln AlaProAla tgct tcagctccgt 806 gaagcgtcag aaggtggcgg gtgaccgagt cacctgagga Cys ggaagcagcc ctggagatgg agccgcggtg 866 aggagtggct agggtgggcg ggggaagaat ggaggcctca aaaaaaaaaa aaaaaaaaaa 923 ggggatactg aaaaaaa ttaatcataa <210> 16 <211> 197 <212> PRT
<213> H. sapiens <400> 16 Met Ala Pro Leu Ser Pro Gly Gly Lys Ala Phe Cys Met Val Tyr Ala Ala Leu Gly Leu Pro Ala Ser Leu Ala Leu Val Ala Thr Leu Arg His Cys Leu Leu Pro Val Leu Ser Arg Pro Arg Ala Trp Val Ala Val His Trp Gln Leu Ser Pro Ala Arg Ala Ala Leu Leu Gln Ala Val Ala Leu Gly Leu Leu Val Ala Ser Ser Phe Val Leu Leu Pro Ala Leu Val Leu Trp Gly Leu Gln Gly Asp Cys Ser Leu Leu Gly Ala Val Tyr Phe Cys Phe Ser Ser Leu Ser Thr Ile Gly Leu Glu Asp Leu Leu Pro Gly Arg Gly Arg Ser Leu His Pro Val Ile Tyr His Leu Gly Gln Leu Ala Leu Leu Gly Tyr Leu Leu Leu Gly Leu Leu Ala Met Leu Leu Ala Val Glu Thr Phe Ser Glu Leu Pro Gln Val Arg Ala Met Gly Lys Phe Phe Arg Pro Ser Gly Pro Val Thr Ala Glu Asp Gln Gly Gly Ile Leu Gly Gln Asp Glu Leu Ala Leu Ser Thr Leu Pro Pro Ala Ala Pro Ala Ser Gly Gln Ala Pro Ala Cys <210> 17 <211> 3102 <212> DNA
<213> H. sapiens <220>
<221> CDS
<222> (274)...(1705) <223> K+Hnovll <400> 17 gcacgcgcaaagcgcccacc tgtgttaata gaaacatacc60 gagacccctg gggtggagct cacccccagcctttcctggg ctcttgcccc agcccagccc120 aggggatcag acccctcaaa ttcagcacccaagacccacc taatgggtag ggagaggggg180 aggaggcctg ggcccgccag ccccgccagggcgcacggcg tccgcttcca ggtgtagcgc240 ctctcgccga cgctgttccc ccccgcgcggcgcgggcggc 294 cggcgcctcc agc atg acc ggc cag agc ctg tgg Met Thr Gly Gln Ser Leu Trp gac gtg gag get gtc gag ggg atc cgc atc aat 342 tcg aac gac gag gtg Asp Val Glu Ala Val Glu Gly Ile Arg Ile Asn Ser Asn Asp Glu Val ggc ggc aag agg ctg cgc cac ctg ctg cgc ttc 390 ttc agg tcg acg ccc Gly Gly Lys Arg Leu Arg His Leu Leu Arg Phe Phe Arg Ser Thr Pro gag acg ctg ggc ttg ctg tgc tcg cgc gag gcc 438 cgc cgc ctc cac att Glu Thr Leu Gly Leu Leu Cys Ser Arg Glu Ala Arg Arg Leu His Ile ctg gag tgc gat tac gac gtc cgg gag ttc tac 486 ctc gac gac cag ttc Leu Glu Cys Asp Tyr Asp Val Arg Glu Phe Tyr Leu Asp Asp Gln Phe gac cgc cct gag ttc ccc gtg cat ttc tat cac 534 aac ctc tac ctg acc Asp Arg Pro Glu Phe Pro Val His Phe Tyr His Asn Leu Tyr Leu Thr ggcaagcttcac gtcatggetgagcta tgtgtcttc tccttcagccag 582 GlyLysLeuHis ValMetAlaGluLeu CysValPhe SerPheSerGln gagatcgagtac tggggcatcaacgag ttcttcatt gactcctgctgc 630 GluIleGluTyr TrpGlyIleAsnGlu PhePheIle AspSerCysCys agctacagctac catggccgcaaagta gagcccgag caggagaagtgg 678 SerTyrSerTyr HisGlyArgLysVal GluProGlu GlnGluLysTrp gacgagcagagt gaccaggagagcacc acgtcttcc ttcgatgagatc 726 AspGluGlnSer AspGlnGluSerThr ThrSerSer PheAspGluIle cttgccttctac aacgacgcctccaag ttcgatggg cagcccctcggc 774 LeuAlaPheTyr AsnAspAlaSerLys PheAspGly GlnProLeuGly aacttccgcagg cagctgtggctggcg ctggacaac cccggctactca 822 AsnPheArgArg GlnLeuTrpLeuAla LeuAspAsn ProGlyTyrSer gtgctgagcagg gtcttcagcatcctg tccatcctg gtggtgatgggg 870 ValLeuSerArg ValPheSerIleLeu SerIleLeu ValValMetGly tccatcatcacc atgtgcctcaatagc ctgcccgat ttccaaatccct 918 SerIleIleThr MetCysLeuAsnSer LeuProAsp PheGlnIlePro gacagccagggc aaccctggcgaggac cctaggttc gaaatcgtggag 966 AspSerGlnGly AsnProGlyGluAsp ProArgPhe GluIleValGlu cactttggcatt gcctggttcacattt gagctggtg gccaggtttget 1014 HisPheGlyIle AlaTrpPheThrPhe GluLeuVal AlaArgPheAla gtggcccctgac ttcctcaagttcttc aagaatgcc ctaaaccttatt 1062 ValAlaProAsp PheLeuLysPhePhe LysAsnAIa LeuAsnLeuIle gacctcatgtcc atcgtccccttttac atcactctg gtggtgaacctg 1110 AspLeuMetSer IleValProPheTyr IleThrLeu ValValAsnLeu gtggtggagagc acacctactttagcc aacttgggc agggtggcccag 1158 ValValGluSer ThrProThrLeuAla AsnLeuGly ArgValAlaGln 2.80 285 290 295 gtcctgaggctg atgcggatcttccgc atcttaaag ctggccaggcac 1206 ValLeuArgLeu MetArgIlePheArg IleLeuLys LeuAlaArgHis tccactggcctc cgctccctgggggcc actttgaaa tacagctacaaa 1254 SerThrGlyLeu ArgSerLetsGlyAla ThrLeuLys TyrSerTyrLys gaagtagggctg ctcttgctctacctc tccgtgggg atttccatcttc 1302 Glu Val Gly Leu Leu Leu Leu Tyr Leu Ser Val Gly Ile Ser Ile Phe tccgtggtg gcctacaccatt gaaaaggaggag aacgagggcctggcc 1350 SerValVal AlaTyrThrIle GluLysGluGlu AsnGluGlyLeuAla accatccct gcctgctggtgg tgggetaccgtc agtatgaccacagtg 1398 ThrIlePro AlaCysTrpTrp TrpAlaThrVal SerMetThrThrVal gggtacggg gatgtggtccca gggaccacggca ggaaagctgactgcc 1446 GlyTyrGly AspValValPro GlyThrThrAla GlyLysLeuThrAla tctgcctgc atcttggcaggc atcctcgtggtg gtcctgcccatcacc 1494 SerAlaCys IleLeuAlaGly IleLeuValVal ValLeuProIleThr ttgatcttc aataagttctcc cacttttaccgg cgccaaaagcaactt 1542 LeuIlePhe AsnLysPheSer HisPheTyrArg ArgGlnLysGlnLeu gagagtgcc atgcgcagctgt gactttggagat ggaatgaaggaggtc 1590 GluSerAla MetArgSerCys AspPheGlyAsp GlyMetLysGluVal ccttcggtc aatttaagggac tattatgcccat aaagttaaatccctt 1638 ProSerVal AsnLeuArgAsp TyrTyrAlaHis LysValLysSerLeu atggcaagc ctgacgaacatg agcaggagctca ccaagtgaactcagt 1686 MetAlaSer LeuThrAsnMet SerArgSerSer ProSerGluLeuSer ttaaatgat tccctacgtt ctccacccca 1735 agccgggagg acttgtcacc LeuAsnAsp SerLeuArg cattgctgag etgcctcttgtgcctctggcacagcccaggcaccttatggttatggtgta1795 aggagtatgc ccagcccctgaggggagagatgcatgggatatgcacccaggtttctttta1855 cagtttttag aatcgtttttagagggtggtgtgtctgacaccatgcctttgcacctttcc1915 atgaaatgac actcactggtctttgcatcgtgggcataaaatgttcaccttttttccaga1975 tgagtacacc cagaatgctaatttttctgtccatcgtgtacgctattctagtgcttgtgg2035 cccagtactg tctatgagttgtcgtgctcctgtttctgaggttgtcgtgtgagttctgta2095 caaaaagccc ccacaagtcgtccagtagaaatgcatctatgaggtcagcaaggatatgat2155 gagattttgc tcacagtcatgtgaaaacaaaatctcagctctttatccattgctttcact2215 tagttttagt accaaaacaaagagaatgcaaagttaagcagacttgaccaatgcaagtct2275 ctaagttgtt tttataaatgatctgtagttccgtggcttgcatgggtgcaccaatcatct2335 ttagaacgat gtacactgatgttcatctcataaatgtcactctttagagaatgttactta2395 gttaaacatg cagtgaagatcgaatttttttcccaagaacagatgtgttagggagagggg2455 cttcagctaa atagtccaaaccctagggtgcttaaagccaagttagtgcaggctgagccc2515 cttggttcac agtcaagcctccttgtttcctagggtgactgtagagaaatgtatttccgg2575 atgaggtttc tgatctaggccatttgaccaaactttgctgtgtctaagatattagcatgt2635 ttttgaaata tttattttttaagatgtttaggagtaaggtcgtgttgtcttcctcaacta2695 aaaagaagtt tactgttgtatcgtctccctgaggtgaacgttgttgggttgctagcaagg2755 cagtagctta atacttttgttgcctactctgaaagctcatcaatgagagcccttttattt2815 ccaagcagaa tttagtcagataattttgcttctaggatatagtatgttgtatatgatgct2875 gtgattgccc tggagttcctgcccatgactggaaacctggtggtatggaagcatgtactc2935 aaaatataga cgtgcacgatggtggtgtggcttacecaggatggaaacactgcagttctt2995 acttgcattc ccactgcctttcatggggggtgactgggtagaggccaggagaaaggaaag3055 agttgtaaaa taaaaaactg ctagttcata aaaaaaaaaa aaaaaaa 3102 <210> 18 <211> 477 <212> PRT
<213> H. sapiens <400> 18 Met Thr Gly Gln Ser Leu Trp Asp Val Ser Glu Ala Asn Val Glu Asp Gly Glu Ile Arg Ile Asn Val Gly Gly Phe Lys Arg Arg Leu Arg Ser His Thr Leu Leu Arg Phe Pro Glu Thr Arg Leu Gly Arg Leu Leu Leu Cys His Ser Arg Glu Ala Ile Leu Glu Leu Cys Asp Asp Tyr Asp Asp Val Gln Arg Glu Phe Tyr Phe Asp Arg Asn Pro Glu Leu Phe Pro Tyr Val Leu His Phe Tyr His Thr Gly Lys Leu His Val Met Ala Glu Leu Cys Val Phe Ser Phe Ser Gln Glu Ile Glu Tyr Trp Gly Ile Aan Glu Phe Phe Ile Asp Ser Cys Cys Ser Tyr Ser Tyr His Gly Arg Lys Val Glu Pro Glu Gln Glu Lys Trp Asp Glu Gln Sex Aap Gln Glu Ser Thr Thr Ser Ser Phe Asp Glu Ile Leu Ala Phe Tyr Asn Asp Ala Ser Lys Phe Asp Gly Gln Pro Leu Gly Asn Phe Arg Arg Gln Leu Trp Leu Ala Leu Asp Asn Pro Gly Tyr Ser Val Leu Ser Arg Val Phe Ser Ile Leu Ser Ile Leu Val Val Met Gly Ser Ile Ile Thr Met Cys Leu Asn Ser Leu Pro Asp Phe Gln Ile Pro Asp Ser Gln Gly Asn Pro Gly Glu Asp Pro Arg Phe Glu Ile Val Glu His Phe Gly Ile Ala Trp Phe Thr Phe Glu Leu Val Ala Arg Phe Ala Val Ala Pro Asp Phe Leu Lys Phe Phe Lys Asn Ala Leu Asn Leu Ile Asp Leu Met Ser Ile Val Pro Phe Tyr Ile Thr Leu Val Val Asn Leu Val Val Glu Ser Thr Pro Thr Leu Ala Asn Leu Gly Arg Val Ala Gln Val Leu Arg Leu Met Arg Ile Phe Arg Ile Leu Lys Leu Ala Arg His Ser Thr Gly Leu Arg Ser Leu Gly Ala Thr Leu Lys Tyr Ser Tyr Lys Glu Val Gly Leu Leu Leu Leu Tyr Leu Ser Val Gly Ile Ser Ile Phe Ser Val Val Ala Tyr Thr Ile Glu Lys Glu Glu Asn Glu Gly Leu Ala Thr Ile Pro Ala Cys Trp Trp Trp Ala Thr Val Ser Met Thr Thr Val Gly Tyr Gly Asp Val Val Pro Gly Thr Thr Ala Gly Lys Leu Thr Ala 5er Ala Cys Ile Leu Ala Gly Ile Leu Val Val Val Leu Pro Ile Thr Leu Ile Phe Asn Lys Phe Ser His Phe Tyr Arg Arg Gln Lys Gln Leu Glu Ser Ala Met Arg Ser Cys Asp Phe GlyAsp Met GluVal ProSerValAsn Leu Asp Tyr Gly Lys Arg Tyr AlaHis Val SerLeu MetAlaSerLeu Thr MetSerArg Lys Lys Asn SerSer Ser LeuSer LeuAsnAspSer Leu Pro Glu Arg <210> 19 <211> 0 <212> DNA

<213> H.
sapiens <220>

<221> CDS

<222> (249)...(3495) <223> K+Hnovl4 <400> 19 gggctggtag cagggatttg ggccgcgcgc catgctccgg tgggcggcga gggcgcgagg gccccgacgg cgcggacgcc cgcgaccccg gatcccggtc ccctcgcgcg ccagctccgg tgcgcattgc cccccgacgg ccggcggggg cggccgagct ctgcgctagg agcgcggggc gggcgccctc ccccggcgcg atggggcggg cagccgcggg gagtccccgc accccggagg cgcctaag c 290 atg acc ccg ttc gcc atg cgg ggc ctc ctg gcg ccg cag aa Me t Pro n Ala Thr Met Phe Arg Gly Leu Leu Ala Pro Gln As ctggac atc acgcgc ttcgacggcacg cac aacttcgtg 338 acc get agt LeuAsp Ile ThrArg PheAspGlyThr His AsnPheVal Thr Ala Ser -ctgggc gcc ggcggg getcttcccgtg gtc tgctctgat 386 aac agt tac LeuGly Ala GlyGly AlaLeuProVal Val CysSerAsp Asn Ser Tyr ggcttc gac acgggc ttcteccggget gag atgcagcgg 434 tgt ctc gtc GlyPhe Asp ThrGly PheSerArgAla Glu MetGlnArg Cys Leu Val ggctgt tgc ttcctt tatgggccagac acc gagctcgtc 482 gcc tcc agt GlyCys Cys PheLeu TyrGlyProAsp Thr GluLeuVal Ala Ser Ser cgccaa atc aaggcc ctggacgagcac aag ttcaagget 530 cag cgc gag ArgGln Ile LysAla LeuAspGluHis Lys PheLysAla Gln Arg Glu gagctg ctg cggaag agcgggctcccg ttc tgtctcctg 578 atc tac tgg GluLeu Leu ArgLys SerGlyLeuPro Phe CysLeuLeu Ile Tyr Trp gatgtg ccc aagaat gagaaaggggag gtg ctcttccta 626 ata ata get AspVal Pro LysAsn GluLysGlyGlu Val LeuPheLeu Ile Ile Ala gtctct aag atcagc gaaaccaagaac cga ggccccgac 674 cac gac ggg ValSer Lys IleSer GluThrLysAsn Arg GlyProAsp His Asp Gly agatgg gag ggtggt ggccggcgccga tat cgggcacga 722 aaa aca ggc ArgTrp Glu GlyGly GlyArgArgArg Tyr ArgAlaArg Lys Thr Gly tccaaa ggcttcaatgccaac cggcggcgg agccgggccgtgctc tac 770 SerLys GlyPheAsnAlaAsn ArgArgArg SerArgAlaValLeu Tyr cacctg tccgggcacctgcag aagcagccc aagggcaagcacaag ctc 818 HisLeu SerGlyHisLeuGln LysGlnPro LysGlyLysHisLys Leu aataag ggggtgtttggggag aaaccaaac ttgcctgagtacaaa gta 866 AsnLys GlyValPheGlyGlu LysProAsn LeuProGluTyrLys Val gccgcc atccggaagtcgccc ttcatcctg ttgcactgtggggca ctg 914 AlaAla IleArgLysSerPro PheIleLeu LeuHisCysGlyAla Leu agagcc acctgggatggcttc atcctgctc gccacactctatgtg get 962 ArgAla ThrTrpAspGlyPhe IleLeuLeu AlaThrLeuTyrVal Ala gtcact gtgccctacagcgtg tgtgtgagc acagcacgggagccc agt 1010 ValThr ValProTyrSerVal CyaValSer ThrAlaArgGluPro Ser gccgcc cgcggcccgcccagc gtctgtgac ctggccgtggaggtc ctc 1058 AlaAla ArgGlyProProSer ValCysAsp LeuAlaValGluVal Leu ttcatc cttgacattgtgctg aatttccgt accacattcgtgtcc aag 1106 PheIle LeuAspIleValLeu AsnPheArg ThrThrPheValSer Lys tcgggc caggtggtgtttgcc ccaaagtcc atttgcctccactac gtc 1154 SerGly GlnValValPheAla ProLysSer IleCysLeuHisTyr Val accacc tggttcctgctggat gtcatcgca gcgctgccctttgac ctg 1202 ThrThr TrpPheLeuLeuAsp ValIleAla AlaLeuProPheAsp Leu ctacat gccttcaaggtcaac gtgtacttc ggggcccatctgctg aag 1250 LeuHis AlaPheLysValAsn ValTyrPhe GlyAlaHisLeuLeu Lys 320 325 33p acggtg cgcctgctgcgcctg ctgcgcctg cttccgcggctggac cgg 1298 ThrVal ArgLeuLeuArgLeu LeuArgLeu LeuProArgLeuAsp Arg tactcg cagtacagcgccgtg gtgctgaca ctgctcatggccgtg ttc 1346 TyrSer GlnTyrSerAlaVal ValLeuThr LeuLeuMetAlaVal Phe gccctg ctcgcgcactgggtc gcctgcgtc tggttttacattggc cag 1394 AlaLeu LeuAlaHisTrpVal AlaCysVal TrpPheTyrIleGly Gln cgggag atcgagagcagcgaa tccgagctg cctgagattggctgg ctg 1442 ArgGlu IleGluSerSerGlu SerGluLeu ProGluIleGlyTrp Leu caggagctggcccgccga ctggagactccc tactacctggtg ggccgg 1490 GlnGluLeuAlaArgArg LeuGluThrPro TyrTyrLeuVal GlyArg aggccagetggagggaac agctccggccag agtgacaactgc agcagc 1538 ArgProAla.GlyGlyAsn SerSerGlyGln SerAspAsnCys SerSer agcagcgaggccaacggg acggggctggag ctgctgggcggc ccgtcg 1586 SerSerGluAlaAsnGly ThrGlyLeuGlu LeuLeuGlyGly ProSer ctgcgcagcgcctacatc acctccctctac ttcgcactcagc agcctc 1634 LeuArgSerAlaTyrIle ThrSerLeuTyr PheAlaLeuSer SerLeu accagcgtgggcttcggc aacgtgtccgcc aacacggacacc gagaag 1682 ThrSerValGlyPheGly AsnValSerAla AsnThrAspThr GluLys atcttctccatctgcacc atgctcatcggc gccctgatgcac gcggtg 1730 IlePheSerIleCysThr MetLeuIleGly AlaLeuMetHis AlaVal gtgtttgggaacgtgacg gccatcatccag cgcatgtacgcc cgccgc 1778 ValPheGlyAsnValThr AlaIleIleGln ArgMetTyrAla ArgArg tttctgtaccacagccgc acgcgcgaccag cgcgactacatc cgcatc 1826 PheLeuTyrHisSerArg ThrArgAspGln ArgAspTyrIle ArgIle caccgtatccccaagccc ctcaagcagcgc atgctggagtac ttccag 1874 HisArgIleProLysPro LeuLysGlnArg MetLeuGluTyr PheGln gccacctgggcggtgaac aatggcatcgac accaccgagctg ctgcag 1922 AlaThrTrpAlaValAsn AsnGlyIleAsp ThrThrGluLeu LeuGln agcctccctgacgagctg cgcgcagacatc gccatgcacctg cacaag 1970 SerLeuProAspGluLeu ArgAlaAspIle AlaMetHisLeu HisLys gaggtcctgcagctgcca ctgtttgaggcg gccagccgcggc tgcctg 2018 GluValLeuGlnLeuPro LeuPheGluAla AlaSerArgGly CysLeu cgggcactgtctctggcc ctgcggcccgcc ttctgcacgccg ggcgag 2066 ArgAlaLeuSerLeuAla LeuArgProAla PheCysThrPro GlyGlu tacctcatccaccaaggc gatgccctgcag gccctctacttt gtctgc 2114 TyrLeuIleHisGlnGly AspAlaLeuGln AlaLeuTyrPhe ValCya tctggctccatggaggtg ctcaagggtggc accgtgctcgcc atccta 2162 SerGlySerMetGluVal LeuLysGlyGly ThrValLeuAla IleLeu gggaagggcgacctg atcggctgt gagctgccccggcgg gagcaggtg 2210 GlyLysGlyAspLeu IleGlyCys GluLeuProArgArg GluGlnVal gtaaaggccaatgcc gacgtgaag gggctgacgtactgc gtcctgcag 2258 ValLysAlaAsnAla AspValLys GlyLeuThrTyrCys ValLeuGln tgtctgcagctgget ggcctgcac gacagccttgcgctg taccccgag 2306 CysLeuGlnLeuAla GlyLeuHis AspSerLeuAlaLeu TyrProGlu tttgccccgcgcttc agtcgtggc ctccgaggggagctc agctacaac 2354 PheAlaProArgPhe SerArgGly LeuArgGlyGluLeu SerTyrAsn s9o 69s 700 ctgggtgetggggga ggctctgca gaggtggacaccagc tccctgagc 2402 LeuGlyAlaGlyGly GlySerAla GluValAspThrSer SerLeuSir ggcgacaataccctt atgtccacg ctggaggagaaggag acagatggg 2450 GlyAspAsnThrLeu MetSerThr LeuGluGluLysGlu ThrAspGly gagcagggccccacg gtctcccca gccccagetgatgag ccctccagc 2498 GluGlnGlyProThr ValSerPro AlaProAlaAspGlu ProSerSer cccctgctgtcccct ggctgcacc tcctcatcctcaget gccaagctg 2546 ProLeuLeuSerPro GlyCysThr SerSerSerSerAla AlaLysLeu ctatccccacgtcga acagcaccc cggcctcgtctaggt ggcagaggg 2594 LeuSerProArgArg ThrAlaPro ArgProArgLeuGly GlyArgGly aggccaggcagggca ggggetttg aaggetgaggetggc ccctctget 2642 ArgProGlyArgAla GlyAlaLeu LysAlaGluAlaGly ProSerAla cccccacgggcccta gaggggcta cggctgccccccatg ccatggaat 2690 ProProArgAlaLeu GluGlyLeu ArgLeuProProMet ProTrpAsn gtgcccccagatctg agccccagg gtagtagatggcatt gaagacggc 2738 ValProProAspLeu SerProArg ValValAspGlyIle GluAspGly tgtggctcggaccag cccaagttc tctttccgcgtgggc cagtctggc 2786 CysGlySerAspGln ProLysPhe SerPheArgValGly GlnSerGly ccggaatgtagcagc agcccctcc cctggaccagagagc ggcctgctc 2834 ProGluCysSerSer SerProSer ProGlyProGluSer GlyLeuLeu actgttecccatggg cccagcgag gcaaggaacacagac acactggac 2882 ThrValProHisGly ProSerGlu AlaArgAsnThrAap ThrLeuAsp aagcttcggcaggcg gtgacagag ctgtcagagcaggtg ctgcagatg 2930 Lys Leu Arg Gln Ala Val Thr Glu Leu Ser Glu Gln Val Leu Gln Met cgggaaggactg cagtcacttcgc caggetgtgcag cttgtcctg gcg 2978 ArgGluGlyLeu GlnSerLeuArg GlnAlaValGln LeuValLeu Ala ccccacagggag ggtccgtgccct cgggcatcggga gaggggccg tgc 3026 ProHisArgGlu GlyProCysPro ArgAlaSerGly GluGlyPro Cys ccagccagcacc tccgggcttctg ca9cctctgtgt gtggacact ggg 3074 ProAlaSerThr SerGlyLeuLeu GlnProLeuCys ValAspThr Gly gcatcctcctac tgcctgcagccc ccagetggctct gtcttgagt ggg 3122 AlaSerSerTyr CysLeuGlnPro ProAlaGlySer ValLeuSer Gly acttggccccac cctcgtccgggg cctcctcccctc atggcaccc cgg 3170 ThrTrpProHis ProArgProGly ProProProLeu MetAlaPro Arg ccctggggtccc ccagcgtctcag agctccccctgg cctcgagcc aca 3218 ProTrpGlyPro ProAlaSerGln SerSerProTrp ProArgAla Thr getttctggacc tccacctcagac tcagagccccct gcctcagga gac 3266 AlaPheTrpThr SerThrSerAsp SerGluProPro AlaSerGly Asg_ ctctgctctgag cccagcacccct gcctccectcct ccttctgag gaa 3314 LeuCysSerGlu ProSerThrPro AlaSerProPro ProSerGlu Glu ggggetaggact gggcccgcagag cctgtgagccag getgagget acc 3362 GlyAlaArgThr GlyProAlaGlu ProValSerGln AlaGluAla Thr agcactggagag cccccaccaggg tcagggggcctg gccttgccc tgg 3410 SerThrGlyGlu ProProProGly SerGlyGlyLeu AlaLeuPro Trp gacccccacagc ctggagatggtg cttattggctgc catggctct ggc 3458 AspProHisSer LeuGluMetVal LeuIleGlyCys HisGlySer Gly acagtccagtgg acccaggaagaa ggcacaggggtc t 3505 gagtaccagc ThrValGlnTrp ThrGlnGluGlu GlyThrGlyVal cctagaactc tgcca catctgctgt tcggcccaac agcgt ggtgtgctgc ctcagagtga aggcagggtg ctccc atgcggcccg ctggctcagg gcagc cacggactcc gcagggagcc tggaagcaaa ctcagagagg ataggctgga 3685 ggaggacctg tccctggggc gctcctgact aggcctctcc cggcctgct cccggtctcc ctctgcaggc gggggcaga3745 t cctctgacct t ggcctgagga aaggaagag ccctgcatgt gcccctgcct c ctttgccatc ctacctgtcc ccaaattttt tattaaaaa ataaactaaa aaaaaaaaaa s a aaaaaataaa a <2 10>20 <2 11>1082 <2 12>PRT

<213> H. Sapiens <400> 20 Met Pro Ala Met Arg Gly Leu Leu Ala Pro Gln Asn Thr Phe Leu Asp Thr Ile Ala Thr Arg Phe Asp Gly Thr His Ser Asn Phe Val Leu Gly Asn Ala Ser Gly Gly Ala Leu Pro Val Val Tyr Cys Ser Asp GIy Phe Cys Asp Leu Thr Gly Phe Ser Arg Ala Glu Val Met Gln Arg Gly Cys Ala Cys Ser Phe Leu Tyr Gly Pro Asp Thr Ser Glu Leu Val Arg Gln Gln Ile Arg Lys Ala Leu Asp Glu His Lys Glu Phe Lys Ala Glu Leu Ile Leu Tyr Arg Lys Ser Gly Leu Pro Phe Trp Cys Leu Leu Asp Val Ile Pro Ile Lys Asn Glu Lys Gly Glu Val Ala Leu Phe Leu Val Ser His Lys Asp Ile Ser Glu Thr Lys Asn Arg Gly Gly Pro Asp Arg Trp Lys Glu Thr Gly Gly Gly Arg Arg Arg Tyr Gly Arg Ala Arg Ser Lys Gly Phe Asn Ala Asn Arg Arg Arg Ser Arg Ala VaI Leu Tyr His Leu Ser Gly His Leu Gln Lys Gln Pro Lys Gly Lys His Lys Leu Asn Lys Gly Val Phe Gly Glu Lys Pro Asn Leu Pro Glu Tyr Lys Val Ala Ala Ile Arg Lys Ser Pro Phe Ile Leu Leu His Cys Gly Ala Leu Arg Ala Thr Trp Asp Gly Phe Ile Leu Leu Ala Thr Leu Tyr Val Ala Val Thr Val Pro Tyr Ser Val Cys Val Ser Thr Ala Arg Glu Pro Ser Ala Ala Arg Gly Pro Pro Ser Val Cys Asp Leu Ala Val Glu Val Leu Phe Ile Leu Asp Ile Val Leu Asn Phe Arg Thr Thr Phe Val Ser Lys Ser Gly Gln Val Val Phe Ala Pro Lys Ser Ile Cys Leu His Tyr Val Thr Thr Trp Phe Leu Leu Asp Val Ile Ala Ala Leu Pro Phe Asp Leu Leu His Ala Phe Lys Val Asn Val Tyr Phe Gly Ala His Leu Leu Lys Thr Val Arg Leu Leu Arg Leu Leu Arg Leu Leu Pro Arg Leu Asp Arg Tyr Ser Gln Tyr Ser Ala Val Val Leu Thr Leu Leu Met Ala Val Phe Ala Leu Leu Ala His Trp Val Ala Cys Val Trp Phe Tyr Ile Gly Gln Arg Glu Ile Glu Ser Ser Glu Ser Glu Leu Pro Glu Ile Gly Trp Leu Gln Glu Leu Ala Arg Arg Leu Glu Thr Pro Tyr Tyr Leu Val Gly Arg Arg Pro Ala Gly Gly Asn Ser Ser Gly Gln Ser Asp Asn Cys Ser Ser Ser Ser Glu Ala Asn Gly Thr Gly Leu Glu Leu Leu Gly Gly Pro Ser Leu Arg Ser Ala Tyr Ile Thr Ser Leu Tyr Phe Ala Leu Ser Ser Leu Thr Ser Val Gly Phe Gly Asn Val Ser Ala Asn Thr Aap Thr Glu Lys Ile Phe Ser Ile Cys Thr Met Leu Ile Gly Ala Leu Met His Ala Val Val Phe Gly Asn Val Thr Ala Ile Ile Gln Arg Met Tyr Ala Arg Arg Phe Leu Tyr His Ser Arg Thr Arg Asp Gln Arg Asp Tyr Ile Arg Ile His Arg Ile Pro Lys Pro Leu Lys Gln Arg Met Leu Glu Tyr Phe Gln Ala Thr Trp Ala Val Asn Asn Gly Ile Asp Thr Thr Glu Leu Leu Gln Ser Leu Pro Asp Glu Leu Arg Ala Asp Ile Ala Met His Leu His Lys Glu Val Leu Gln Leu Pro Leu Phe Glu Ala Ala Ser Arg Gly Cys Leu Arg Ala Leu Ser Leu Ala Leu Arg Pro Ala Phe Cys Thr Pro Gly Glu Tyr Leu Ile His Gln Gly Asp Ala Leu Gln Ala Leu Tyr Phe Val Cys Ser Gly Ser Met Glu Val Leu Lys Gly Gly Thr Val Leu Ala Ile Leu Gly Lys Gly Asp Leu Ile Gly Cys Glu Leu Pro Arg Arg Glu Gln Val Val Lys Ala Asn Ala Asp Val Lys Gly Leu Thr Tyr Cys Val Leu Gln Cys Leu Gln Leu Ala Gly Leu His Asp Ser Leu Ala Leu Tyr Pro Glu Phe Ala Pro Arg Phe Ser Arg Gly Leu Arg Gly Glu Leu Ser Tyr Asn Leu Gly 690 695 7pp Ala Gly Gly Gly Ser Ala Glu Val Asp Thr Ser Ser Leu Ser Gly Asp Asn Thr Leu Met Ser Thr Leu Glu Glu Lys Glu Thr Asp Gly Glu Gln Gly Pro Thr Val Ser Pro Ala Pro Ala Asp Glu Pro Ser Ser Pro Leu Leu Ser Pro Gly Cys Thr Ser Ser Ser Ser Ala Ala Lys Leu Leu Ser Pro Arg Arg Thr Ala Pro Arg Pro Arg Leu Gly Gly Arg Gly Arg Pro Gly Arg Ala Gly Ala Leu Lys Ala Glu Ala Gly Pro Ser Ala Pro Pro Arg Ala Leu Glu Gly Leu Arg Leu Pro Pro Met Pro Txp Asn Val Pro Pro Asp Leu Ser Pro Arg Val Val Asp Gly Ile Glu Asp Gly Cys Gly Ser Asp Gln Pro Lys Phe Ser Phe Arg Val Gly Gln Ser Gly Pro Glu Cys Ser Ser Ser Pro Ser Pro Gly Pro Glu Ser Gly Leu Leu Thr Val Pro His Gly Pro Ser Glu Ala Arg Asn Thr Asp Thr Leu Asp Lys Leu Arg Gln Ala Val Thr Glu Leu Ser Glu Gln Val Leu Gln Met Arg Glu Gly Leu Gln Ser Leu Arg Gln Ala Val Gln Leu Val Leu Ala Pro His Arg Glu Gly Pro Cys Pro Arg Ala Ser Gly Glu Gly Pro Cys Pro Ala Ser Thr Ser Gly Leu Leu Gln Pro Leu Cys Val Asp Thr Gly Ala Ser Ser Tyr Cys Leu Gln Pro Pro Ala Gly Ser Val Leu Ser Gly Thr Trp Pro His Pro Arg Pro Gly Pro Pro Pro Leu Met Ala Pro Arg Pro Trp Gly Pro Ala Ser Gln Ser Pro TrpProArgAla Thr Phe Pro Ser Ala Trp Thr Thr Ser Asp Ser Pro ProAlaSerGly Asp Cys Ser Glu Leu Ser Glu Ser Thr Pro Ala Pro ProProSerGlu Glu Ala Pro Ser Gly Arg Thr Pro Ala Glu Pro Ser GlnAlaGluAla Thr Thr Gly Val Ser Gly Glu Pro Pro Gly Ser Gly LeuAlaLeuPro Trp Pro Pro Gly Asp His Ser Glu Met Val Leu Gly CysHisGlySer Gly Val Leu Ile Thr ' 1060 1065 1070 Gln Trp Gln Glu Glu Gly Gly Val Thr Thr <210> 21 <211> 1800 <212> DNA

<213> H. Sapiens <220>

<221> CDS

<222> (346)...(1057) <223> K+Hnov28, splice <400> 21 atttgaatga tcttaagtac 60 ctgggttact agtatagttc tcctagactc ttcctccttc tttctctgaa ctctatggta 120 aatcttcagt ggaatacagg ctcttagttc cagatgggtt acatgtagaa ctttgccctg 180 ggccctaggg tagtaggttt gaatgctttc ttccccagat cagctgagca cctctgttgg 240 aggacgagta gtggaaaaag gtttttctgg tgtttggcct actttcttct gtctgttttt 300 ctattttcct ctcctcttga agttatatat gctatcatat agtttccctg agcag 357 aaacctgggc atg tcttgaagac gat gcatcactgg aat gga Met Asp Asn Gly gac tgg tat atg atg act cca gtcacattaaat gta gga 405 ggc gac ggt Asp Trp Tyr Met Met Thr Pro ValThrLeuAsn Val Gly Gly Asp Gly cac ttg aca acg tct ctc aca ttgacgcgttac ccg tcc 453 tat acc gat His Leu Thr Thr Ser Leu Thr LeuThrArgTyr Pro Ser Tyr Thr Asp atg ctt get atg ttt ggg gac ttccccacaget cga cct 501 gga ggg gac Met Leu Ala Met Phe Gly Asp PheProThrAla Arg Pro Gly Gly Asp caa ggc tac ttt att gat gat ggacctcttttc cga gtc 549 aat cga tat Gln Gly Tyr Phe Ile Asp Asp GlyProLeuPhe Arg Val Asn Arg Tyr ctc aac tta aga act tca ttg accttaccgttg gat aag 59'7 ttc gaa ttt Leu Asn Leu Arg Thr Ser Leu ThrLeuProLeu Asp Lys Phe Glu Phe gaa ttt ctg ctt cgg aaa gca gatttttaccag att ccc 645 gat gaa gag Glu Phe Leu Leu Arg Lys Ala AspPheTyrGln Ile Pro Asp Glu Glu ttg att cag tgt ctc aat aag cct tat ccc atg gat 693 gat cct ttg act Leu Ile Gln Cys Leu Asn Lys Pro Tyr Pro Met Asp Asp Pro Leu Thr ttt gaa gaa gtt gtg gag agt act aag ctt tct aag 741 ctg tct cgg tac Phe Glu Glu Val Val Glu Ser Thr Lys Leu Ser Lys Leu Ser Arg Tyr tcc aac cca gtg get gtc acg caa acc atc acc act 789 atc ata cta aag Ser Asn Pro Val Ala Val Thr Gln Thr Ile Thr Thr Ile Ile Leu Lys gtc cat tcc tta cta gaa tca aat ttt acc aag tgg 837 ggc atc tat aat Val His Ser Leu Leu Glu Ser Asn Phe Thr Lys Trp Gly Ile Tyr Asn aag cac atg atg gac acc tgc cag tcc ttt act ttt 885 aga gac gtt gga Lys His Met Met Asp Thr Cys Gln Ser Phe Thr Phe Arg Asp Val Gly ccc tgt gat tat cac cag tct ctt gtc cac ctg atg 933 gaa gtt agg gaa Pro Cys Asp Tyr His Gln Ser Leu Val His Leu Met Glu Val Arg Glu tac att aca aaa caa ggt atc cgc acc cgg gtg cat 981 ttc acg aac cac Tyr Ile Thr Lys Gln Gly Ile Arg Thr Arg Val His Phe Thr Asn His atg agt gag cgg gcc aat aca gtg cac aac tgg act 1029 gaa aac gag ttc Met_Ser Glu Arg Ala Asn Thr Val His Asn Trp Thr Glu Asn Glu Phe tgt agg cta gcc cgg aag gac t 1077 aca gac gatctccgac cctgccacag Cys Arg Leu Ala Arg Lys Thr Asp Asp gttcctggaa agactctcca ggaaatggaagatactgattttttttttta aatcacagtg1137 tgagatattt tttttctttt aaatagttgtatttatttgaaggcagtgag gaccagaagg1197 aagttttgtg ctttggcaga ctcctccatgttttgttcccttccccctga gtatgcatgt1257 gcctgttcag agtctceaga taccttttttataaaaagaagtctgaaaat cattatggta1317 tataatctac ccttaacaga gcttttcttattacagtgctaaaatgattt ctgataaaat1377 ggtccctaac tcaactagaa ggctaaaaatacaagaatgaaagaataagc agagtactca1437 tgatgccttt gagaaaaatc aaaacatcatgtagggtgacctagtttcca aaccaataaa1497 taagtagtat tgtaatatta aaggaaaactgttccaatcatttaaaagta cttattaagt1557 actgcttttt acagttatga caactgtttctttctatgcatataaatcaa ggaaccaaat1617 atctgtagcc atggaaatgt ctgactagaaatatttatattgaattctga atacaaaatg1677 tccctgtggt agaaaactta ctctttatgcctggtgcagtataattccca agtgtactgt1737 ctaccagaaa aaaaaaacaa aactaataaaaaatgaaatatgaaaaaaaa aaaaaaaaaa1797 aaa <210> 22 <211> 1836 <212> DNA

<213> H, Sapiens <220>

<221> CDS

<222> (382)...(1093) <223> K+Hnov28 splice 2 <400> 22 gaggaatgtt atgattttgt tttgt cagctttt taatattagg tcacttttaa60 gacta ga acctatagct tctctcttct tgggaaag gagaaagaga aaatgattac120 agaccacatg gt ttgtagagaa aaatccattt t ataatctaac cataatcaca180 ctgcagtgg atggttaagg ttatccttgtatgcctggct tgctg ctgtatgt gaatgttaac cccaaagact240 acttg gc cctttagatg tcgctgaact ctata cgctttcaaa ctcccacatt300 agtta aaaagtattt tcaagaagag caaaactcaa ttgaagtt tccctgaaac ctgggctctt tacaaggcaa tt gaagacgcat cactggagca atggataatgga gactggggc tatatgatg 411 g MetAapAsnGly AspTrpGly TyrMetMet act ccagtcaca ttaaatgtaggtgga cacttgtat acaacgtct 459 gac Thr ProValThr LeuAsnValGlyGly HisLeuTyr ThrThrSer Asp ctc acattgacg cgttacccggattcc atgcttgga getatgttt 507 acc Leu ThrLeuThr ArgTyrProAspSer MetLeuGly AlaMetPhe Thr ggg gacttcccc acagetcgagaccct caaggcaat tactttatt 555 ggg Gly AspPhePro ThrAlaArgAspPro GlnGlyAsn TyrPheIle Gly gat gatggacct cttttccgatatgtc ctcaacttc ttaagaact 603 cga Asp AspGlyPro LeuPheArgTyrVal LeuAsnPhe LeuRrgThr Arg 60 65 7p tca ttgacctta ccgttggattttaag gaatttgat ctgcttcgg 651 gaa Ser LeuThrLeu ProLeuAspPheLys GluPheAsp LeuLeuArg Glu aaa gcagatttt taccagattgagccc ttgattcag tgtctcaat 699 gaa Lys AlaAspPhe TyrGlnIleGluPro LeuIleGln CysLeuAsn Glu gat aagcctttg tatcccatggatact tttgaagaa gttgtggag 747 cct Asp LysProLeu TyrProMetAspThr PheGluGlu ValValGlu Pro ctg agtactcgg aagctttctaagtac tccaaccca gtggetgtc 795 tct Leu SerThrArg LysLeuSerLysTyr SerAsnPro ValAlaVal Ser atc acgcaacta accatcaccactaag gtccattcc ttactagaa 843 ata Ile ThrGlnLeu ThrIleThrThrLys ValHisSer LeuLeuGlu Ile ggc tcaaattat tttaccaagtggaat aagcacatg atggacacc 891 atc Gly SerAsnTyr PheThrLysTrpAsn LysHisMet MetAspThr Ile aga tgccaggtt tcctttacttttgga ccctgtgat tatcaccag 939 gac Arg CysGlnVal SerPheThrPheGly ProCysAsp TyrHisGln Asp gaa tctcttagg gtccacctgatggaa tacattaca aaacaaggt 987 gtt Glu SerLeuArg ValHisLeuMetGlu TyrIleThr LysGlnGly Val ttc atccgcaac acccgggtgcatcac atgagtgag cgggccaat 1035 acg Phe IleArgAsn ThrArgValHisHis MetSerGlu ArgAlaAsn Thr gaa aac aca gtg gag cac aac tgg act ttc tgt agg cta gcc cgg aag 1083 Glu Asn Thr Val Glu Hia Asn Trp Thr Phe Cys Arg Leu Ala Arg Lys aca gac gac t gatctccgac cctgccacag gttcctggaa agactctcca 1133 Thr Asp Asp ggaaatggaagatactgatttttttttttaaatcacagtgtgagatattttttttctttt1193 aaatagttgtatttatttgaaggcagtgaggaccagaaggaagttttgtgctttggcaga1253 ctcctccatgttttgttcccttccccctgagtatgcatgtgcctgttcagagtctccaga1313 taccttttttataaaaagaagtctgaaaatcattatggtatataatctacccttaacaga1373 gcttttcttattacagtgctaaaatgatttctgataaaatggtccctaactcaactagaa1433 ggctaaaaatacaagaatgaaagaataagcagagtactcatgatgcctttgagaaaaatc1493 aaaacatcatgtagggtgacctagtttccaaaccaataaataagtagtattgtaatatta1553 aaggaaaactgttccaatcatttaaaagtacttattaagtactgctttttacagttatga1613 caactgtttctttctatgcatataaatcaaggaaccaaatatctgtagccatggaaatgt1673 ctgactagaaatatttatattgaattctgaatacaaaatgtccctgtggtagaaaactta1733 ctctttatgcctggtgcagtataattcccaagtgtactgtctaccagaaaaaaaaaacaa1793 aactaataaaaaatgaaatatgaaaaaaaaaaaaaaaaaaaaa 1836 <210> 23 <211> 1751 <212> DNA
<213> H. sapiens <220>
<221> CDS
<222> (297)...(1008) <223> K+Hnov28 splice 3 <400> 23 ccatgtttcttaccatgtct tgccagagct ttagaaatttgctctgcagtttgctttaca60 ggttgatttgggattgaagt gtgtgagagg gaactgactaaggcagttcagtagctggga120 aactgtttgtttaaatgctt ttgaattgta gataaaaataaattcacattggcatcatta180 gtatctgagcatttctcagt gtcttaaggc tggctctccatgagtgctggctgattgact240 ctcatctatatcgtttccct gaaacctggg ctcttgaagacgcatcactggagcag 299 atg Met gat aat gac tgg ggc tat atg atg cca gtc tta aat 347 gga act gac aca Asp Asn Pro Val Leu Asn Gly Asp Thr Trp Gly Tyr Met Met Thr Asp gta ggt cac ttg tat aca acg tct aca ttg cgt tac 395 gga ctc acc acg Val Gly His Leu Tyr Thr Thr Ser Thr Leu Arg Tyr Gly Leu Thr Thr ccg gat atg ctt gga get atg ttt gac ttc aca get 443 tcc ggg ggg ccc Pro Asp Met Leu Gly Ala Met Phe Asp Phe Thr Ala Ser Gly Gly Pro cga gac caa ggc aat tac ttt att gat gga ctt ttc 491 ect gat cga cct Arg Asp Gln Gly Asn Tyr Phe Ile Asp Gly Leu Phe Pro Asp Arg Pro cga tat ctc aac ttc tta aga act ttg acc ccg ttg 539 gtc tca gaa tta Arg Tyr Leu Asn Phe Leu Arg Thr Leu Thr Pro Leu Val Ser Glu Leu gat ttt aag gaa ttt gat cgg aaa gca gat ttt tac 587 ctg ctt gaa cag Asp Phe Lys Glu Phe Asp Arg Lys Ala Asp Phe Tyr Leu Leu Glu Gln att gag ccc ttg att cag aat gat aag cct ttg tat 635 tgt ctc cct ccc Ile Glu Pro Leu Ile Gln Asn Asp Lys Pro Leu Tyr Cys Leu Pro Pro atg gat act ttt gaa gaa gag ctg agt act cgg aag 683 gtt gtg tct ctt Met Asp Thr Phe Glu Glu Glu Leu Ser Thr Arg Lys Val Val Ser Leu tct aag tac tcc aac cca gtc atc acg caa cta acc 731 gtg get ata atc Ser Lys Tyr Ser Asn Pro Val Ile Thr Gln Leu Thr Val Ala Ile Ile acc act aag gtc cat tcc gaa ggc tca aat tat ttt 779 tta cta atc acc Thr Thr Lys Val His Ser Glu Gly Ser Asn Tyr Phe Leu Leu Ile Thr aag tgg aat aag cac atg acc aga tgc cag gtt tcc 827 atg gac gac ttt Lys Trp Asn Lys His Met Thr Arg Cys Gln Val Ser Met Asp Asp Phe act ttt gga ccc tgt gat cag gaa tct ctt agg gtc 875 tat cac gtt cac Thr Phe Gly Pro Cys Asp Gln Glu Ser Leu Arg Val Tyr His Val His ctg atg gaa tac att aca ggt ttc atc cgc aac acc 923 aaa caa acg cgg Leu Met Glu Tyr Ile Thr Gly Phe Ile Arg Asn Thr Lys Glri Thr Arg gtg cat cac atg agt gag aat gaa aca gtg gag cac 971 cgg gcc aac aac Val His His Met Ser Glu Asn Glu Thr Val Glu His Arg Ala Asn Asn tgg act ttc tgt agg cta aag aca gac t gatctccgac 1018 gcc cgg gac Trp Thr Phe Cys Arg Leu Lys Thr Asp Ala Arg Asp cctgccacag gttcctggaa agactctccaggaaatggaagatactgatt ttttttttta1078 aatcacagtg tgagatattt tttttcttttaaatagttgtatttatttga aggcagtgag1138 gaccagaagg aagttttgtg ctttggcagactcctccatgttttgttccc ttccccctga1198 gtatgcatgt gcctgttcag agtctccagataccttttttataaaaagaa gtctgaaaat1258 cattatggta tataatctac ccttaacagagcttttcttattacagtgct aaaatgattt1318 ctgataaaat ggtccctaac tcaactagaaggctaaaaatacaagaatga aagaataagc1378 agagtactca tgatgccttt gagaaaaatcaaaacatcatgtagggtgac ctagtttcca1438 aaccaataaa taagtagtat tgtaatattaaaggaaaactgttccaatca tttaaaagta1498 cttattaagt actgcttttt acagttatgacaactgtttctttctatgca tataaatcaa1558 ggaaccaaat atctgtagcc atggaaatgtctgactagaaatatttatat tgaattctga1618 atacaaaatg tccctgtggt agaaaacttactctttatgcctggtgcagt ataattccca1678 agtgtactgt ctaccagaaa aaaaaaacaaaactaataaaaaatgaaata tgaaaaaaaa1738 aaaaaaaaaa aaa 1751 <210> 24 <211> 1542 <212> DNA

<213> H. sapiens <220>

WO 99/43696 PCTlUS99103826 <221> CDS

<222> (881...(799) <223> K+Hnov2 8, splice <400> 24 cgggcatctc ccggcccggc cgcatttccc tgaaacctgg cgcagcagcc gccgccgccg gctcttgaag acgcatcact 114 ggagcag atg gat aat gga gac tgg ggc tat atg Met ly Asp Tyr Asn Met Gly Asp Trp G

atgactgacccagtcaca ttaaatgtaggt ggacacttgtataca acg 162 MetThrAspProValThr LeuAsnValGly GlyHisLeuTyrThr Thr tctctcaccacattgacg cgttacccggat tccatgcttggaget atg 210 SerLeuThrThrLeuThr ArgTyrProAsp SerMetLeuGlyAla Met tttgggggggacttcccc acagetcgagac cctcaaggcaattac ttt 258 PheGlyGlyAspPhePro ThrAlaArgAsp ProGlnGlyAsnTyr Phe attgatcgagatggacct cttttccgatat gtcctcaacttctta aga 306 IleAspArgAspGlyPro LeuPheArgTyr ValLeuAsnPheLeu Arg 60 65 ?0 acttcagaattgacctta ccgttggatttt aaggaatttgatctg ctt 354 ThrSerGluLeuThrLeu ProLeuAspPhe LysGluPheAspLeu Leu ?5 80 85 cggaaagaagcagatttt taccagattgag cccttgattcagtgt ctc 402 ArgLysGluAlaAspPhe TyrGlnIleGlu ProLeuIleGlnCys Leu aatgatcctaagcctttg tatcccatggat acttttgaagaagtt gtg 450 AsnAspProLysProLeu TyrProMetAsp ThrPheGluGluVal Val gagctgtctagtactcgg aagctttctaag tactccaacccagtg get 498 GluLeuSerSerThrArg LysLeuSerLys TyrSerAsnProVal Ala gtcatcataacgcaacta accatcaccact aaggtccattcctta cta 546 ValIleIleThrGlnLeu ThrIleThrThr LysValHisSerLeu Leu gaaggcatctcaaattat tttaccaagtgg aataagcacatgatg gac 594 GluGlyIleSerAsnTyr PheThrLysTrp AsnLysHisMetMet Asp accagagactgccaggtt tcctttactttt ggaccctgtgattat cac 642 ThrArgAspCysGlnVal SerPheThrPhe GlyProCysAspTyr His caggaagtttctcttagg gtccacctgatg gaatacattacaaaa caa 69~

GlnGluValSerLeuArg ValHisLeuMet GluTyrIleThrLys Gln ggtttcacgatccgcaac acccgggtgcat cacatgagtgagcgg gcc ?38 GlyPheThrIleArgAsn ThrArgValHis HisMetSerGluArg Ala 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 aag aca gac gac t gatctccgac cctgccacag gttcctggaa agactctcca 839 Lys Thr Asp Asp ggaaatggaagatactgatttttttttttaaatcacagtgtgagatattttttttctttt899 aaatagttgtatttatttgaaggcagtgaggaccagaaggaagttttgtgctttggcaga959 ctcctccatgttttgttcccttccccctgagtatgcatgtgcctgttcagagtctccaga1019 taccttttttataaaaagaagtctgaaaatcattatggtatataatctacccttaacaga1079 gcttttcttattacagtgctaaaatgatttctgataaaatggtccctaactcaactagaa1139 ggctaaaaatacaagaatgaaagaataagcagagtactcatgatgcctttgagaaaaatc1199 aaaacatcatgtagggtgacctagtttccaaaccaataaataagtagtattgtaatatta1259 aaggaaaactgttccaatcatttaaaagtacttattaagtactgctttttacagttatga1319 caactgtttctttctatgcatataaatcaaggaaccaaatatctgtagccatggaaatgt1379 ctgactagaaatatttatattgaattctgaatacaaaatgtccctgtggtagaaaactta1439 ctctttatgcctggtgcagtataattcccaagtgtactgtctaccagaaaaaaaaaacaa1499 aactaataaaaaatgaaatatgaaaaaaaaaaaaaaaaaaaaa 1542 <210> 25 <211> 237 <212> PRT
<213> H. sapiens <400> 25 Met Asp Asn Gly Asp Trp Gly Tyr Met Met Thr Asp Pro Val Thr Leu Asn Val Gly Gly His Leu Tyr Thr Thr Ser Leu Thr Thr Leu Thr Arg Tyr Pro Asp Ser Met Leu Gly Ala Met Phe Gly Gly Asp Phe Pro Thr Ala Arg Asp Pro Gln Gly Asn Tyr Phe Ile Asp Arg Asp Gly Pro Leu Phe Arg Tyr Val Leu Asn Phe Leu Arg Thr Ser Glu Leu Thr Leu Pro Leu Asp Phe Lys Glu Phe Asp Leu Leu Arg Lys Glu Ala Asp Phe Tyr Gln Ile Glu Pro Leu Ile Gln Cys Leu Asn Asp Pro Lys Pro Leu Tyr Pro Met Asp Thr Phe Glu Glu Val Val Glu Leu Ser Ser Thr Arg Lys Leu Ser Lys Tyr Ser Asn Pro Val Ala Val Ile Ile Thr Gln Leu Thr Ile Thr Thr Lys Val His Ser Leu Leu Glu Gly Ile Ser Asn Tyr Phe Thr Lys Trp Asn Lys His Met Met Asp Thr Arg Asp Cys Gln Val Ser Phe Thr Phe Gly Pro Cys Asp Tyr His Gln Glu Val Ser Leu Arg Val His Leu Met Glu Tyr Ile Thr Lys Gln Gly Phe Thr Ile Arg Asn Thr Arg Val His His Met Ser Glu Arg Ala Asn Glu Asn Thr Val Glu His Asn Trp Thr Phe Cya Arg Leu Ala Arg Lys Thr Asp Asp <210> 26 <211> 3204 <212> DNA
<213> H. Sapiens <220>
<221> CDS
<222> (182)...(1349) <223> K+Hnov42 <400> 26 cggccgaacc ttgggtgt gg tgtgtcccca agggcaggaa 60 gacagagtgc gtgcgtgtgg ggtggcgaag at gaagggcggg aggagaaaaa120 ggaggcga ccgagtgggt ggagggaggg ggtgggagga tg ggacccagcg ggggcagcgc180 ggaccagg ggagggtggc ggctcactca g tg cc ac 229 a agg ctg gga cgg ttc aag gtg ctg a aac ggc agc ccc aag a M et ly Arg Lys Arg Val Thr Leu Phe Leu Asn Gly Ser Pro Lys Asn G

gtggtt getgtatatgga actttatctgat ttgctttctgtggcc agc 277 ValVal AlaValTyrGly ThrLeuSerAsp LeuLeuSerValAla Ser agtaaa ctcggcataaaa gccaccagtgtg tataatgggaaaggt gga 325 SerLys LeuGlyIleLys AlaThrSerVal TyrAsnGlyLysGly Gly ctgatt gatgatattget ttgatcagggat gatgatgttttgttt gtt 373 LeuIle AspAspIleAla LeuIleArgAsp AspAspValLeuPhe Val tgtgaa ggagagccattt attgatcctcag acagattctaagcct cct 421 CysGlu GlyGluProPhe IleAspProGln ThrAspSerLysPro Pro 65 70 75 g0 gaggga ttgttaggattc cacacagactgg ctgacattaaatgtt gga 469 GluGly LeuLeuGlyPhe HisThrAspTrp LeuThrLeuAsnVal Gly gggcgg tactttacaact acacggagcact ttagtgaataaagaa cct 517 GlyArg TyrPheThrThr ThrArgSerThr LeuValAsnLysGlu Pro gacagt atgctggcccac atgtttaaggac aaaggtgtctgggga aat 565 AspSer MetLeuAlaHis MetPheLysAsg LysGlyValTrpGly Asn aagcaa gatcatagagga getttcttaatt gaccgaagtcctgag tac 6i3 LysGln AspHisArgGly AlaPheLeuIle AspArgSerProGlu Tyr ttcgaa cccattttgaac tacttgcgtcat ggacagctcattgta aat 661 PheGlu ProIleLeuAsn TyrLeuArgHis GlyGlnLeuIleVal Asn gatggc attaatttattg ggtgtgttagaa gaagcaagatttttt ggt 709 AspGly IleAsnLeuLeu GlyValLeuGlu GluAlaArgPhePhe Gly attgac tcattgattgaa cacctagaagtg gcaataaagaattct caa 757 IleAsp SerLeuIleGlu HisLeuGluVal AlaIleLysAsnSer Gln ccaccg gaggatcattca ccaatatcccga aaggaatttgtccga ttt 805 ProProGlu Asp Ser Pro Ser Arg Glu Phe Arg Phe His Ile Lys Val ttgctagca act acc aag gaa ctg tgc cag ttg aac B53 cca tca cga ggt LeuLeuAla Thr Thr Lys Glu Leu Cys Gln Leu Asn Pro Ser Arg Gly ttcagtggt get ctt tct ttg gac cga tac aac ttc 901 gat cgt ctt att PheSerGly Ala Leu Ser Leu Asp Arg Tyr Asn Phe Asp Arg Leu Ile aaaatggcc aat agc cgc aat ctt cat gca ctt tgc 949 tta tgt gca aat LysMetAla Asn Ser Arg Asn Leu His Ala Leu Cys Leu Cys Ala Asn tgtgcaaat ctt cga get ctc tct tca gtg gac tgt 997 gaa gat gga ctt CysAlaAsn Leu Arg Ala Leu Ser Ser Val Asp Cys Glu Asp Gly Leu gcgaatctc cag gtc aag ctc tgt aat gca gga gca 1045 gga atg tct gaa AlaAsnLeu Gln Val Lys Leu Cys Asn Ala Gly Ala Gly Met Ser Glu tccctgaaa ctg aat ttt gat cct ggt ctt gcc aat 1093 tgt gag tct aaa SerLeuLys Leu Asn Phe Asp Pro Gly Leu Ala Asn Cys Glu Ser Lys ttagaaggt get ctg aaa gtg gat gaa gga cag atg 1141 aat ggt atg agt LeuGluGly Ala Leu Lys Val Asp Glu Gly Gln Met Asn Gly Met Ser acaggaatt aac aga gtg acc tta aat gca ttg aag 1189 ctg get aaa aag ThrGlyIle Asn Arg Val Thr Leu Asn Ala Leu Lys Leu Ala Lys Lys aactgtaac ctc gga gca ctg gca act gat gag aat 1237 aga act gga tta AsnCysAsn Leu Gly Ala Leu Ala Thr Asp Glu Asn Arg Thr Gly Leu tgtgatctg tct tgt gat caa gaa aac ctg ggg tcc 1285 ggg ctt gcc aga CysAspLeu Ser Cys Asp Gln Glu Asn Leu Gly Ser Gly Leu Ala Arg aacgtgaag gga ata ttt gag atg aca cca cac atg 1333 get gaa ctg cta AsnValLys Gly Ile Phe Glu Met Thr Pro His Met Ala Glu Leu Leu tcacaaagt gtc t gagaattttaggggctggaggaagatgtaaagatgaaaa1389 aga a SerGlnSer Val Arg tgttttcctt cactcagttgtctagaagaataacactgt1449 atcacttttc a tttctccacc aaggaaattt attatgcttgttttgagtgg 1509 taaaaaaaaa tgcataaggg catttagagg aaaaaact ga ctttttttcc ttttaacagaaaagcactcattaatagat1569 atattctgat t gtagggaaac atggggtaggggggtttacc 1629 tagatattgc tggttttatg tgccttttga accaggca ta gtatctatta taaataggcatgatgtggaataccatctt1689 tatttgcttt a ggtttgagat atggaaagcacaacatatgc 1749 gcatttgagg aattatattt attttaattt attgaatt cc tagatgcagt aaattgttaaaactttatga 1809 atggatattt aaacttggaa aaggttgt tc aggtttataa tgatgcctcccctctttaaaacctgtcac1869 atagctttag t accgtatgaa taagactcttttcaggttcattttataat1929 tatggtgaga t tcagactccc gtttactt tt taggacagaa attaaagtaatatccagttctactgattg1989 cagtagctaa t agacagagtggaaagaaagacatcattgtacatcactgtcattccaaaggtacagtgtaa2049 ctctggatggaggaataacttacctatcactacaacacttacaaatgagaatttctcaga2109 atttcattctaggcaagttccactcaacaccagatcaagcaattctatctatttacacta2169 ttagcctagttttctcatacagtcatcacaagcataggaagatacttcaaaaccaaaaaa2229 accaaggtgcatcattaatattcatttaattcaaataccaaatagtttacatagggccag2289 cttagaaatagatactaaatccagagctactgcaatcaaagcttatatgagtgaatatgg2349 tagagttgcctgctaaaaggcaatgtaatataattgcagctagaaccctacagtggggaa2409 tgaggaattttaaacacacatttgattacagccaccaaaaaaatagacgtaaaaataaag2469 gcatttggctggtccaagatgtaattttcaatcagtcagcacctgtgattcttttactta2529 tttttttgtggttttttttttttaaacaaattttagcccaattttcttgagtcattctct2589 ctctgcagcagcagaggaagggcctgtacctccctaccaatgacttggtgtccttatttt2649 ctaccccaagagcagggatattagctgtgtccaaatgggttctgaattctacagactcat2709 caacatgaggcaaggaatcattgaaaaccacctgtgtctcctttgggagaatgacatatc2769 tttagtatttacgtagcttattcttctatatctacatatgcaaagctttccttaacagta2829 aagggtacatatgcatagtgggaggagatcagacctttacaagtgaaggaaagcaacttc2889 agaaatgaattattttctttgctttattatttttaccaagacagagaagtattgtattga2949 gagataatctattttcataatcaatatgtgcctaaattatatttaaatcatttcactctg3009 tactatattttcaggaattacagaatgtggtattcattcacttaaaggtacctctgtaga3069 aataacctaaaactgcagaaggatctgaaagatctaaacatggtgtgcttagaaactgca3129 gattttagatctaatgtatactgcattaataaatgatataaagtgtttgttgaaaaaaaa3189 aaaaaaaaaaaaaaa 3204 <210> 27 <211> 389 <212> PRT
<213> H. sapiens <400> 27 Met Arg Arg Val Thr Leu Phe Leu Asn Gly Ser Pro Lys Asn Gly Lys_ Val_Val Ala Val Tyr Gly Thr Leu Ser Asp Leu Leu Ser Val Ala Ser Ser Lys Leu Gly Ile Lys Ala Thr Ser Val Tyr Asn Gly Lys Gly Gly Leu Ile Asp Asp Ile Ala Leu Ile Arg Asp Asp Asp Val Leu Phe Val Cys Glu Gly Glu Pro Phe Ile Asp Pro Gln Thr Asp Ser Lys Pro Pro Glu Gly Leu Leu Gly Phe His Thr Asp Trp Leu Thr Leu Asn Val Gly Gly Arg Tyr Phe Thr Thr Thr Arg Ser Thr Leu Val Asn Lys Glu Pro Asp Ser Met Leu Ala His Met Phe Lys Asp Lys Gly Val Trp Gly Asn Lys Gln Asp His Arg Gly Ala Phe Leu Ile Asp Arg Ser Pro Glu Tyr Phe Glu Pro Ile Leu Asn Tyr Leu Arg His Gly Gln Leu Ile Val Asn Asp Gly Ile Asn Leu Leu Gly Val Leu Glu Glu Ala Arg Phe Phe Gly Ile Asp Ser Leu Ile Glu His Leu Glu Val Ala Ile Lys Asn Ser Gln Pro Pro Glu Asp His Ser Pro Ile Ser Arg Lys Glu Phe Val Arg Phe Leu Leu Ala Thr Pro Thr Lys Ser Glu Leu Arg Cys Gln Gly Leu Asn Phe Ser Gly Ala Asp Leu Ser Arg Leu Asp Leu Arg Tyr Ile Asn Phe Lys Met Ala Asn Leu Ser Arg Cys Asn Leu Ala His Ala Asn Leu Cys Cys Ala Asn Leu Glu Arg Ala Asp Leu Ser Gly Ser Val Leu Asp Cys Ala Asn Gln Gly Val Lys Leu Cys Asn Ala Glu Gly Leu Met Ser Ala Ser Leu Leu Cys Asn Phe Asp Pro Gly Leu Lys Ala Lys Glu Ser Asn Leu Glu Ala Asn Leu Lys Val Asg Glu Gly Ser Gln Gly Gly Met Met Thr Gly Asn Leu Arg Val Thr Leu Asn Ala Lys Leu Ile Ala Lys Lys Asn Cys Leu Arg Gly Ala Leu Ala Thr Asp Leu Glu Asn Thr Gly Asn Cys Asp Ser Gly Cys Asp Gln Glu Asn Leu Arg Gly Leu Leu Ala Ser Asn Val Gly Ala Ile Phe Glu Met Thr Pro Leu His Lys Glu Leu Met Ser Gln Val Arg Sex <210> 28 <211> 1246 <212> DNA

<213> H. sapiens <220>

<221> CDS

<222> (432)...(1092) <223> K+Hnov44, splice <400> 28 cagaaaacca ccgctccgcc ttgccaggag60 cgcaggtcct tcttgatcat ctagaactga tctgcagaac tctccaggaa ggcggggggc120 cacgtggcta gcctgcctga agttctcacc ttctaatggc ctgggactcc acttccgtgg180 tgcagctgcg ctgggggctg ggggctcccg atgtctaagc ctcaggtgaa agggagccat240 ttcacctttc ttgcgcccgc aggggcatga tttctcagac cgtgcaaatc acacttcagg300 ccctggcctc atgcagccct tcagcatccc gcagccggag agggaagaag agagagacag360 gcgccagggg aggacagcct ttcctgcctc actacagtga gccatccagt gctggagagg420 tggagaccca ctagatgtgc acaagaggct accgagccgt 470 g atg ctg ggg ttt gcc atg atg ggc ttc tca gtc cta atg Met Leu Gly Phe Ala Met Met Gly Phe 5er Val Leu Met ttc ttc ctc gga aca acc cta aag ttt atg ctc agc 518 ttg att cct att Phe Phe Leu Gly Thr Thr Leu Lys Phe Met Leu Ser Leu Ile Pro Ile cag aga gaa tcg acc tgc gcc atc aca gat atc atg 566 gaa act cac gac Gln Arg Glu Ser Thr Cys Ala IIe Thr Asp Ile Met Glu Thr His Asp gac tgg gac tgt gcc ttc tgt ggt cac tgc cac ggt 614 ctg acc gtg cag Asp Trp Asp Cys Ala Phe Cys Gly Hia Cys His Gly Leu Thr Val Gln ggg aag ccg tgt ctt cag ttt gtg ctc agc cat cca 662 tac gtg aac ggt Gly Lys Pro Cys Leu Gln Phe Val Leu Ser His Pro Tyr Val Asn Gly cag aaa ctc cta cat tat gaa gag gtc cag ata aat 710 get aat get ccc Gln Lys Leu Leu His Tyr Glu Glu Val Gln Ile Asn Ala Asn Ala Pro aag tgc tac aca cct aag cac caa aga aat gat ttg 758 ttt tgc gat ctc Lys Cys Phe Tyr Thr Pro Lys Cys His Gln Asp Arg Asn Asp Leu Leu aacagt ctg gac aaagaattcttc gatcacaaaaat ggaact 806 get ata AsnSer Leu Asp LysGluPhePhe AspHisLysAsn GlyThr Ala Ile cccttt tgc ttc agtccagccagc caatctgaagat gtcatt 854 tca tac ProPhe Cys Phe SerProAlaSer G1nSerGluAsp ValIle Ser Tyr cttata aag tat caaatggetatc ttccactgttta ttttgg 902 aaa gac LeuIle Lys Tyr GlnMetAlaIle PheHisCysLeu PheTrp Lys Asp ccttca act ctg ggtggtgccctg attgttggcatg gtgaga 950 ctg cta ProSer Thr Leu GlyGlyAlaLeu IleValGlyMet ValArg Leu Leu ttaaca cac ctg ttactgtgtgaa aaatatagcact gtagtc 998 caa tcc LeuThr His Leu LeuLeuCysGlu LysTyrSerThr ValVal Gln Ser agagat gta ggt aaagtaccttat atagaacagcat cagttc 1046 gag gga ArgAsp Val Gly LysValProTyr IleGluGlnHis GlnPhe Glu Gly aaactg att atg aggagcaaagga agagcagagaaa tctt 1092 tgc agg LysLeu Ile Met ArgSerLysGly ArgAlaGluLys Ser Cys Arg aagacggtgg tcagatgtct gtgatttctg 1152 ccaaattaaa caactgagga gtgctggcct cctaattatg gtaaaaggta ataattaaag 1212 cctgtctgca tatcatattt aactaataat tcatgtggga aaaaaaaa 1246 aaaaaaaaaa aaaaaa <210> 29 <211> 1111 <2I2> DNA

<213> H. sapiens <220>

<221> CDS

<222> (297)...(957) <223> K+Hnov44, 2 splice <400> 29 aaaaaccatgacttgtggca ccagaagaga gccggggacttcaatccaagaaagcagaga60 agataccaaagaaggaccga gaagggcaaa gcaaagaagactgtaccatgtcctaagctg120 aggcaggcggcaggcgtggt gcacaagaag tctgagtgtgaggggctcttttctctccac180 tgccaatgacagcctttcct gcctcaggga agaagagagagacagactacagtgatggag240 acccactagatgtgcacaag aggctgccat ccagtgctggagaggaccgagccgtg 299 atg Met ctg ggg gcc atg atg ggc ttc tca atg ttc ttg ctc 347 ttt gtc cta ttc Leu Gly Ala Met Met Gly Phe Ser Met Phe Leu Leu Phe Val Leu Phe gga aca att cta aag cct ttt atg att cag gaa gaa 395 acc ctc agc aga Gly Thr Ile Leu Lys Pro Phe Met Ile Gln Glu Glu Thr Leu Ser Arg WO 9914369b PCT/US99103826 tcgacctgc actgccatccac acagatatcatg gacgactggctggac 443 SerThrCys ThrAlaIleHis ThrAspIleMet AspAspTrpLeuAsp tgtgccttc acctgtggtgtg cactgccacggt caggggaagtacccg 491 CysAlaPhe ThrCysGlyVal HisCysHisGly GlnGlyLysTyrPro tgtcttcag gtgtttgtgaac ctcagccatcca ggtcagaaagetctc 539 CysLeuGln ValPheValAsn LeuSerHisPro GlyGlnLysAiaLeu ctacattat aatgaagagget gtccagataaat cccaagtgcttttac 5B7 LeuHisTyr AsnGluGluAla ValGlnIleAsn ProLysCysPheTyr acacctaag tgccaccaagat agaaatgatttg ctcaacagtgetctg 635 ThrProLys CysHisGlnAsp ArgAsnAspLeu LeuAsnSerAlaLeu gacataaaa gaattcttcgat cacaaaaatgga actcccttttcatgc 683 AspIleLys GluPhePheAsp HisLysAsnGly ThrProPheSerCys ttctacagt ccagccagccaa tctgaagatgtc attcttataaaaaag 731 PheTyrSer ProAlaSerGln SerGluAspVal IleLeuIleLysLys tatgaccaa atggetatcttc cactgtttattt tggccttcactgact 779 TyrAspGln MetAlaIlePhe HisCysLeuPhe TrpProSerLeuThr ctgctaggt ggtgccctgatt gttggcatggtg agattaacacaacac 827 LeuLeuGly GlyAlaLeuIle ValGlyMetVal ArgLeuThrGlnHis ctgtcctta ctgtgtgaaaaa tatagcactgta gtcagagatgaggta 875 LeuSerLeu LeuCysGluLys TyrSerThrVal ValArgAspGluVal ggtggaaaa gtaccttatata gaacagcatcag ttcaaactgtgcatt 923 GlyGlyLys ValProTyrIle GluGlnHisGln PheLysLeuCysIle atgaggagg agcaaaggaaga gcagagaaatct t 967 aagacggtgg MetArgArg SerLysGlyArg AlaGluLysSer 210 ' 215 220 ccasattaaa gtgatttctg caactgagga gtgctggcct cctaattatg tcagatgtct cctgtctgca tatcatattt 1087 aactaataat tcatgtggga gtaaaaggta ataattaaag aaaaaaaaaa 1111 aaaaaaaaaa aaaa <210> 30 <211> 220 <212> PRT

<2I3> H, apiens s <400> 30 MetLeuGly PheAlaMetMet GlyPheSerVal LeuMetPhePheLeu Leu Gly Thr Thr Ile Leu Lys Pro Phe Met Leu Ser Ile Gln Arg Glu Glu Ser Thr Cys Thr Ala Ile His Thr Asp Ile Met Asp Asp Trp Leu Asp Cys Ala Phe Thr Cys Gly Val His Cys His Gly Gln Gly Lys Tyr Pro Cys Leu Gln Val Phe Val Asn Leu Ser His Pro Gly Gln Lys Ala Leu Leu His Tyr Asn Glu Glu Ala Val Gln Ile Asn Pro Lys Cys Phe Tyr Thr Pro Lys Cys His Gln Asp Arg Asn Asp Leu Leu Asn Ser Ala Leu Asp Ile Lys Glu Phe Phe Asp His Lys Asn Gly Thr Pro Phe Ser Cys Phe Tyr Ser Pro Ala Ser Gln Ser Glu Asp Val Ile Leu Ile Lys Lys Tyr Asp Gln Met Ala Ile Phe His Cys Leu Phe Trp Pro Ser Leu Thr Leu Leu Gly Gly Ala Leu Ile Val Gly Met Val Arg Leu Thr Gln His Leu Ser Leu Leu Cys Glu Lys Tyr Ser Thr Val Val Arg Asp Glu Val Gly Gly Lys Val Pro Tyr Ile Glu Gln His Gln Phe Lys Leu Cys Ile Met Arg Arg Ser Lys Gly Arg Ala Glu Lys Ser <210> 31 <211> 22 <212> DNA
<213> Artificial Sequence <220>
<223> consensus sequences <400> 31 tatccacatc aatggacaaa gc 22 <210> 32 <211> 20 <212> DNA
<213> Artificial Sequence <400> 32 tgcataactg gctgggtgta 20 <210> 33 <211> 22 <212> DNA
<213> Artificial Sequence <400> 33 tgacatcact ggatgaactt ga 22 <210> 34 <211> 20 <212> DNA
<213> Artificial Sequence <400> 34 tgcctgcaaa gtttgaacat 20 <210> 35 <211> 22 <212> DNA
<213> Artificial Sequence <400> 35 tgacatcact ggatgaactt ga 22 <210> 36 <211> 20 <212> DNA
<213> Artificial Sequence <400> 36 tgcctgcaaa gtttgaacat 20 <210> 37 <211> 20 <212> DNA
<213> Artificial Sequence <400> 37 acctggtggt atggaagcat 20 <210> 38 <211> 19 <212> DNA

<213> Artificial Sequence <900> 38 tttctcctgg cctctaccc lg <210> 39 <211> 19 <212> DNA

<213> Artificial Sequence <400> 39 tccctcttgg gtgaccttc 19 <210> 40 <211> 20 <212> DNA

<213> Artificial Sequence <400> 40 atctttgtca gccaccagct 20 <210> 41 <211> 24 <212> DNA
<213> Artificial Sequence <400> 41 aggtgtgctg ccatctgctg ttcg 24 <210> 42 <211> 24 <212> DNA
<213> Artificial Sequence <400> 42 agcctatcct ctctgagagtcagg 24 <210> 43 <211> 21 <212> DNA

<213> Artificial Sequence <400> 43 aagcagagta ctcatgatgcc 21 <210> 44 <211> 20 <212> DNA

<213> Artificial Sequence <400> 44 tctggtagac agtacagtgg 20 <210> 45 <211> 20 <212> DNA

<213> Artificial Sequence <400> 45 catttggctg gtccaagatg 20 <210> 46 <211> 20 <212> DNA

<213> Artificial Sequence <400> 46 agtcattggt agggaggtac <210> 47 <211> 20 <212> DNA

<213> Artificial Sequence <400> 47 catgcttcta cagtccagcc 20 <210> 48 <211> 20 <212> DNA

<213> Artificial Sequence <400> 48 ggtcctcagt tgcagaaatc 20 <210> 49 <211> 45 <212> DNA

<213> Artificial Sequence <400> 49 tggtgggctg tggtgaccatgacaactgtg ggctatgggg acatg 45 <210> 50 <211> 45 <212> DNA

<213> Artificial Sequence <400> 50 tggtgggcag tggtcaccat gaccactgtgggctacggggacatg 45 <210> 5I

<211> 45 <212> DNA

<213> Artificial Sequence <400> 51 tggtgggcag tcgtctccat gacaactgtaggctatggagacatg 45 <210> 52 <211> 45 <212> DNA

<213> Artificial Sequence <400> 52 tggtgggcag tggtaaccat gacaacagtgggttacggcgatatg 45 <210> 53 <211> 45 <212> DNA

<213> Artificial Sequence <400> 53 tggtgggctg tggtcaccat gacgaccctgggctatggagacatg 45 <210> 54 <211> 45 <212> DNA

<213> Artificial Sequence <400> 54 tggtgggggg tggtcacagt caccaccatcggctatggggacaag 45 <210> 55 <211> 45 <212> DNA

<213> Artificial Sequence <400> 55 tggtgggcag tggtcaccat gaccacggttggctatggggacatg 45 <210> 56 <211> 45 <212> DNA

<213> Artificial Sequence <400> 56 tggtgggccg tggtcaccat gacgaccctgggctatggagacatg 45 <210> 5?

<211> 45 <212>~DNA

<213> Artificial Sequence <400> 57 tggtgggctg tggtcaccatgacgacactgggctacggagacatg 45 <210> 58 <211> 45 <212> DNA

<213> Artificial Sequence <400> 58 tggtgggctg tggtgaccatgacaactgtgggctatggggacatg 45 <210> 59 <211> 47 <212> DNA

<213> Artificial Sequence <400> 59 ttcctgttct ccattgagaccgaaacaaccattgggtatggcttccg 47 <210> 60 <211> 47 <212> DNA

<213> Artificial Sequence <400> 60 tttttattct caatagagacagaaaccaccattggttatggctaccg 47 <210> 61 <211> 47 <212> DNA

<213> Artificial Sequence <400> 61 ttcctcttct ccattgagacccagacaaccataggctatggtttcag 47 <210> 62 <211> 47 <212> DNA

<213> Artificial Sequence <400> 62 ttcctgttct cggtggagac atcggctatgggttccg 47 gcagacgacc <210> 63 <211> 47 <212> DNA

c213> Artificial Sequence <400> 63 ttcctcttct cccttgaatc attggctatggcttccg 47 ccaaaccacc <210> 64 <211> 4'7 <212> DNA

<213> Artificial Sequence <400> 64 tttctctttt ccctggaatc attggctatggagtccg 47 ccagacaacc c210> 65 c211> 47 <212> DNA

<213> Artificial Sequence <400> 65 ttccttttct ccattgaggt ccaagtgact attggctttg gggggcg 47 <210> 66 <211> 47 <212> DNA
<213> Artificial Sequence <400> 66 tttctcttct ccattgaagt tcaagttacc attgggtttg gagggag 47 <210> 67 <211> 50 <212> DNA
<213> Artificial Sequence <400> 67 gcgctctact tcaccttcag cagcctcacc agtgtgggct tcggcaacgt 50 <210> 68 <211> 15 <212> PRT
<213> Artificial Sequence <220>
<223> consensus sequences <400> 68 Trp Trp Ala Val Val Ser Met Thr Thr Val Gly Tyr Gly Asp Met <210> 69 <211> 15 <212> PRT
<213> Artificial Sequence <400> 69 Trp Trp Ala Val Val Thr Met Thr Thr Leu Gly Tyr Gly Asp Met <210> 70 <211> 15 <212> PRT
<213> Artificial Sequence <400> 70 Trp Trp Gly Val Val Thr Val Thr Thr Ile Gly Tyr Gly Asp Lys <210> 71 <211> 15 <212> PRT
<213> Artificial Sequence <400> 71 Trp Trp Ala Val Val Thr Met Thr Thr Val Gly Tyr Gly Asp Met <210> 72 <211> 15 <212> PRT
<213> Artificial Sequence <400> 72 Phe Leu Phe Ser Ile Glu Val Gln Val Thr Ile Gly Phe Gly Gly <210> 73 <211> 15 <212> PRT
<213> Artificial Sequence <400> 73 Phe Leu Phe Ser Leu Glu Ser Gln Thr Thr Ile Gly Tyr Gly Val <210> 74 <211> 15 <212> PRT
<213> Artificial Sequence <400> 74 Phe Leu Phe Ser Ile Glu Thr Glu Thr Thr Ile Gly Tyr Gly Tyr <210> 75 <211> 15 <212> PRT
<213> Artificial Sequence <400> 75 ' Phe Leu Phe Ser Ile Glu Thr Gln Thr Thr Ile Gly Tyr Gly Phe <210> 76 <211> 15 <212> PRT
<213> Artificial Sequence <400> 76 Phe Leu Phe Ser Val Glu Thr Gln Thr Thr Ile Gly Tyr Gly Phe <210> 77 <211> 15 <212> PRT
<213> Artificial Sequence <400> 77 Phe Leu Phe Ser Leu Glu Ser Gln Thr Thr Ile Gly Tyr Gly Phe <210> 78 <211> 15 <212> PRT
<213> Artificial Sequence <400> 78 Phe Leu Phe Ser Ile Glu Thr Glu Thr Thr Ile Gly Tyr Gly Phe <210> 79 <211> 16 <212> PRT

<213> Art ificial Sequence <400> 79 AlaLeu Phe ThrPheSer SerLeuThrSerVal GlyPheGlyAsn Tyr <210> 80 <211> 257 1 <212> DNA

<213> H, Sapiens <220>

<221> CDS

<222> (11 0)...(1285) <400> 80 gctgccgcgc ctgtagcact ccagacggtc 60 cccggaactg cggaggcggg gaactaggtg ggccacgtca gcggggccac gtgggtgcc 118 ccagggctcg atg cggggtcccg cgg agg Met Arg Arg ggcgcg ctg gcgggcgcc ttggccgcgtacgcc gcgtacctggtg 166 ctt GlyAla Leu AlaGlyAla LeuAlaAlaTyrAla AlaTyrLeuVal Leu ctgggc ctg ttggtggcg cggctggaggggccg cacgaagccagg 214 gcg LeuGly Leu LeuValAla ArgLeuGluGlyPro HisGluAlaArg Ala ctccga gag ctggagacg ctgcgggcgcagctg cttcagcgcagc 262 gcc LeuArg Glu LeuGluThr LeuArgAlaGlnLeu LeuGlnArgSer Ala ccgtgt get gcccccgcc ctggacgccttcgtg gagcgagtgctg 310 gtg ProCys Ala AlaProAla LeuAspAlaPheVal GluArgValLeu Val gcggcc cgg ctggggcgg gtcgtgcttgetaac gettcggggtcc 358 gga AlaAla Arg LeuGlyArg ValValLeuAlaAsn AlaSerGlySer Gly gccaac tcg gaccccgcc tgggacttcgcctct getctcttcttc 406 gcc AlaAsn Ser AspProAla TrpAspPheAlaSer AlaLeuPhePhe Ala gccagc ctg atcaccacc gtgggctatgggtac acaacgccactg 454 acg AlaSer Leu IleThrThr ValGlyTyrGlyTyr ThrThrProLeu Thr actgat ggc aaggccttc tccatcgcctttgcg ctcctgggcgtg 502 gcg ThrAsp Gly LysAlaPhe SerIleAlaPheAla LeuLeuGlyVal Ala ccgacc atg ctgctgctg accgcctcagcccag cgcctgtcactg 550 acc ProThr Met LeuLeuLeu ThrAlaSerAlaGln ArgLeuSerLeu Thr ctgctgact cacgtgcccctg tcttggctgagcatg cgttggggc tgg 598 LeuLeuThr HisValProLeu SerTrpLeuSerMet ArgTrpGly Trp gacccccgg cgggcggcctgc tggcacttggtggcc ctgttgggg gtc 646 AspProArg ArgAlaAlaCys TrpHisLeuVaIAla LeuLeuGly Val gtagtgacc gtctgctttctg gtgccggetgtgatc tttgcccac ctc 694 ValValThr ValCysPheLeu ValProAlaValIle PheAlaHis Leu gaggaggcc tggagcttcttg gatgccttctacttc tgctttatc tct 742 GluGluAla TrpSerPheLeu AspAlaPheTyrPhe CysPheIle Ser ctgtccacc atcggcctgggc gactacgtgcccggg gaggcccct ggc 790 LeuSerThr IleGlyLeuGly AspTyrValProGly GluAlaPro Gly cagccctac cgggccctctac aaggtgctggtcaca gtctacctc ttc 838 GlnProTyr ArgAlaLeuTyr LyaValLeuValThr ValTyrLeu Phe ctgggcctg gtggccatggtg ctggtgctgcagacc ttccgccac gtg 886 LeuGlyLeu ValAlaMetVal LeuValLeuGlnThr PheArgHis Val 245 250 . 255 tccgacctc cacggcctcacg gagctcatcctgctg ccccctccg tg~ 934 SerAspLeu HisGlyLeuThr GluLeuIleLeuLeu ProProPro Cys 26~ 265 270 275 cctgccagt ttcaatgcggat gaggacgatcgggtg gacatcctg ggc 982 ProAlaSer PheAsnAlaAsp GluAspAspArgVal AspIleLeu Gly ccccagccg gagtcgcaccag caactctctgccagc tcccacacc gac 1030 ProGlnPro GluSerHisGln GlnLeuSerAlaSer SerHisThr Aap tacgettcc atccccaggtag ctggggcagcctctg ccaggcttg ggt 1078 TyrAlaSer IleProArg* LeuGlyGlnProLeu ProGlyLeu Gly gtgcctggc ctgggactgagg ggtccaggcgaccag agctggctg tac 1126 ValProGly LeuGlyLeuArg GlyProGlyAspGln SerTrpLeu Tyr aggaatgtc cacgagcacagc aggtgatcttgaggc cttgccgtc cac 1174 ArgAsnVal HisGluHisSer Arg* Ser* Gly LeuAlaVal His cgtctctcc tttgtttcccag catctggetgggatg tgaagggca gca 1222 ArgLeuSer PheValSerGln HisLeuAlaGlyMet * ArgAla Ala ctccctgtc cccatgtcccgg getccactgggcacc aacataacc ttg 1270 LeuProVal ProMetSerArg AlaProLeuGlyThr AsnIleThr Leu ttctctgtc ctttctctcatcctct tacactgtg 1325 t tctctctggc tctctggcat Phe Ser Val Leu Ser tctcgctgcctctgtctttccctcttgctgtctctgtttctcattctctttcatgttccg1385 tctgtgtctctcaattaaccactcgtcaactgctgattctactgggctgtgggctcagac1445 ctcatttcaggcaccagattggtcgctacaccctggacaagtgactgcccgtctctgagc1505 cttgatttcctcagctgccaaatgggaagaatagaagaatttgcccctaaacccctcctg1565 tgtgctggccctgtgctagacagtgctggagacatagttgggggtggagaactgccctta1625 tggagcttgcagtccagtgaggtggacagacctgtccccagacagtgatggcccaaaatg1685 gtcaggactttaatggaggaggtgaggtgttgaaagcacaggcagagtggtcagggctga1745 agtcggagaagcatagggactaggcccaatccagcctggaaagtcagggaggacttccta1805 gaggaagggacatcgaactaagacctgaactatgagaaataggcaggaagaagttgtacc1865 tgactcatttttctcaggtgtctccagggagcaggacccatggagggacccctggtgtag1925 gcctgggcgatagactcttcctcagcagcctggcaggcaggaaacagacataggacccca1985 gcccagatctgaatggcatgggaggtgctgcccttaaccatgacaccattgtaagagctg2045 tccacatttgtatgttgtgccctggaatcagcctggttgagctcaaatcccaacttagcc2105 acgtctggcctgtgtccttgggcagtcacactacctctctgattttgtttccttatctgt2165 aaaatggtgatcatcataatacaacttcaaaaggatttcaggctgagtgtggtggctcac2225 gcctatacacccagcactttggaaggctgaggaaggaggatcgcttgaggccaggagttt2285 gagactagcctaggcaacacagtgaggccttatctcaacaacaaccacaaaatctaaaaa2345 ttagctgggtgtggtggtgcatgcctgtgatcctggctacttcagaggctgaggtggaag2405 gatcacttgaggccaggagtttgaggctgcagtgagttatgatggcactgctgcactcca2465 gcctgcgggacagagtgagaccctgtctgaaagaaagagagaaagaaagaaagaaagaga2525 gagaaagaaagaaagaaagaaagggaaagatggaaggaaggaagga 2571 <210> 81 <211> 388 <212> PRT
<213> H. sapiens <400> 81 Met Arg Arg Gly Ala Leu Leu Ala Gly Ala Leu Ala Ala Tyr Ala Ala Tyr Leu Val Leu Gly Ala Leu Leu Val Ala Arg Leu Glu Gly Pro His Glu Ala Arg Leu Arg Ala Glu Leu Glu Thr Leu Arg Ala Gln Leu Leu Gln Arg Ser Pro Cys Val Ala Ala Pro Ala Leu Asp Ala Phe Val Glu Arg Val Leu Ala Ala Gly Arg Leu Gly Arg Val Val Leu Ala Asn Ala Ser Gly Ser Ala Asn Ala Ser Asp Pro Ala Trp Asp Phe A1a Ser Ala Leu Phe Phe Ala Ser Thr Leu Ile Thr Thr Val Gly Tyr Gly Tyr Thr Thr Pro Leu Thr Asp Ala Gly Lys Ala Phe Ser Ile Ala Phe Ala Leu Leu Gly Val Pro Thr Thr Met Leu Leu Leu Thr Ala Ser Ala Gln Arg Leu Ser Leu Leu Leu Thr His Val Pro Leu Ser Trp Leu Ser Met Arg Trp Gly Trp Asp Pro Arg Arg Ala Ala Cys Trp His Leu Val AIa Leu Leu Gly Val Val Val Thr Val Cys Phe Leu Val Pro Ala Val Ile Phe Ala His Leu Glu Glu Ala Trp Ser Phe Leu Asp Ala Phe Tyr Phe Cys Phe Ile Ser Leu Ser Thr Ile Gly Leu Gly Asp Tyr Val Pra Gly Glu Ala Pro Gly Gln Pro Tyr Arg Ala Leu Tyr Lys Val Leu Val Thr Val Tyr Leu Phe Leu Gly Leu Val Ala Met Val Leu Val Leu Gln Thr Phe Arg His Val Ser Asp Leu His Gly Leu Thr Glu Leu Ile Leu Leu Pro Pro Pro Cys Pro Ala Ser Phe Asn Ala Asp Glu Asp Asp Arg Val Asp Ile Leu Gly Pro Gln Pro Glu Ser His Gln Gln Leu Ser Ala Ser Ser His Thr Asp Tyr Ala Ser Ile Pro Arg Leu Gly Gln Pro Leu Pro Gly Leu Gly Val Pro Gly Leu Gly Leu Arg Gly Pro Gly Asp Gln Ser Trp 325 330 ~ 335 Leu Tyr Arg Asn Val His Glu His Ser Arg Ser Gly Leu Ala Val His Arg Leu Ser Phe Val Ser Gln His Leu Ala Gly Met Arg Ala Ala Leu Pro Val Pro Met Ser Arg Ala Pro Leu Gly Thr Asn Ile Thr Leu Phe Ser Val Leu Ser <210> 82 <211> 3300 <212> DNA
<213> H. sapiens <220>
<221> CDS
<222> (50)...(1285) <400> 82 aaatgcctgc tgaataaga 58 ccgtgcagct atg cggagcgcgc gcg agcccgtctc gca Met Ala Ala cctgacttg ctggatcctaaa tctgccgetcag aactccaaaccgagg 106 ProAspLeu LeuAspProLys SerAlaAlaGln AsnSerLysProArg ctctcgttt tccacgaaaccc acagtgcttget teccgggtggagagt 154 LeuSerPhe SerThrLyaPro ThrValLeuAla SerArgValGluSer gacacgacc attaatgttatg aaatggaagacg gtctccacgatattc 202 AspThrThr IleAsnValMet LysTrpLysThr ValSerThrIlePhe ctggtggtt gtcctctatctg atcatcggagcc accgtgttcaaagca 250 LeuValVal ValLeuTyrLeu IleIleGlyAla ThrValPheLysAla ttggagcag cctcatgagatt tcacagaggacc accattgtgatccag 298 LeuGluGln ProHisGluIle SerGlnArgThr ThrIleValIleGln aagcaaaca ttcatatcccaa cattcctgtgtc aattcgacggagctg 346 LysGlnThr PheIleSerGln HisSerCysVal AsnSerThrGluLeu gatgaactc attcagcaaata gtggcagcaata aatgcagggattata 394 Asp Glu Leu Ile Gln Gln Ile Val Ala Ala Ile Asn Ala Gly Ile Ile loo 105 ll0 115 ccgttaggaaacacctcc aatcaaatcagtcac tgggatttggga agt 442 ProLeuGlyAsnThrSer AsnGlnIleSerHis TrpAspLeuGly Ser tccttcttctttgetggc actgttattacaacc ataggatttgga aac 490 SerPhePhePheAlaGly ThrValIleThrThr IleGlyPheGly Asn atctcaccacgcacagaa ggcggcaaaatattc tgtatcatctat gcc 538 IleSerProArgThrGlu GlyGlyLysIlePhe CysIleIleTyr Ala ttactgggaattcccctc ttt'ggttttctcttg getggagttgga gat 586 LeuLeuGlyIleProLeu PheGlyPheLeuLeu AlaGlyValGly Asp cagctaggcaccatattt ggaaaaggaattgcc aaagtggaagat acg 634 GlnLeuGlyThrIlePhe GlyLysGlyIleAla LysValGluAsp Thr tttattaagtggaatgtt agtcagaccaagatt cgcatcatctca aca 682 PheIleLysTrpAsnVal SerGlnThrLysIle ArgIleIleSer Thr atcatatttatactattt ggctgtgtactcttt gtggetctgcct gcg 730 IleIlePheIleLeuPhe GlyCysValLeuPhe ValAlaLeuPro Ala atcatattcaaacacata gaaggctggagtgcc ctggacgccatt tat 778 IleIlePheLysHiaIle GluGlyTrpSerAla LeuAspAlaIle Tyr tttgtggttatcactcta acaactattggattt ggtgactacgtt gca 826 PheValValIleThrLeu ThrThrIleGlyPhe GlyAspTyrVal Ala ggtggatccgatattgaa tatctggacttctat aagcctgtcgtg tgg 874 GlyGlySerAspIleGlu TyrLeuAspPheTyr LysProValVal Trp ttctggatccttgtaggg cttgettactttget getgtcctgagc atg 922 PheTrpIleLeuValGly LeuAlaTyrPheAla AlaValLeuSer Met attggagattggctccga gtgatatctaaaaag acaaaagaagag gtg 970 IleGlyAspTrpLeuArg ValIleSerLysLys ThrLysGluGlu Val ggagagttcagagcacac getgetgagtggaca gccaacgtcaca gcc 1018 GlyGluPheArgAlaHis AlaAlaGluTrpThr AlaAsnValThr Ala gaattcaaagaaaccagg aggcgactgagtgtg gagatttatgac aag 1066 GluPheLysGluThrArg ArgArgLeuSerVal GluIleTyrAsp Lys ttc cag cgg gcc acc tcc atc aag cgg aag ctc tcg gca gaa ctg get 1114 Phe Gln Arg Ala Thr Ser Ile Lys Arg Lys Leu Ser Ala Glu Leu Ala WO 99/43696 PC'fIUS99/03826 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 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 gag agt atc tat ctg aat ggt ttg acg cca cac tgt get ggt gaa gag 1258 Glu Ser Ile Tyr Leu Asn Gly Leu Thr Pro His Cys Ala Gly Glu Glu att get gtg att gag aac atc aaa tag ccctctcttt aaataacctt 1305 Ile Ala'Val Ile Glu Asn Ile Lys aggcatagccataggtgaggacttctctatgctctttatgactgttgctggtagcatttt1365 ttaaattgtgcatgagctcaaagggggaacaaaatagatacacccatcatggtcatctat1425 catcaagagaatttggaattctgagccagcactttctttctgatgatgcttgttgaacgg'1485 tccactttctttgatgagtggaatgacaagcaatgtctgatgcctttttgtgcccagact1545 gttttcctctctctttccctaatgtgccataaggcctcagaatgaatgagaattgtttct1605 ggtaacaatgtagctttgagggatcagttcttaacttttcagggtctacctaactgagcc1665 tagatatggaccatttatggatgacaacaattttttttttgtaaatgacaagaaattctt1725 atgcagccttttacctaagaaattttctgtcagtgccttatcttatgaagaaacagaacc1785 tctctagctaatgtgtggtttctccttccctgcccccacccctaggctcacctctgcagt1845 cttttaccccagttctcccatttgaataccataccttgctggaaacagtgtgtaaaatga1905 ctgaagtgatgatgcccgaagatgaaatagatgccaaattagatggacattgaagcaaca1965 ctcagcgttgcctagcgttaaaggcactgcagagaaatgaggtgcagaggtggcccctct2025 gagtatttatttgactcaggtaccagtggtacatatatacagtgtaattatgaccaggct2085 ggtaaaattggctgctcgcaaacaatccccttttttcctggcagtatttggaatttatca2145 tttattaataactatacatttttaaaggcagaagaagaaaatctatctatcatctatcta2205 tctatctatctatctatctatctatctatctatctatctatctatctaaatgacctgaca2265 gaagaaaactgttaaaaatggatattattggaggggatttaaaacagtgggtgtgaatta2325 tcattctgatggaaagaaaatagcaaaacaatgtgttacaagtatttgctaataaacagt2385 atactgccagcttctaattgctttttgatgtatgaaaggcttatataattttcttttcgt2445 tgggtgacttttgccagatgagaggaggtggcacagtggtgagtgcagggcacagtccta2505 gccttctgtgggtatacttttggagttgtgacttggctgtgagggcagaagttgaagttg2565 ggatcactgtgactttgcacatggaaaaatgcagattgcaggcataattcatctctgaca2625 ttagagaaaaagctgttatagcacaatttaaattttgagagtttgctgtgtttttttttc2685 acataaaagaggctgattattctttttagtttaattttatatcctgtaattctttggatg2745 gttccaagattcagaaaaaattcagtaaatgcaccccgtaaattgctaccctttccttta2805 ttttcatacttagatctgctgtacattgtatatatatataatttttaaaatgcagaaaga2865 aaataatttccctaaatataattgcaaactgatttcttttacttttttgtgtctgggggt2925 gggagctgtatctgaataagtggcattcagattagggtcttgaaaaataaacccagaatc2985 tttaaaagaagcaaataaactaatagacgcttattttccaaaatttaaatttaagctaga3045 aatgtaaatattcaattaatttgttaaaagtacttttataaagttaaaaaaaatccaacc3105 aaaattttagaaagtcaggctcttttagaaagaaagctacacccatttcctcaaataact3165 gttccgaaaatttatatggtggaatgcgccatgtataaactgtgaattgtattgacaaat3225 aaagtttgtaattaaagtcaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa3285 aaaaaaaaaaaaaaa 3300 <210> 83 <211> 411 <212> PRT
<213> H. sapiens <400> 83 Met Ala Ala Pro Asp Leu Leu Asp Pro Lys Ser Ala Ala Gln Asn Ser Lys Pro Arg Leu Ser Phe Ser Thr Lys Pro Thr Val Leu Ala Ser Arg Val Glu Ser Asp Thr Thr IIe Asn Val Met Lys Trp Lys Thr Val Ser Thr Ile Phe Leu Val Val Val Leu Tyr Leu Ile Ile Gly Ala Thr Val Phe Lys Ala Leu Glu Gln Pro His Glu Ile Ser Gln Arg Thr Thr Ile Val Ile Gln Lys Gln Thr Phe Ile Ser Gln His Ser Cys Val Asn Ser Thr Glu Leu Asp Glu Leu Ile Gln Gln Ile Val Ala Ala Ile Asn Ala Gly Ile Ile Pro Leu Gly Asn Thr Ser Asn Gln Ile Ser His Trp Asp Leu Gly Ser Ser Phe Phe Phe Ala Gly Thr Val Ile Thr Thr Ile Gly Phe Gly Asn Ile Ser Pro Arg Thr Glu Gly Gly Lys Ile Phe Cys Ile Ile Tyr Ala Leu Leu Gly Ile Pro Leu Phe Gly Phe Leu Leu Ala Gly Val Gly Asp Gln Leu Gly Thr Ile Phe Gly Lys Gly Ile Ala Lys Val Glu Asp Thr Phe Ile Lys Trp Asn Val Ser Gln Thr Lys Ile Arg Ile Ile Ser Thr Ile Ile Phe Ile Leu Phe Gly Cys Val Leu Phe Val Ala Leu Pro Ala Ile Ile Phe Lys His Ile Glu Gly Trp Ser Ala Leu Asp Ala Ile Tyr Phe Val Val Ile Thr Leu Thr Thr Ile Gly Phe Gly Asp Tyr Val Ala Gly Gly Ser Asp Ile Glu Tyr Leu Asp Phe Tyr Lys Pro Val Val Trp Phe Trp Ile Leu Val Gly Leu Ala Tyr Phe Ala Ala Val Leu Ser Met Ile Gly Asp Trp Leu Arg Val Ile Ser Lys Lys Thr Lys Glu Glu Val Gly Glu Phe Arg Ala His Ala Ala Glu Trp Thr Ala Asn Val Thr Ala Glu Phe Lys Glu Thr Arg Arg Arg Leu Ser Val Glu Ile Tyr Asp Lys Phe Gln Arg Ala Thr Ser Ile Lys Arg Lys Leu Ser Ala Glu Leu Ala Gly Asn His Asn Gln Glu Leu Thr Pro Cys Arg Arg Thr 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 Gly Glu Glu Ile Ala Val Ile Glu Asn Ile Lys <210> 84 <211> 20 <212> DNA
<213> H. sapiens <400> 84 catagccata ggtgaggact 20 <210> 85 <211> 20 <212> DNA

<213> H. sapiens <400> 85 gagaggaaaa cagtctgggc 20 <210> 86 <211> 20 <212> DNA
<213> H. Sapiens <400> 86 ggacatcgaa ctaagacctg 20 <210> 87 <211> 20 <212> DNA
<213> H. Sapiens <400> 87 tcccatgcca ttcagatctg 20

Claims (14)

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, 18, 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:1, 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.