WO1997038004A1

WO1997038004A1 - Gene family associated with neurosensory defects

Info

Publication number: WO1997038004A1
Application number: PCT/US1997/005903
Authority: WO
Inventors: Patsy Nishina; Konrad Noben-Trauth; Juergen Naggert; Michael North
Original assignee: Axys Pharmaceuticals, Inc.; The Jackson Laboratory
Priority date: 1996-04-10
Filing date: 1997-04-10
Publication date: 1997-10-16
Also published as: JP2000509255A; CA2251603A1; EP0892807A1; AU2450797A

Abstract

Nucleic acid compositions are provided that encode a family of mammalian proteins expressed in the retina and brain. Members of the gene family are genetically linked to various neurosensory defects, including cochlear degeneration, peripheral retinal degeneration and cone-rod retinal dystrophy. The nucleic acid compositions find use in identifying DNA sequences encoding homologous or related proteins; for production of the encoded 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 treatment of neurosensory defects, identification of retinal cells based on expression, and the like. The DNA is further used as a diagnostic for genetic predisposition to the linked neurosensory defect.

Description

GENE FAMILY ASSOCIATED WITH NEUROSENSORY DEFECTS

INTRODUCTION Sensory neurons give us our perception of the world, by transducing phenomena such as light and sound into signals that can be received and understood by the brain. However, neurons can also be fragile, and susceptible to a number of hereditary and/or age related degenerative disorders. Understanding the genes and gene products that comprise and control neurosensory signaling pathways may provide the basis for future medical advances in this area.

Neurodegenerative disorders result from the premature death of nerve cells in the brain and spinal cord; for example tracts of the acoustic system in degenerative hearing disorders. Such neuronal degeneration has been attributed to genetic defects, transmissible infectious agents, toxic substances, immune system disorders and other as yet undetermined mechanisms. A recent hypothesis is that active photoreceptor cell death, which is characteristic of these genetically distinct disorders, is mediated by a common induction of apoptosis.

Inherited eye disorders are the major cause of childhood blindness in the developed world. Many of these are retinal dystrophies. The retina is the sensory tunic of the eye, containing light sensitive receptors, a complex of neurons, and pigmented epithelium, arranged in discrete layers. In humans, the macula is the portion of the retina that lies directly behind the lens. Cones, the photoreceptor cells responsible for central vision, are heavily concentrated in the macula. The peripheral retina is composed mainly of rods, which are responsible for side and night vision.

Choroidoretinal dystrophies and degenerations, all of which are currently incurable and untreatable, are a common form of retinal dystrophy. Cone-rod retinal dystrophy (CRD) is a severe example, characteristically leading to early blindness. A loss of color vision and visual acuity is accompanied by widespread, advancing retinal pigmentation and chorioretinal atrophy of the central and peripheral retina. Linkage analysis of a large lineage of autosomal dominant CRD has mapped the disease to chromosome 19q, linked to the polymorphic marker D19S47. It has been suggested that the disease locus for CRD, which affects the central as well as peripheral retina, may also be involved in age-related macular degeneration (ARMD) .

Hereditary peripheral retmopathies are also relatively common. Retinitis pigmentosa (RP) , for example, affects approximately 1.5 million people worldwide. Substantial genetic heterogeneity has been observed in th s condition, with over 20 chromosomal loc identified. A predisposition to retinitis pigmentosa can be inherited by autosomal dominant, autosomal recessive, X-linked or digenic modes. In spite of causal heterogeneity, there is significant clinical similarity among RP subtypes. Common signs and symptoms include early electroretinographic abnormalities, ophthalmoscopic findings, and progressively worsening tunnel vision.

It is interesting to note that the mouse mutation, tubby, leads to both retinal and cochlear degeneration, indicating a common element in both sensory pathways. It has also been observed that rare monogenic forms of human severe obesity are often accompanied by blindness and deafness: the best characterized are Bardet Biedl syndrome and Alstrom syndrome. Studying these diseases, although important in their own right, may also provide critical clues to the molecular mechanisms leading to an obese state.

The prevalence and clinical consequences of sensory neuronal defects make it of interest to characterize tubby and related genes that may be associated with vision and hearing defects.

Relevant Literature Overviews of photoreceptor dystrophies may be found in Cotlier et al . (1995) Surv. Ophthalmology 40:51-61; Bird (1995) Am. J. Ophthal ■ 119:543-562; and Adler (1996) Arch Ophthal. 114:79-83. Evans et al . (1994) Nature Genetics 6:210-213 describes the genetic mapping of cone- rod retinal dystrophy. Shugart et al . (1995) Am J Hum Genet. 57:499- 502 disclose fine genetic mapping of a gene for autosomal recessive retinitis pigmentosa (RP 14) on chromosome 6p21. Berson (1996) Proc Natl Acad Sc USA 93:4526-4528 review retinitis pigmentosa.

Ohle iller et al . (1995) Neuroreport 6:845-9 and Heckenlively et al . (1995) P.N.A.S. 92:11100-11104 describe hearing loss and progressive retinal degeneration in tubby mice. The retinal degeneration is characterized by loss of photoreceptor cells, resulting m abnormal electroencephalograms by 3 weeks of age. Jones et al . (1992) Genomics 14:197-9 localize the tub locus to a specific region of chromosome 7, and demonstrate that it is distinct from the insulin-2 locus. The cholecystokinin receptor gene is shown to tightly linked to the tub locus in Samuelson et al . (1995) Genome 6:242-6. The mouse tub mutation is described in Coleman and Eicher (1990) J Hered 81:424-7 as an autosomal recessive mutation located on chromosome 7, which causes slowly developing but ultimately severe obesity.

Bennett et al . (1996) Nature Medicine 2:649 demonstrate that injection into rd/rd mice of a recombinant replication defective adenovirus that contains wild-type cDNA encoding βPDE delays photoreceptor death. Adenovirus vectors are described in Englehardt et al . (1993) Nature Genetics 4:27-34, and in Wang and Finer (1996) Nature Medicine 2: 714.

SUMMARY OF THE INVENTION Nucleic acid compositions are provided that encode a family of mammalian proteins expressed in the retina and brain. Members of the gene family are genetically linked to various neurosensory defects, including cochlear degeneration, peripheral retinal degeneration and cone-rod retinal dystrophy. The nucleic acid compositions find use in identifying DNA sequences encoding homologous or related proteins; for production of the encoded protein; and in studying associated physiological pathways. In addition, modulation of the gene activity in vi vo is used for prophylactic and therapeutic purposes, such as treatment of neurosensory defects, identification of retinal cells based on expression, and the like. The DNA is further used as a diagnostic for genetic predisposition to the linked neurosensory defect. One family member, tub, is associated with mature onset obesity in an animal model, and may be used as in assays and therapies directed to preventing or treating obesity.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates the N-terminal splicing at the human and mouse TUB locus.

Figure 2A and Figure 2B show the intron/exon boundaries for TULP1 [SEQ ID NO:12] and TULP2 [SEQ ID NO:14]. The arrows above the sequence lines indicate splice junctions. DESCRIPTION OF THE SPECIFIC EMBODIMENTS A family of genes whose members are associated with various defects in sensory neurons are provided (TULP family) . Among the linked diseases are cochlear defects, retinitis pigmentosa (RP-14) and combined rod-cone dystrophy (CRD) . One family member, tub, is also associated with a genetic predisposition to adult onset obesity. The nucleotide sequences of human and mouse cDNAs and genomic regions are provided. The coding region sequences are highly conserved between family members at the carboxy terminus, and variable at the amino terminus.

The nucleic acid compositions find use in identifying DNA sequences encoding homologous or related proteins; for production of the encoded protein; and in studying associated physiological pathways in vivo and in vi tro . The nucleic acids are useful in modulating gene activity for diagnostic, prophylactic and therapeutic purposes, such as treatment of neurosensory defects, identification of retinal cells based on expression, and the like. The DNA is further used as a diagnostic for genetic predisposition to the specific genetically linked defect. The encoded proteins are useful as an immunogen to raise antibodies that specifically identify TULP expressing cells, in drug screening assays directed at neurosensory defects, and for therapeutic purposes. The amino terminal domain of TUB [SEQ ID NO: 10, positions 1- 139] has been shown to direct nuclear localization of the protein. As used herein, the generic term "TULP" or "TULP family" designates the family of genes that includes the specific sequences provided in the SEQLIST and designated in Table 1. By family is intended one or more of the gene or gene products, up to and including TUB, TULP1, TULP2, TULP3 and TULP4. A family member is any one of the genes in the TULP family. Unless otherwise indicated, the sequences are of mammalian origin, and generally refer to the human sequences. In some animal models for TULP function, non-mammalian homologs, e.g. C. elegans , D. melanogaster , etc. are of interest. Within a species, the sequence similarity between family members is high in the carboxy terminal portion of the protein, where there is usually at least about 50% identity at the amino acid level. In t ub and tulp4 different transcriptional products are formed by alternative exon splicing in the 5' end of the gene. All members of the TULP family are expressed in the retina, although not for all splice variants. In some cases the genes are also expressed in other tissues. Exemplary members of the TULP gene family are as follows:

TABLE 1 TULP FAMILY MEMBERS

SEQ ID NO Sequence Molecule Size 1 Mouse tub Form I cDNA dsDNA 2119 bp

2 translation of above amino acid 459 aa

3 Mouse tub Form II cDNA A dsDNA 2434 bp

4 translation of above amino acid 505 aa

5 tub mutation dsDNA 480 bp 6 translation of above amino acid 33 aa

7 Human TUB Form 6 cDNA dsDNA 1426 bp

8 translation of above amino acid 460 aa

9 Human TUB Form 1 cDNA ds DNA 3060 bp 10 translation of above amino acid 561 aa 11 Human TUB 5' region genomic DNA 5995 bp

12 Human TULP1 cDNA ds DNA 2115 bp

13 translation of above amino acid 542 aa

14 Human TULP2 cDNA ds DNA 1734 bp

15 translation of above amino acid 520 aa 16 Human TULP3 cDNA ds DNA 1482 bp

17 translation of above amino acid 442 aa

18 Mouse TULP4 cDNA ds DNA 1743 bp

19 translation of above amino acid 506 aa 56 Human TUB Form 1; 5' RACE ds cDNA 2112 bp 57 Human TUB Form 2; 5' RACE ds cDNA 2368 bp

58 translation of above amino acid 518 aa

59 Human TUB Form 3; 5' RACE ds cDNA 1936 bp

60 translation of above amino acid 512 aa

61 Human TUB Form 4; 5' RACE ds cDNA 1890 bp 62 translation of above • amino acid 506 aa

63 Human TUB Form 5; 5* RACE ds cDNA 2109 bp

64 Human TUB Form 6; 5' RACE ds cDNA 2088 bp

The sequences of the human and mouse tub cDNA and encoded protein sequences are provided as SEQ ID NO:l through 10. The genomic region 5' to the human TUB locus is provided as SEQ ID NO: 11. The cDNA and encoded protein sequences of splicing variants of the human TUB locus are provided as SEQ ID Nos:56 through 64. Six cDNA splice variants of TUB have been identified, and are designated as Form 1 through 6. The encoded proteins have a common carboxy-terminal sequence [SEQ ID NO: 8], and vary in the amino terminal sequences. Forms 1 through 4 have unique amino termini; Forms 5 and 6 vary from each other only in the non-translated cDNA sequences.

As used herein, tub designates a coding region, gene or gene product that maps to the exact chromosomal position of the tub mutation described by Coleman and Eicher, supra , and mammalian, particularly human, homologs thereof. The human tub locus maps to chromosome 11, between the polymorphic markers D11S909 and D11S1331. It is expressed at high levels in brain, eye and testis, and at lower levels in various adult and fetal tissues, including small and large intestine, ovary and adipose tissue. Different transcriptional products are formed by alternative exon splicing in the 5' end of the gene.

The term "tub" or " tubby" encompasses both the normal mammalian sequence and the mutated sequence responsible for the tub phenotype. The tub mutation confers a genetic predisposition to maturity onset obesity in mice. The tub mutation is also associated with adult-onset degeneration of the retina and cochlea. The mutation in tub/tub mice is a G to T transversion at position 1704 resulting in a splicing defect and a truncated protein.

The sequence of the human TULP1 gene and ts predicted protein product are provided as SEQ ID NOs: 12-13. The TULP1 locus is associated with a predisposition to retinitis pigmentosa, form RP-14. TULP1 localizes to human chromosome 6p21. Two markers, D6S439 and D6S291, that flank TULP1 have been reported not to recombine with the RP 14 locus in a human kindred (Shugart et al . (1995) Am J Hum Genet. 57:499-502) demonstrating that TULP1 is tightly linked to the RP 14 locus. The expression of TULP1 is restricted to the retina.

Loss of function mutations m TULP1 have been shown to co- segregate with retinitis pigmentosa in kindred studies. Such mutations include but are not limited to a point mutation in exon 11 causing an ammo acid substitution of Arg to Pro at a.a. 420 [SEQ ID NO:13]; and a point mutation in exon 12 causing an amino acid substitution of Phe to Leu at A.A 491 [SEQ ID NO:13]. The presently known polymorphisms that are associated with blindness are located in the conserved carboxy terminal portion of the protein.

The sequence of the human TULP2 gene and its predicted protein product are provided as SEQ ID Nos: 14-15. The expression of TULP2 is restricted to the retina and testes. Retinal expression in adult tissue is relatively low. The TULP2 locus is associated with a genetic predisposition to combined rod cone dystrophy, a disease causing early chorioretmal atrophy of the central and peripheral retina. TULP2 is tightly linked to framework marker WI-9028 on chromosome 19q, which maps within the reported linked interval for CRD. The locus for rod cone dystrophy maps between D19S212 and D19S214.

The sequence of human TULP3 and its predicted protein product are provided as SEQ ID Nos: 16-17. The human TULP3 gene maps to chromosome 12pl3.2-12pl .3. The gene is expressed in the retina. The sequence of mouse tulp4 and its predicted protein product are provided as SEQ ID Nos: 18-19. Different transcriptional products are formed by alternative exon splicing in the 5' end of the gene. The syntenic location of TULP4 on the human chromosome is 19q.

TULP NUCLEIC ACID COMPOSITIONS

Nucleic acids encoding TULP proteins may be cDNA, mRNA or genomic DNA, or a fragment thereof. The term "gene" shall be intended to mean an open reading frame encoding a specific TULP polypeptide, as exemplified in Table 1, as well as trancπbed adjacent 5' and 3' non- coding nucleotide sequences, in either direction. The gene may further encompass non-transcribed regulatory regions adjacent to the transcribed regions. The gene may be introduced into an appropriate vector for extrachromosomal maintenance or for integration into the host. The term "cDNA" as used herein is intended to include all nucleic acids that share the arrangement of sequence elements found in native mature mRNA species, where sequence elements are exons, 5' non-coding regions and 3' non-coding regions. Normally mRNA species have contiguous exons, with the intervening introns deleted, to create a continuous open reading frame.

Genomic TULP sequences have non-contiguous open reading frames, where introns interrupt the coding regions . A genomic sequence of interest comprises the nucleic acid present between an initiation codon and 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 5 kb of flanking genomic DNA at either the 5' or 3' end of the coding region. The genomic DNA may be isolated as a fragment of 50 kbp or smaller. A preferred genomic sequence will lack those sequences that are linked to TULP m a native chromosome but which do not contribute to the biological function of the TULP gene.

Genomic regions of interest include the non-transcribed sequences 5' to a TULP family gene, usually from about one to six thousand bp of sequence. This region of DNA contains the native promoter elements that direct expression of the linked TULP gene. The non-transcribed region 5' to human TUB locus is provided in SEQ ID NO:11. The 3' portion of this sequence [nt. 5535 to 5995; SEQ ID NO: 11] is transcribed, but untranslated. The sequence of this 5' region may be utilized for promoter elements, including enhancer binding sites, that provide for expression in tissues where TUB s expressed. The tissue specific expression is useful for determining the pattern of expression, and for providing promoters that mimic the native pattern of expression. Methods for the identification of specific DNA motifs involved in the binding of transcriptional factors are known in the art, e.g. sequence similarity to known binding motifs, gel retardation studies, etc. For examples, see Blackwell et al . (1995) Mol Med 1: 194-205; Mortlock et al . (1996) Genome Res. 6: 327-33; and Joulm and Richard-Foy (1995) Eur J Biochem 232: 620-626.

The nucleic acid compositions of the subject invention encode all or a part of the subject polypeptides. 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 25 nt, usually at least 30 nt, more usually at least about 50 nt . Such small DNA fragments are useful as primers for PCR, hybridization screening, etc. Larger DNA fragments, i . e . greater than 100 nt are useful for production of fragments of the encoded polypeptide.

Where it is desirable to generate probes or primers that distinguish one family member from other members of the gene family, sequences may be derived from the less conserved region of the genes. Such sequences include the 3' terminus, of about one thousand bp , of each of the TULP family cDNA sequences. Probes useful for identifying homologous genes, or multiple family members may be derived from the conserved region of the genes, which includes roughly the 5' 500-1000 bp of each of the TULP family cDNA sequences. For use in amplification reactions, such as PCR, a pair of primers will be used. The exact composition of the primer sequences is not critical to the invention, but for most applications the primers will hybridize to the subject sequence under stringent conditions, as known in the art. It is preferable to choose a pair of primers that will generate an amplification product of at least about 50 nt, preferably at least about 100 nt. Algorithms for the selection of primer sequences are generally known, and are available in commercial software packages. Amplification primers hybridize to complementary strands of DNA, and will prime towards each other. The DNA sequences are obtained in substantial purity, generally as a sequence other than a sequence of an intact mammalian chromosome. Usually, the DNA will be obtained substantially free of other nucleic acid sequences that do not include a TULP sequence or fragment thereof, generally being at least about 50%, usually at least about 90% pure and are typically "recombinant", i.e. flanked by one or more nucleotides with which it is not normally associated on a naturally occurring chromosome.

The DNA sequences may be used in a variety of ways. They may be used as probes for identifying other TULP genes, including novel family members, homologs and syntenic homologs. Identification of TULP homologs is based on similarity of sequence, chromosomal synteny, or both. The term homology is used to indicate a likeness of structure and conservation of biological function. Calculations of nucleic acid or amino acid sequence identity, as described below, provide a convenient method of identifying homologous or related genes, herein "homologs". Such homologs may be members of a gene family present in the same genome, or may be corresponding genes from different species. Chromosomal synteny may be used to further distinguish between homologous genes when there is sufficient evolutionary conservation between the genomes that are being compared, e.g. between mammalian species. A "syntenic homolog" has both sequence identity to the reference gene, and has the corresponding chromosomal location in relation to closely linked genes. Syntenic homologs have a high probability of sharing spatial and temporal localization of gene expression, and of encoding proteins that fill equivalent biological roles.

Mammalian homologs have substantial sequence similarity to the subject sequences, i.e. greater than 50% sequence identity with the amino acid or nucleotide sequence of the subject TULP sequence, as listed in Table 1. 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. Algorithims for sequence analysis are known in the art, such as BLAST, described in Altschul et al . (1990) J Mol Biol 215:403-10.

Non-identical nucleic acids with sequence similarity are detected by hybridization under low stringency conditions, for example, at 50°C and 10XSSC (0.9 M saline/0.09 M sodium citrate) and remain bound when subjected to washing at 55°C in 1XSSC. By using probes, particularly labeled probes of DNA sequences, one can isolate homologous or related genes. The source of homologous genes may be any mammalian species, e.g. primate species, particularly human; murines, such as rats and mice, canines, felines, bovines, ovines, equines, etc.

For hybridization probes, it may be desirable to use nucleic acid analogs, in order to improve the stability and and binding affinity. A number of modifications have been described that alter the chemistry of the phosphodiester 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' -0' -5' -S-phosphorothioate, 3' -S-5' -O-phosphorothioate, 3'- CH2-5' -O-phosphonate and 3' -NH-5' -O-phosphoroamidate. Peptide nucleic acids replace the entire phosphodiester backbone with a peptide linkage.

Sugar modifications are also used to enhance stability and affinity. The a-anomer of deoxyribose may be used, where the base is inverted with respect to the natural b-anomer. The 2' -OH of the ribose sugar may be altered to form 2'-0-methyl or 2'-0-allyl sugars, which provides resistance to degradation without comprising affinity.

Modification of the heterocyclic bases must maintain proper base pairing. Some useful substitutions include deoxyuridine for deoxythymidine; 5-methyl-2' -deoxycytidine and 5-bromo-2'-deoxycytidine for deoxycytidine. 5- propynyl-2' -deoxyuridine and 5-propynyl-2' - deoxycytidine have been shown to increase affinity and biological activity when substituted for deoxythymidine and deoxycytidine, respectively.

Nucleic acid probes may also be used to identify expression of the gene in a biological specimen, e.g. retinal cells. 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. A biological specimen is used as a source of mRNA. 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 fractionated by electrophoresis, e.g. capillary or gel electrophoresis, transferred to a suitable support, e.g. nitrocellulose and then probed with a fragment of the subject DNA as a probe. Other techniques may also find use, including oligonucleotide ligation assays, binding to solid state arrays, etc. Detection of mRNA having the subject sequence is indicative of TULP gene expression in the sample.

It will be understood by one of skill in the art that low basal levels of transcription are present in many normal cell types, or that a relatively rare cell type may have a high level of expression that cannot readily be detected in mRNA prepared from whole tissue. By specific expression, it is intended that mRNA levels are increased above the basal levels observed in other cells by at least about 100 fold, more usually by at least about 1000 fold. It will be further understood that malignant, or transformed, cells may express genes in an aberrant fashion.

Synthesis of TULP Proteins

The subject genes may be employed for producing all or portions of the TULP proteins. For expression, an expression cassette may be employed, providing for a transcriptional and translational initiation region, which may be inducible or constitutive, where the coding region is under the transcriptional control of the transcriptional initiation region, and a transcriptional and translational termination region. Various transcriptional initiation regions may be employed which are functional in the expression host. In some cases, e.g. gene therapy vectors, it may be desirable to utilize the native promoter sequences as described above.

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, or cells of a higher organism such as vertebrates, particularly mammals, e.g. COS 7 cells, may be used as the expression host cells. In many situations, it may be desirable to express the gene in mammalian cells, where the protein w ll benefit from native folding and post-translational modifications. Small peptides can also be synthesized in the laboratory.

With the availability of the protein in large amounts, by employing an expression host, the protein may be isolated and purified in accordance with conventional ways. A lysate may be prepared of the expression host and the lysate purified using HPLC, exclusion chromatography, gel electrophoresis, affinity chromatography, or other purification technique. The purified protein will generally be at least about 80% pure, preferably at least about 90% pure, and may be up to and including 100% pure. Pure is intended to mean free of other proteins, as well as cellular debris.

A host may be treated with an intact TULP protein, or an active fragment thereof to modulate or reduce neurosensory and/or obesity- associated conditions. Desirably, the peptides will not induce an immune response, particularly an antibody response. Xenogeneic analogs may be screened for their ability to provide a therapeutic effect without raising an immune response. The protein or peptides may also be administered to in vi tro cell cultures.

Various methods for administration may be employed. The polypeptide formulation may be given orally, or may be injected intravascularly, subcutaneously, peritoneally, etc. The dosage of the therapeutic formulation will vary widely, depending upon the nature of the disease, the frequency of administration, the manner of administration, the clearance of the agent from the host, and the like. The initial dose may be larger, followed by smaller maintenance doses. The dose may be administered as infrequently as weekly or biweekly, or fractionated into smaller doses and administered daily, semi-weekly, etc. to maintain an effective dosage level. In many cases, oral administration will require a higher dose than if administered intravenously. The amide bonds, as well as the amino and carboxy termini, may be modified for greater stability on oral administration.

The subject peptides may be prepared as formulations at a pharmacologically effective dose in pharmaceutically acceptable media, for example normal saline, PBS, etc. The additives may include bactericidal agents, stabilizers, buffers, or the like. In order to enhance the half-life of the subject peptide or subject peptide conjugates, the peptides may be encapsulated, introduced into the lumen of liposomes, prepared as a colloid, or another conventional technique may be employed that provides for an extended lifetime of the peptides.

The peptides may be administered as a combination therapy with other pharmacologically active agents. The additional drugs may be administered separately or in conjunction with the peptide compositions, and may be included in the same formulation.

The polypeptide is used for the production of antibodies, where short fragments provide for antibodies specific for the particular motif, 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 TULP protein. Antibodies may be raised to isolated peptides corresponding to these domains, or to the native protein, e.g. by immunization with cells expressing a TULP gene, immunization with liposomes having a TULP protein inserted in the membrane, etc.

Antibodies are prepared in accordance with conventional ways, where the expressed polypeptide or protein is used as an immunogen, by itself or conjugated to known immunogenic carriers, e.g. KLH, pre-S HBsAg, other viral or eukaryotic proteins, or the like. Various adjuvants may be employed, with a series of injections, as appropriate. For monoclonal antibodies, after one or more booster injections, the spleen is isolated, the lymphocytes immortalized by cell fusion, and then screened for high affinity antibody binding. The immortalized cells, i . e . hybridomas, producing the desired antibodies may then be expanded. For further description, see Monoclonal Antibodies: A Laboratory Manual, Harlow and Lane eds., Cold Spring Harbor Laboratories, Cold Spring Harbor, New York, 1988. If desired, the mRNA encoding the heavy and light chains may be isolated and mutagenized by cloning in E. col i , and the heavy and light chains mixed to further enhance the affinity of the antibody. Alternatives to in vivo immunization as a method of raising antibodies include binding to phage "display" libraries, usually in conjunction with in vi tro affinity maturation.

Diagnostic Uses

The subject compositions have a number of diagnostic uses, either as isolated family members, or as a panel of different sequences. The TULP genes and fragments thereof, encoded protein, and anti-TULP antibodies are useful in the identification of individuals predisposed to neurosensory degenerative conditions, e.g. cochlear degeneration and hearing loss; retinitis pigmentosa; combined rod cone dystrophy, etc. The characterization is useful in determining further treatment of the patient. Sequences of interest for diagnostic purposes include but are not limited to the conserved portion of the molecule as previously described. The conserved regions are identified by sequence similarity, and conservation of intron/exon structure.

Specifically, TULP1 is associated with peripheral retinal dystrophies. In humans, TULP1 is tightly linked to the RP-14 locus. TUB is associated with retinal degeneration and cochlear degeneration in an animal model. TULP2 is associated with combined cone-rod dystrophy. In humans TULP2 is tightly linked to the CRD locus.

Loss of function mutations in TULP1 have been shown to co- segregate with retinitis pigmentosa in kindred studies. Such mutations include but are not limited to a point mutation in exon 11 causing an amino acid substitution of Arg to Pro at a.a. 420 [SEQ ID NO:13]; and a point mutation in exon 12 causing an amino acid substitution of Phe to Leu at A.A 491 [SEQ ID NO: 13].

TUB nucleic acids and proteins are also useful for diagnostic applications related to obesity. In mice carrying the tubby mutation, age related reduction in metabolic rate, rather than an increase in food intake, leads to accumulation of fat mass. Accumulation of fat mass and the severity of complications such as diabetes and atherosclerosis can be modified by genetic and environmental factors. The gene is expressed in the hypothalamus, and may be a component of signaling in the brain satiety center. TUB mutations that lead to a genetic predisposition to obesity may be determined by the use of the subject TUB sequences.

DNA from a patient having having one or more neurosensory defects is analyzed for the presence of a predisposing mutation in a TULP gene.

The diagnosis may be performed in conjunction with kindred studies to determine whether a mutation of inteest co-segregates with disease phenotype in a family.

The presence of a mutated TULP sequence that affects the activity or expression of the encoded gene product may confer an increased susceptibility to the condition. Specific mutations of interest include any mutation that leads to neurosensory defects, e . g. retinal degeneration, including insertions, substitutions and deletions in the coding region sequence, introns that affect splicing, promoter or enhancer that affect the activity and expression of the protein.

For purposes of comparison and as an assay control, "normal" TULP sequences are provided in the SEQLIST, as described in Table 1. The normal sequence shall be understood to include sequence variants in non-coding regions that do not affect the level of expression of the gene, coding region variants that do not change the amino acid sequence, e.g. "third position" changes, and changes that result in an altered amino acid sequence but maintain substantially all of the normal protein function.

Biochemical studies may be performed to determine whether a candidate mutation in the coding region or control regions predisposes to disease. For example, the activity of a candidate TULP protein may be compared with the wild-type protein activity. A change in the promoter or enhancer sequence that downregulates expression may also result in predisposition to neurosensory defects. Expression levels of a candidate variant allele are compared to expression levels of the normal allele by various methods known in the art. Methods for determining promoter or enhancer strength include quantitation of the expressed natural protein; insertion of the variant control element into a vector with a reporter gene such as β-galactosidase, chloramphenical acetyltransferase, etc. that provides for convenient quantitation; and the like.

Retinal dystrophies of interest include retinitis pigmentosa, combined cone rod dystrophy, age related macular dystrophy, Stargardt's macular dystrophy, Best's disease, pigment pattern dystrophies, central alveolar choroidal dystrophy, dominant drusen, hereditary hemorrhagic macular dystrophy, North Carolina macular dystrophy, pericentral choroidal dystrophy, adult foveomacular dystrophy, benign concentric annular macular dystrophy, central aureolar pigment epithelial dystrophy, congenital macular coloboma, dominantly inherited cystoid macular edema, familial foveal retmoschisis, fenestrated sheen macular dystrophy, progressive foveal dystrophy, slowly progressive macular dystrophy, Sorsby's pseudomflammatory dystrophy, progressive cone dystrophy, Leber' s congenital amaurosis and Goldman-Favre syndrome.

A number of methods are used to determine the presence of a predisposing mutation in an individual. Genomic DNA is isolated from the individual or individuals that are to be tested, from any nucleated cellular source, such as blood, hair shafts, saliva, mucous, biopsy material, feces, etc. Where large amounts of DNA are available, the genomic DNA may be used directly. Alternatively, the region of interest is cloned into a suitable vector and grown in sufficient quantity for analysis, or amplified by conventional techniques. Cells that express TULP genes, such as retinal cells, may be used as a source of mRNA, which may be assayed directly or reverse transcribed into cDNA for analysis. Methods using PCR amplification can be performed on the DNA from a single cell, although it is convenient to use at least about 10 cells. A detectable label may be included n an amplification reaction. Suitable labels include fluorochromes, e.g. fluorescein isothiocyanate (FITC), rhodamine, Texas Red, phycoerythπn, allophycocyanin, 6-carboxyfluorescem (6-FAM), 2' , '-dιmethoxy-4' ,5' - dichloro-6-carboxyfluorescein (JOE), 6-carboxy-X-rhodamine (ROX) , 6-carboxy-2' , 4' , 7 ' , 4 , 7-hexachlorofluorescem (HEX) , 5-carboxyfluorescein (5-FAM) or N,N,N' ,N' -tetramethyl-6- carboxyrhodamine (TAMRA) , radioactive labels, e.g. P, S, H; etc. The label may be a two stage system, where the amplified DNA is conjugated to biotin, haptens, etc. having a high afifnity 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.

Hybridization with the variant sequence may also be used to determine its presence, by Southern blots, dot blots, etc. The hybridization pattern of a control and variant sequence to an array of oligonucleotide probes immobilised on a solid support, as described in US 5,445,934, or in WO95/35505, may also be used as a means of detecting the presence of variant sequences. In one embodiment of the invention, an array of oligonucleotides are provided, where discrete positions on the array are complementary to at least a portion of mRNA or genomic DNA encoding one or more TULP proteins. Such an array may comprise a series of oligonucleotides, each of which can specifically hybridize to a nucleic acid, e.g. mRNA, cDNA, genomic DNA, etc. from one of the TULP family members. The complete array may include all of the TULP family members, including the splice variants of TUB. Wild- type sequences and polymorphisms may be represented. For example, 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.

Single strand conformational polymorphism (SSCP) analysis, denaturing gradient gel electrophoresis (DGGE) , and heteroduplex analysis in gel matrices are used to detect conformational changes created by DNA sequence variation as alterations in electrophoretic mobility. The amplified or cloned fragment may be sequenced by dideoxy or other methods, and the sequence of bases compared to the normal sequence. Various methods are known in the art that utilize oligonucleotide ligation as a means of detecting mutations, see Riley et al . (1990) N. A. R. 18:2887-2890; and Delahunty et al . (1996) Am. J. Hum. Genet. 58:1239-1246. Alternatively, where the predisposing mutation creates or destroys a recognition site for a restriction endonuclease, the fragment is digested with that endonuclease, and the products size fractionated to determine whether the fragment was digested. Fractionation is performed by gel electrophoresis, particularly acrylamide or agarose gels.

Antibodies specific for TULP polymorphisms may be used in screening immunoassays. A reduction or increase in a TULP protein and/or presence of disease associated polymorphisms is indicative that a candidate neurosensory defect is TULP-associated. Immunoassays may utilize a patient sample from a patient suspected of having TULP- associated neurosensory defect. Samples, as used herein, include biological fluids such as blood, cerebrospinal fluid, tears, saliva, lymph, dialysis fluid and the like; organ or tissue culture derived fluids; and fluids extracted from physiological tissues. Also included in the term are derivatives and fractions of such fluids.

Diagnosis may be performed by a number of methods. The different methods all determine the absence or presence or altered amounts of normal or abnormal TULP protein in patient cells suspected of having a predisposing polymorphism. For example, detection may utilize staining of cells or histological sections, performed in accordance with conventional methods. The antibodies of interest are added to the cell sample, and incubated for a period of time sufficient to allow binding to the epitope, usually at least about 10 minutes. The antibody may be labeled with radioisotopes, enzymes, fluorescers, chemiluminescers, or other labels for direct detection. Alternatively, a second stage antibody or reagent is used to amplify the signal. Such reagents are well known in the art. For example, the primary antibody may be conjugated to biotin, with horseradish peroxidase-conjugated avidin added as a second stage reagent. 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.

An alternative method for diagnosis depends on the in vi tro detection of binding between antibodies and TULP protein in a lysate. Measuring the concentration of TULP protein binding in a sample or fraction thereof may be accomplished by a variety of specific assays. A conventional sandwich type assay may be used. For example, a sandwich assay may first attach TULP-specific antibodies to an insoluble surface or support. Other immunoassays are known in the art and may find use as diagnostics. Ouchterlony plates provide a simple determination of antibody binding. Western blots may be performed on protein gels or protein spots on filters, using a detection system specific for TULP protein as desired, conveniently using a labeling method as described for the sandwich assay.

Regulation of TULP Gene Expression The TULP genes are useful for analysis of expression, e.g. in determining developmental and tissue specific patterns of expression, and for modulating expression in vi tro and m vivo . Modulation of expression may be used to up-regulate desired TULP genes in specific target tissues, e.g. retina, hypothalamus, etc., or to down-regulate undesired, e.g. disease-associated, TULP genes.

Of particular interest is intraocular gene delivery, e.g. sub- retinal injection, ocular implants, etc. The therapeutic gene is delivered through a suitable vector, e.g. a plasmid or viral vector. Viral vectors known in the art include modified retroviral genomes such as moloney leukemia virus and human immunodeficiency virus. Retroviral vectors typically include viral sequences that are required for packaging, integration and expression of the inserted TULP genes. The vectors are "defective" in the ability to encode viral proteins required for productive infection. Replication requires growth in a packaging cell line that provides the gag, pol , and env proteins necessary for completion of the infectious cycle. Adenovirus vectors are also of interest, as described in Li et al . (1994) Invest. Qphthalmol. Vis. Sci. 35:2543-2549; and Bennett et al . supra . Micro- injection may be employed, fusion, or the like for introduction of genes into a suitable host cell. See, for example, Dhawan et al . (1991) Science 254:1509-1512 and Smith et al . (1990) Molecular and Cellular Biology 3268-3271.

An expression vector will have a transcriptional initiation region oriented to produce functional mRNA. The native transcriptional initiation region, or an exogenous transcriptional initiation region may be employed. The promoter may be introduced by recombinant methods m vi tro, or as the result of homologous integration of the sequence into a chromosome. Many strong promoters are known in the art, including the b-actin promoter, SV40 early and late promoters, human cytomegalovirus promoter, retroviral LTRs, methallothionein responsive element (MRE) , tetracycline- ducible promoter constructs, etc.

Expression 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.

Antisense molecules are used to down-regulate expression of TULP genes in cells. The anti-sense reagent may be antisense oligonucleotides (ODN) , particularly synthetic ODN having chemical modifications from native nucleic acids, or nucleic acid constructs that express such anti-sense molecules as RNA. The antisense sequence is complementary to the mRNA of the targeted gene, and inhibits expression of the targeted gene products . Antisense molecules inhibit gene expression through various mechanisms, e.g. by reducing the amount of mRNA available for translation, through activation of RNAse H, or steric hindrance. One or a combination of antisense molecules may be administered, where a combination may comprise two or more different sequences. Antisense molecules may be produced by expression of all or a part of the target gene sequence in an appropriate vector, where the transcriptional initiation is oriented such that an antisense strand is produced as an RNA molecule. Alternatively, the antisense molecule is a synthetic oligonucleotide. Antisense oligonucleotides will generally be at least about 7, usually at least about 12, more usually at least about 20 nucleotides in length, and not more than about 500, usually not more than about 50, more usually not more than about 35 nucleotides in length, where the length is governed by efficiency of inhibition, specificity, including absence of cross-reactivity, and the like. It has been found that short oligonucleotides, of from 7 to 8 bases in length, can be strong and selective inhibitors of gene expression (see Wagner et al . (1996) Nature Biotechnology 14:840-844) .

A specific region or regions of the endogenous sense strand mRNA sequence is chosen to be complemented by the antisense sequence. Selection of a specific sequence for the oligonucleotide may use an empirical method, where several candidate sequences are assayed for inhibition of expression of the target gene in an in vi tro or animal model. A combination of sequences may also be used, where several regions of the mRNA sequence are selected for antisense complementation. Antisense oligonucleotides may be chemically synthesized by methods known in the art (see Wagner et al . (1993) supra , and Milligan et al . , supra . ) Preferred oligonucleotides are chemically modified from the native phosphodiester structure, in order to increase their intracellular stability and binding affinity. Such modifications have been previously discussed with respect to the use of probes.

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 vi tro and administered to the patient, or may be encoded on an expression vector, from which the ribozyme is synthesized in the targeted cell (for example, see International patent application WO 9523225, and Beigelman et al. (1995) Nucl. Acids Res 23:4434-42) . Examples of oligonucleotides with catalytic activity are described in WO 950676 . Conjugates of anti-sense ODN with a metal complex, e.g. terpyπdylCu(II) , capable of mediating mRNA hydrolysis are described in Bashkin et al . (1995) Appl Biochem B otechnol 54:43-56.

Models for TULP Biological Function The subject nucleic acids can be used to generate genetically modified non-human animals or site specific gene modifications in cell lines. The term "transgenic" is intended to encompass genetically modified animals having a deletion or other knock-out of TULP gene activity, or having an exogenous TULP gene that is stably transmitted in the host cells. Transgenic animals may be made through homologous recombination, where the TULP 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. Of interest are transgenic mammals, e.g. cows, pigs, goats, horses, etc., and particularly rodents, e.g. rats, mice, etc.

Investigation of gene function may also utilize non-mammalian models, particularly using those organisms that are biologically and genetically well-characterized, such as C. elegans, D . melanogas ter and S. cerevisiae. For example, transposon (Tel) insertions in the nematode homolog of a TULP gene, e.g. tub (fl0b5.4) are made. The sub_ject gene sequences may be used to knock-out or to complement defined genetic lesions in order to determine the physiological and biochemical pathways involved in TULP function. A number of human genes have been shown to complement mutations in lower eukaryotes. Drug screening may be performed in combination with complementation studies. Many mammalian genes have homologs in yeast and lower animals. The study of such homologs' physiological role and interactions with other proteins can facilitate understanding of biological function. In addition to model systems based on genetic complementation, yeast has been shown to be a powerful tool for studying protein-protein interactions through the two hybrid system described in Chien et al . (1991) P.N.A.S. 88:9578-9582.

The modified cells or animals are useful in the study of TULP function and regulation. For example, a series of small deletions and/or substitutions may be made in a TULP gene to determine the functional role of different domains. Specific constructs of interest may include anti-sense TULP, which will block TULP expression, expression of dominant negative TULP mutations, and over-expression of a TULP gene. A detectable marker, such as lac Z may be introduced into the TULP locus, where upregulation of TULP expression will result in an easily detected change in phenotype.

These animals are also useful for exploring models of inheritance of neurosensory and obesity related disorders, e.g. dominant v. recessive; relative effects of different alleles and synergistic effects between TUB, TULP1 , TULP2 and TULP3 and other disease genes elsewhere in the genome.

One may also provide for expression of the TULP gene or variants thereof in cells or tissues where it is not normally expressed or at abnormal times of development. In addition, by providing expression of TULP protein in cells in which it is otherwise not normally produced, one can induce changes in cell behavior.

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

For embryonic stem (ES) cells, an ES cell line may be employed, or embryonic cells may be obtained freshly from a host, e.g. mouse, rat, guinea pig, etc. Such cells are grown on an appropriate fibroblast-feeder layer or grown in the presence of appropriate growth factors, such as leukemia inhibiting factor (LIF) . When ES cells have been transformed, they may be used to produce transgenic animals. After transformation, the cells are plated onto a feeder layer in an appropriate medium. Cells containing the construct may be detected by employing a selective medium. After sufficient time for colonies to grow, they are picked and analyzed for the occurrence of homologous recombination or integration of the construct. Those colonies that are positive may then be used for embryo manipulation and blastocyst injection. Blastocysts are obtained from 4 to 6 week old superovulated females. The ES cells are trypsinized, and the modified cells are injected into the blastocoel of the blastocyst. After injection, the blastocysts are returned to each uterine horn of pseudopregnant females. Females are then allowed to go to term and the resulting litters screened for mutant cells having the construct. By providing for a different phenotype of the blastocyst and the ES cells, chimeric progeny can be readily detected.

The chimeric animals are screened for the presence of the modified gene and males and females having the modification are mated to produce homozygous progeny. If the gene alterations cause lethality at some point in development, tissues or organs can be maintained as allogeneic or congenic grafts or transplants, or in in vi tro culture. The transgenic animals may be used in functional studies, drug screening, etc., e.g. to determine the effect of a candidate drug on retinal disease.

Drug Screening Assays

By providing for the production of large amounts of TULP proteins, one can identify ligands or substrates that bind to, modulate or mimic the action of TULP protein. The protein may have the biological activity associated with the wild-type protein, or may have a loss of function mutation due to a point mutation in the coding sequence, substitution, insertion, deletion, etc., including scanning mutations as previously discussed.

Areas of investigation are the development of neurosensory defect or obesity treatments. Drug screening identifies agents that provide a replacement or enhancement for TULP function in affected cells. Of particular interest are screening assays for agents that have a low toxicity for human cells. A wide variety of assays may be used for this purpose, including labeled in vi tro protein-protein binding assays, protein-DNA 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, transcriptional regulation, etc. 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 a TULP protein. Generally a plurality of assay mixtures are run in parallel with different agent concentrations to obtain a differential response to the various concentrations. Typically, one of these concentrations serves as a negative control, i.e. at zero concentration or below the level of detection.

Candidate agents encompass numerous chemical classes, though typically they are organic molecules, preferably small organic compounds having a molecular weight of more than 50 and less than about 2,500 daltons. Candidate agents comprise functional groups necessary for structural interaction with proteins, particularly hydrogen bonding, and typically include at least an amine, carbonyl, hydroxyl or carboxyl group, preferably at least two of the functional chemical groups . The candidate agents often comprise cyclical carbon or heterocyclic structures and/or aromatic or polyaromatic structures substituted with one or more of the above functional groups. Candidate agents are also found among biomolecules including, but not limited to: peptides, saccharides, fatty acids, steroids, purines, pyrimidines, derivatives, structural analogs or combinations thereof. Candidate agents are obtained from a wide variety of sources including libraries of synthetic or natural compounds. For example, numerous means are available for random and directed synthesis of a wide variety of organic compounds and biomolecules, including expression of randomized oligonucleotides and oligopeptides. Alternatively, libraries of natural compounds in the form of bacterial, fungal, plant and animal extracts are available or readily produced. Additionally, natural or synthetically produced libraries and compounds are readily modified through conventional chemical, physical and biochemical means, and may be used to produce combinatorial libraries. Known pharmacological agents may be subjected to directed or random chemical modifications, such as acylation, alkylation, esterification, amidification, etc. to produce structural analogs.

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

A variety of other reagents may be included in the screening assay. These include reagents like salts, neutral proteins, e.g. albumin, detergents, etc that are used to facilitate optimal protein- protein binding and/or reduce non-specific or background interactions. Reagents that improve the efficiency of the assay, such as protease inhibitors, nuclease inhibitors, anti-microbial agents, etc. may be used. The mixture of components are added in any order that provides for the requisite binding. Incubations are performed at any suitable temperature, typically between 4 and 40°C. Incubation periods are selected for optimum activity, but may also be optimized to facilitate rapid high-throughput screening. Typically between 0.1 and 1 hours will be sufficient.

The compounds having the desired pharmacological activity may be administered in a physiologically acceptable carrier to a host for treatment of neurosensory defect or obesity attributable to a defect in TULP gene or protein function. The compounds may also be used to enhance TULP function. The therapeutic agents may be administered in a variety of ways, orally, topically, parenterally e.g. subcutaneously, intraperitoneally, by viral infection, mtravascularly, etc. Inhaled treatments are of particular interest. Depending upon the manner of introduction, the compounds may be formulated in a variety of ways . The concentration of therapeutically active compound in the formulation may vary from about 0.1-100 wt.%. The pharmaceutical compositions can be prepared in various forms, such as granules, tablets, pills, suppositories, capsules, suspensions, salves, lotions and the like. Pharmaceutical grade organic or inorganic carriers and/or diluents suitable for oral and topical use can be used to make up compositions containing the therapeutically- active compounds. Diluents known to the art include aqueous media, vegetable and animal oils and fats. Stabilizing agents, wetting and emulsifying agents, salts for varying the osmotic pressure or buffers for securing an adequate pH value, and skin penetration enhancers can be used as auxiliary agents. A pathway of particular interest is sensory neuron apoptosis.

Mutations in the b subunit of cGMP phosphodiesterase cause retinal degeneration in mice with the rdJ mutation and in humans, and in rdl /rdl mice an abnormal accumulation of cGMP appears to trigger apoptosis of the photoreceptor cells.

Drug screening assays may be performed with mutant and wild-type TULP protein to detect agents that mimic or act as agonists or antagonists for TULP function. The interaction of TULP protein with other proteins in these pathways is of particular interest, and may be detected in a variety of assays, e.g. yeast two hybrid system, in vi tro protein-protein binding assays, genetic complementation, etc. There are a number of characterized genes and gene products that operate to regulate or effect apoptosis.

Complementation in animal and yeast models is particularly useful in the study of apoptosis. The genetics of programmed cell death has been well-defined in several animal models. Both C. elegans and D. melanogas ter regulate apoptosis through the expression of two gene products, ced-3 and ced-9, and rpr and hid, respectively. The relative simplicity of these pathways is attractive for biochemical and genetic analysis. Both animals are used as screening tools in conjunction with the subject gene sequences, and with their corresponding TULP homologs.

A number of apoptotic and anti-apoptotic genes are expressed in neurons and photoreceptors, and may be involved in retinal degeneration. These cells depend on factors such as nerve growth factor and brain derived neurotrophic factor for survival, and may undergo apoptosis where the factor or its receptor are mutated. Among the anti-apoptotic genes of interest are bcl -2, bcl -xL and mcl -1 . Inducers of apoptosis include fas (CD95), myc, bax, bcl -xs , TNF receptor and the family of cysteine proteases that includes interleukin 1 b- converting enzyme.

The availability of the subject gene sequences provides a means of analyzing the biology and biochemistry of specific neural degeneration through in vi tro and in vivo drug screening, the use of transgenic animals, complementation of specific genetic lesions, etc . , as previously described. EXPERIMENTAL

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

Identification of the Mouse Tubby Gene The tubby mutation arose spontaneously in the C57BL/6J mouse strain. Homozygotes are recognizable by increased body weight at 3 to 4 months in males and at 4 to 6 months in females. Both sexes are fertile. The increased weight is composed of excess adipose tissue.

Blood glucose is normal, but plasma insulin is increased prior to obvious signs of obesity and may rise to 20 times normal by 6 months.

The islets of Langerhans are moderately enlarged with signs of hyperactivity and the mice display early onset retinal degeneration leading to blindness.

Materials and Methods

Genetic mapping of the tub locus . DNA samples isolated from the progeny of crosses between C57BL/6-tub/tub, CAST/Ei, AKR or N0D.N0N-H2Λ were genotyped for simple sequence length polymorphisms (Dietrich et al . (1994) Nature Genet. 7:220-245) . All recombinants were progeny tested with a minimum of 20 offspring to confirm phenotypic classification. PCR amplification was performed as described in Naggert et al . (1995) Nature Genet. 10:135-141. The amplification primers used were as follows: Marker Forward Primer Reverse Primer

D7Pjnl l SEQ ID NO:20 SEQ ID NO:21

TTCACAAAAGCACACCTGG GTCCCAAGGATGGAGACCT

D7Pjnl2 SEQ ID NO:22 SEQ ID NO:23 TGGTGAGCAAAACAAGGAAC TGGGGAAAGCAATTTCTGG

D7Pjn24 SEQ ID NO:24 SEQ ID NO:25 GCCTGTCAGCAAGGACCTT CCATGTCCCAAACAAGATGG

YAC clones were obtained by PCR screening of mouse YAC DNA pools from Research Genetics, Inc. (Huntsville, AL) and Pl clones were obtained from Genome Systems (St. Louis, MO) . Briefly, DNA from YAC or Pl pools was used as a template in PCR with a specific primer pair as shown above. Only pools comprising a YAC or Pl that contains the sequence tag defined by the primer pair will yield an amplification product. Then the process is repeated with the subpools corresponding to the positive superpools. In the YACS this process is continued until a single positive YAC can be identified. In the case of Pis, no subpools for the secondary pools exist, so that the secondary pools are plated, transferred to nylon filter and screened with the labeled sequence tag obtained with the specific primer pair. A positive Pl pool is then isolated.

Additional Pl and cosmid clones were made from YAC967d4, which spans most of the minimal genetic interval, and were used in direct cDNA selection against cDNA from adult testis, brain and eye of C57BL/6 mice. Ten randomly chosen cosmids were used in the cDNA selection. Pis used include 3636, 1848, 2617, Y, 14.6, 4171, 17.12, 4154, and 24.2. cDNAs for selection were a mixture obtained from testis, brain and eye mRNA. The selection was carried out as described by Lovett, Current protocols in Human Genetics { eds . Dracopoli et al . ) 6.3.1-13 (Current Protocols, NY 1994) and modified by Segre et al . (1995) Genomics 28:549-559. mRNA prepara tion . Whole organs from C57BL/6J and C57BL/6-tub/tub were flash frozen in liquid nitrogen, homogenized in 500 mM NaCl, 10 mM Tris pH 7.2, 10 mM EDTA, 2% SDS and incubated with 250 μg/ml proteinase K (EM Sciences, Gibbstown, NJ) for 2 hours at 3 °C. Oligo-dT cellulose (Pharmacia, Piscataway, NJ) was added to the homogenate, placed on a shaking incubator for several hours and loaded onto PolyPrep chromatography column (BioRad, Richmond, CA) . After washing in 100 mM NaCl, 10 mM Tris, pH 7.2, 0.1 mM EDTA, poly A⁺ RNA was eluted in 10 mM Tris pH 7.2, 10 mM EDTA. Northern blot analysis . 2-5 μg poly A RNA was fractionated on a 1% agarose-formaldehyde gel, transferred to Hybond N+ membrane (Amersham) and hybridized with the indicated probes in the presence of 500 mM NaP04, 7% SDS, ImM EDTA at 65°C. Blots were washed in 40 mM NaP04, 1% SDS, 1 mM EDTA at 65°C, followed by a stringent wash in 0.1%SDS, 0.1XSSC at 68°C. Integrity, equal loading and transfer efficiency were assessed by control hybridization with a rat GAPDH probe.

An intron specific probe was generated by amplification of genomic PCR product of C13F2 and C13R with oligonucleotide primers C13F3 and C13R3. Nested PCR was used to generate the intron specific fragment in order to obtain a cleaner probe. Probe C15 was obtained by EcoRI digestion of the cDNA clone cl5 from the cDNA selection. Probes were random labeled with ³²P[αdCTP] (Amersham, Arlington Heights, IL) . Genomic DNA was PCR amplified with oligonucleotide primers flanking the donor splice site, C13F2 and C13R, and was gel purified and manually sequenced by dideoxy cycle sequencing (Sequitherm, Epicentre Technologies, Madison, Wl) . Primer 2.61F1 was used with C13R to obtain a probe DNA fragment for northern blots by amplifying cDNA. Random hexamer priming, as described by Sambrook et al . , supra , was used to label the amplification product..

Primers |

2.61F [SEQ ID NO:26] ACCTGAGGCAGCAGAAGCT

C13R [SEQ ID NO:27] CAGCCAGTCTCTGGTTGGT

C13F2 [SEQ ID NO:28] TGCAGAACAAGACGCCAGT

C13F3 [SEQ ID NO:29] GATGTTGTACGCATGGTGC

C13R3 [SEQ ID NO:30] TGGAGACAGGGAGACCAGG

Reverse transcription-PCR . RT-PCR was performed with RNA from adult tissues using primers 2.40R and 2.40F, or GAPDH. The tub gene specific primers span two introns with a combined length of about 1 kb. Two μg poly A+ RNA were treated with DNAse I (Boehringer Mannheim, Indianapolis, IN) and reverse transcribed using Superscript™ Preamplification System (Gibco/BRL, Gaithersburg, MD) . PCR was performed using 1-10 ng sscDNA, primer 2.40F [SEQ ID NO: 31] GATGGCAAGAAGGTGTTCC and 2.40R [SEQ ID NO:32] TCATTGCGGGGGCGGATAC and AmpliTaq™ (Perkin Elmer, CA) under the following conditions: 95°C 1 min denaturation, 94°C 20 sec, 58°C 20 sec, 72°C 30 sec for 49 cycles followed by 72°C 2 min. Forward and reverse GAPDH oligomers were [SEQ ID NO:33] ATGGTGAAGGTCGGTGTGAA and [SEQ ID NO:34] ACCAGTAGACTCCACGACAT, respectively. The amplification products were electrophoresed in 1% agarose gel, transferred to Hybond N+ (Amersham) and hybridized with either exon or GAPDH cDNA probes. cDNA library screening. A mouse testis cDNA library from mouse strain CD-I (Stratagene, La Jolla, CA) inserted into lambda UNI-ZAP XR was screened according to the manufacturer's instructions with the 1.6 kb 2.61F-C13R PCR probe, identifying 24 plaques, two of which were purified and sequenced automatically (Prism, Applied Biosystems, Foster City, CA) . Clone length was between 1 and 2.5 kb. The coding region cDNA sequence of Form I is described in the sequence listing, SEQ ID NO:l. The predicted amino acid sequence is SEQ ID NO:2. The coding region cDNA sequence of Form II is described in the sequence listing SEQ ID NO: 3, the predicted am o acid sequence is SEQ ID NO: 4.

Results Genetic Mapping. Tubby was previously mapped in an interspecific (CSlBL/6-tub/tub X CAST/EIIF-L intercross to 2.4±1.4 cM from Hbb . Markers across a 20 cM interval encompassing Hbb were tested to identify areas of recombination and to define more closely the minimal tub region, using the DNA from the cross described above. Three mapping crosses were used to refine the minimal region containing the gene to between markers D7Mι t94 and D7Mι t325.

A total of 1468 meioses were tested in mapping outcrosses with CAST/Ei. 60 microsatellite markers were used, 91% of which were polymorphic between B6 and CAST. The minimal region containing tub identified by the CAST/Ei outcrosses was between markers D7Mι tl24 and D7Mι t328 with a genetic distance of 0.27 ± 0.14 cM.

In the N0D.N0N-H2iT intercross with C57BL/6 tub/tub, 820 mice or 1640 meioses were tested. Initially, 680 meioses were tested proximally with D7Mι tl 85 and distally with D7Mι tl30. As a narrower region was identified, 458 and 502 meioses were tested with proximal markers, D7Mι tl26 and D7P n2, respectively. Of 44 markers contained within the largest interval tested, 34 (77%) were polymorphic between C57BL- tub/tub and

Overall, 20 recombinant mice were identified in this intercross. The minimal region containing tub lay between markers D7Mιt219 and D7Mιtl30 with a genetic distance of 0.18 ± 0.11 cM.

775 F2 progeny, or 1550 meioses, were tested with D7M tl26 and D 7M t l 30 as the flanking markers in the (C57BL/6- ub/tub X AKR) F_]_ intercross. Only nine of the 34 markers mapping to this region were polymorphic between these parentals. The minimal genetic interval containing tub, between D7Pjnl2 and D7Mit328, corresponds to a distance of 0.19 ± 0.11 cM.

Physi cal Mapping. A YAC contig was established spanning the minimal genetic region, establishing order and distance for those markers not separated by recombinants. The minimal genetic interval was shown to be flanked by crossovers at D7Mi t94 and D7Mit325, which could be mapped within Pl clones 524 and 242, respectively. The location of the tub gene relative to each crossover was unambiguously determined by progeny testing. Animals carrying crossovers in the region were mated to tub/tub homozygotes and the progeny examined for the tubby phenotype (50% tubby if the crossover chromosome still contained the tubby gene, 0% tubby if the crossover chromosome had lost the tubby gene) . Both flanking markers were shown to map within YAC67d4, giving a maximal physical separation of 650 kb. A high resolution physical map of the region was constructed by Pl, BAC and cosmid assembly using STSs derived from end sequencing Pis, by subcloning and sequencing cosmid pools derived from YAC 132bll (1 Mb, non-chimaeric) and by searching public databases.

Selected 0.6-1.5 kb cDNA clones were sequenced and analyzed for similarities to known sequences in GenBank using the BLASTN program (described in Altshul et al . (1990) J. Mol. Bio. 215:403-410), and for overlaps using the AssemblyLIGN program (Kodak, NY) . Unique cDNA clones and single clones from groups of overlapping clones were hybridized to Southern blots of EcoRI digested Pl DNA. Positive clones that mapped to the minimal region were analyzed for genomic alterations and aberrant expression between C57BL/6 and C57BL/6- tub/tub mice by Southern and northern blot analysis. One cDNA clone, c33, from a DNA contig of 12 overlapping sequences, showed an altered hybridization pattern in tubby derived mRNA when compared to C57BL/6. Tubby mice express a slightly larger transcript in brain and testis, 6.6 kb vs . 6.3 kb. Furthermore, clone c33 identified a 2.1 kb transcript in tubby derived mRNA that is not observed in C57BL/6.

To determine the molecular basis of these differences, oligonucleotide primers were made according to the cDNA sequences from the contig of overlapping clones and used to PCR amplify gene specific fragments from cDNA and genomic DNA. Several oligonucleotide combinations derived from the carboxyterminal portion of the gene, as - 31 - described above, generated an amplification product from tubby derived cDNA that was 300 bp longer than from C57BL/6 cDNA. The genomic nucleotide sequence was compared, and it was found that there was a G to T transversion in the tubby donor splice site, changing the wild- type donor splice site consensus sequence from GTGAGT to TTGAGT. To confirm that the larger transcript observed in tub was due to the presence of this unspliced carboxy terminal intron, a PCR generated probe specific for the intron was hybridized to a northern blot. The probe detected a transcript only in the tubby mRNA, but not in wild- type. Comparison of the sequence surrounding this donor splice site in standard inbred strain from historically independent lineages, AKR/J, BALB/cJ, DBA/2J, two wild-derived strains, CZECHII/Ei and SKIVE/Ei, as well as from rabbit and rat, showed conservation of the C57BL/6 sequence, suggesting that the nucleotide change is not a normal allelic form, but a mutation leading to the abnormal transcripts. The 2.1 kb transcript is likely to arise from truncation of the full length transcript by introduction of a polyadenylation site contained in the unspliced intron. This is supported by hybridization analysis with a sequence 3' of the unspliced intron, which does not hybridize to the 2.1 kb transcript.

Northern blot analysis of adult tissues shows strong expression of tubby in brain, eye and testis. Using a more sensitive RT-PCR assay, gene expression was also detected in the small and large intestine, ovary and adipose tissue of adult mice. To assemble a full-length cDNA, 24 clones were isolated from a mouse testis oligo-dT primed cDNA library (Stratagene, La Jolla, CA) . Two forms were identified. The sequence of Form I (SEQ ID N0:1) from nt 393-2579 is identical to Form II (SEQ ID NO: 3) from nt 248-2434. The 5' end of the coding regions differ, resulting in a Form I protein that is 46 amino acids shorter than Form II.

The predominantly hydrophilic nature of the predicted amino acid sequence, and absence of a signal sequence, suggest a cytosolic localization for the protein. The carboxy terminal 260 amino acids show a strong similarity (62% identity) to a putative mouse testis- specific phosphodiesterase (GenBank accession number X69827), as well as the C. elegans 48.2K protein (GenBank Q09306, 59% identity) . The aminoterminal portion of the tubby gene shows no similarity to any known protein in database searches (BLASTP) . Characterization of the Human Tubby Gene The human tubby gene was isolated from a human cDNA library by the following methods.

A cDNA library generated from human brain mRNA and cloned into lambda gtll (Clontech, Palo Alto, CA) was used to isolate the human tubby gene. The phage library was plated at 1.2 x 10 pfu/plate onto E. coli Y1090 m standard bacterial medium. The plates were incubated for 9 hours at 37°C. Two nitrocellulose filters were lifted from each plate as described in Sambrook et al . , supra . , pp.2.114. The filters were hybridized in 10% dextran sulfate, 1% SDS, IM NaCl, 100 μg/ml

32 salmon testes DNA and the P labeled probes described below, at 65°C for 16 hr.

The hybridization probes are PCR amplification products of cDNA sequences isolated by exon trapping with the Pl clone 3636, as described in Example 1. The cDNA sequences were cloned into the pSPL3b vector (BRL, Bethesda, MD) and amplified according to the manufacturer's instructions. A 171 bp probe was generated having the sequence of SEQ ID NO:35, and a 99 bp probe was generated having the sequence of SEQ ID NO:36. The DNA was labeled by random hexamer priming, as described in Example 1.

After hybridization, the filters were washed at 65°C in a buffer of 2 x SSC, 0.1% SDS for 45 m , followed by two washes in 0.2 x SSC, 0.1% SDS for 45 minutes each. Positive plaques were isolated and rescreened. A total of 18 positive plaques were identified. The cDNA inserts from the positive plaques were amplified by PCR and subcloned. Briefly, agar plugs containing positive phage plaques were picked, and resuspended in 10 mM Tris, 1 mM EDTA to elute phage. A PCR reaction was set up with phage eluate and primers specific for the region of lambda gtll flanking the insert. The individual amplification products were digested with EcoRI, purified by gel electrophoresis and QIAEX II™ gel extraction kit (Qiagen) , and inserted into pUC9 at the EcoRI site. The subcloned inserts ranged in size from 1.0-3.3 kb.

Nine of the plasmids were purified using a QIAGEN™ plasmid kit according to the manufacturer's instructions, and sequenced automatically (Prism, Applied Biosystems, Foster City, CA) . The sequences were assembled, edited and analyzed using a suite of programs, including the BLASTN program (described in Altshul et a l . (1990) J. Mol. Bio. 215:403-410), and for overlaps using the AssemblyLIGN program (Kodak, NY) . The human Form I cDNA sequence is shown in SEQ ID NO:7. The predicted amino acid sequence is shown in SEQ ID NO:8

Isolation of TULP1 cDNA To identify tubby related genes involved in retinal degeneration, a human retinal cDNA library was screened with the conserved 3' coding region of human tubby gene as a probe, under low stringency conditions . The TULP1 gene was identified by this screening method. 77% aa identity was observed in the conserved region between TULP1 and TUB. In contrast to TUB, probing a variety of ti-ssue northern blots with TULP1 showed no hybridizing bands. Thus, TULP1 expression is restricted to retina.

Gene specific PCR primers for TULP1 were used to determine its chromosomal location, using the Stanford G3 Radiation Hybrid panel. TULP1 localizes to chromosome 6p21.3. Two markers, D6S439 and D6S291, that flank TULP1 have been reported not to recombine with the RP 14 locus in a human kindred (Shugart et al . (1995) Am J Hum Genet. 57:499- 502) demonstrating that TULP1 is tightly linked to the RP 14 locus.

Northern blot analysis of adult human tissues showed that TUB hybridized to a ~7-7.5 kb transcript with strong expression in heart, brain, testis, ovary, thyroid, and spinal cord after 48 hour exposure. It was also detected in skeletal muscle, prostate, small intestine, trachea and adrenal gland. A 2.4 kb TUB transcript was observed in liver and thyroid. No bands were observed on the same northern blots when hybridized with a TULP1 probe.

Methods

Adul t brain cDNA isola tion . To isolate the TUB gene, approximately 1.2x10 plaque forming units of human adult brain cDNA lambda gtll library were plated according to the manufacturer's

32 instructions (Clontech) . P labeled hybridization probes were prepared from two TUB sequences, ET-3636. p01.a04 (nt 1422 to 1593, 171 bp, GenBank Accession No. U52433) and ET-3636.p01.d01 (nt 1323 to 1421,

99 bp) by random hexamer priming, as described previously (Sambrook et al . Molecular Cloning: a Laboratory Manual 2nd ed. (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 1989) ) .

Filters lifted from the phage plates were hybridized with labeled probe in 10% dextran sulfate, 1% SDS, IM NaCl, 100 μg/ml of salmon testes DNA, at 65°C for 18 hr. After hybridization, filters were washed at 65°C in 2xSSC, 0.1% SDS for 45 min; 0.2xSSC, 0.1% SDS for 45 min and 0.2xSSC, 0.1% SDS for 45 min. Following plaque purification, cDNA inserts were PCR amplified using lambda gtll primers (BRL) and directly cloned into pCR2.1 for sequencing, according to the manufacturer's instructions (Invitrogen) . Automated fluorescence sequencing was utilized (Prism, Applied Biosystems) .

Retinal cDNA isola tion . To identify TULP1 , approximately 1x10 pfus of human retinal cDNA lambda gtll library (Clontech) were

32 hybridized as described above with a P labeled-EcoRI/Sac II fragment (1-962 bp) of Image EST clone 221670 (Research Genetics, Genbank accession no. H92408) at 65°C overnight. The membranes were washed sequentially for 1 hour each with 2xSSC, 0.1% SDS at 50°C, lxSSC, 0.1% SDS at 50°C, and 0.5xSSC, 0.1% SDS at 60°C. Positive plaques were purified and processed as above. Full length cDNA. To isolate the flanking 5' sequences, the Marathon-Ready cDNA kit (Clonetech) was used according to manufacturer's protocol. Amplifications products were gel purified (Qiagen) and sequenced automatically (Prism, Applied Biosystems) or manually by dideoxy cycle sequencing (Sequitherm, Epicentre Technologies) . Alternately, gel purified products were subcloned into TA cloning vector according to manufacturer's instruction (BRL), electroporated into DH10B cells, grown, and plasmids isolated by standard protocol prior to sequencing (Ausubel, et al . Current Protocols in Molecular Biology. Greene Publishing Associates and Wiley- Interscience, New York, updated to 1995) .

Southern analysis . Genomic DNAs from a number of animal species were digested with EcoR I and the DNA transferred to nylon membranes by

32 standard protocol (Clontech) . The membranes were hybridized with P

32 labeled Hind III fragment (281-1833 bp) of TUB cDNA, and P labeled- EcoRI/ BstX I fragment containing the 5' 365 bp of Image EST clone

221670, which contains the 3' end of TULP1. Blots were washed in

2xSSC, 0.05% SDS at room temp, for 2x10 min. and at 60°C for 20 min, then twice with 0.2xSSC, 0.1% SDS at 60°C for 20 min. each.

Northern analysis . Human multiple tissue northern blots MTN I,

32 II and III (Clontech) were hybridized with the P labeled Hind III

32 fragment (281-1833bp) of TUB cDNA and P labeled-EcoRI/BstX I fragment of Image EST clone 221670 in 5x SSPE, lOx Denhardt's, 2%SDS, 100 μg/ml of sheared salmon sperm DNA and 50% formamide at 42°C for 18 hr, then washed at 2xSSC, 0.05% SDS at room temperature for 3x10 min, and at O.lxSSC, 0.1%SDS at 50°C for 2x20 min. Radia tion hybrid mapping. Oligonucleotide primers for PCR amplification were constructed from the novel 5' end of TUB, generating a product of 225 bp for cDNA and ~850 bp for genomic DNA: (SEQ ID NO: 37) CTTAAACCCACTCCATCCTGTG (SEQ ID NO: 38) ATCTCCCTTCCTTCCTTCCAGT.

Amplification primers for the 3' non-coding region for TUB, generating a product of 221bp were constructed: (SEQ ID NO:39) TGCCTGGGAATCCTGCTGC; (SEQ ID NO:40) TCCTAAGGGTCCTGCCACT. For TULPl, generating a product of 92 bp, the following primers were constructed:

(SEQ ID NO: 41) CGAAAACGGAGCAAGACAG; (SEQ ID NO:42) TATGAGGCTCTCCAGCGTC. The MacVector computer program (Oxford) was used to design primer sets. After confirming by sequencing that the appropriate product was amplified, the retention patterns for each oligonucleotide pair were obtained by PCR assay in the Stanford G3 Radiation Hybrid panel (Cox et al . (1990) Science 250:245-250) . Data entered into an online database was analyzed by RHMAP software developed by Boehnke et al . (1991) Am J Hum Genet 49:1174-1188. It is evident from the above results that TULPl is a novel human gene expressed specifically in retinal tissue. The chromosomal location of TULPl is tightly linked to the locus for retinitis pigmentosa 14.

Loss of function mutations in TULPl have been shown to co- segregate with retinitis pigmentosa in kindred studies. Such mutations include but are not limited to a point mutation in exon 11 causing an amino acid substitution of Arg to Pro at A.A. 420 [SEQ ID NO: 13]; and a point mutation in exon 12 causing an amino acid substitution of Phe to Leu at A.A 491 [SEQ ID NO:13].

Isolation of TULP2 cDNA

The human TULP2 gene was isolated from a human cDNA library by the following methods.

TULP2 was identified as a member of the tubby gene family. TULP2 cDNA was isolated by hybridization of a probe from the mouse p46 sequence, at reduced stringency, to a human cDNA library. The mouse p46 gene was previously identified as a cDNA sequence in a public database, with homology to tubby. TULP2 extends approximately 700 bp further than p46 on its 5' end, and has numerous nucleotide differences throughout the length of the gene. The p46 sequence has the GenBank accession number X69827.

Approximately 1 x 10 pfu of human testis cDNA library in lambda

DR2 (Clontech) were plated according to the manufacturer's instructions, using K802 as bacterial host. After over night incubation at 37°C, 2 membranes were lifted from each plate. Those membranes were hybridized in 10% dextran sulfate, 1% SDS, IM NaCl,

32 lOOug/ml of salmon testes DNA and P labeled probes at 65°C for 16 hr.

The labeled probe was a PCR amplification product from a mouse testis cDNA library, using primers MP46.1 (SEQ ID NO:43)

5'-TCTACAGAGACAAACTATGCCC-3' and MP46.2 (SEQ ID NO: 44)

5'-GGAAATGTGCTACACCATC CTC-3', which were designed using the published mouse P46 gene sequence. After hybridization, 3 washes were performed at 55°C: 2xSSC, 0.1% SDS for 45 mm, 0.2xSSC, 0.1% SDS for 45 m , 0.2xSSC, 0.1% SDS for 45 mm. 34 positive plaques were detected after overnight exposure with X ray film. 28 positive clones were isolated after tertiary screening. The positive TULP2 clones were converted to plasmid DNA following the manufacturer's protocol and sequenced according to standard protocols. Human multiple tissue northern blots MTNI, II and III (Clontech)

32 were hybridized with the P labeled PCR amplification product of

TULP2, using primers HP46.F1 (SEQ ID NO:45)

5'-CCACTAAATGAACAGGAGTCGC-3' and HP46.R1 (SEQ ID NO: 6)

5'-GAAACTGGACAAGCAGATGCTG-3' . The probe corresponds to nt 1360-1650 of TULP2 (SEQ ID NO:14) . The hybridization was done m ExpressHyb solution (Clontech) at 60°C for 2 hr, according to the manu acturer's instructions. The blots were washed 3 times in 2xSSC, 0.05%SDS at room temp, followed by washing with O.lxSSC, 0.1%SDS at 55°C 2 x 40 mm., with O.lxSSC, 0.1% SDS at 65°C for 40 min. The TULP2 transcript was detected only in testis, with an approximate size of 1.8 kb.

In order to detect retinal expression, a human retinal cDNA library (Clontech) was plated, and filters lifted, as described above. Using the same TULP2 probe and hybridization conditions, positive plaques were identified at a frequency of 1/10 plaques, indicating low level expression in adult retina tissue.

The genomic location of TULP2 was mapped using the Genebridge radiation hybrid panel. Oligonucleotide primers for PCR amplification were constructed from the 2nd exon from 3' end of TULP2 (position 1360- 1521), generating a product of 162 bp both cDNA and genomic DNA. The primers used were: (SEQ ID NO:47) HP46.F1 5 '-CCACTAAATGAACAGGAGTCGC-3' (SEQ ID NO:48) HP46.R2 5'-TTGGAAGTTCTTCACCGAAGCC-3'

The PCR conditions were 94°C, 45 sec; 55°C, 45 sec; 72°C, 60 sec for a total of 30 cycles. After confirming by sequencing that the appropriate product was amplified, the retention patterns for each oligonucleotide pair were obtained by PCR assay in the Genebridge radiation hybrid panel (see Walter et al . (1994) Nature Genetics 7:22- 28) . Data entered into an online database was analyzed by RHMAP software developed by Boehnke et al . (1991) Am J Hum Genet 49:1174- 1188. The public domain mapping data may be obtained through the Whitehead Institute/MIT Center for Genome Research, Human Genomic Mapping Project, Data Release 10 (May 1996) . This data corresponds to the integrated maps announced in Hudson et . al . (1995) Science 270:1945-1954. Hudson et al . provide a detailed description of the materials and methods used to construct these maps. Further mapping information may be found in Dib et al . (1996) Nature 380:152-154.

The Genebridge mapping data for TULP2 and WI-9028 is as follows: WI-9028 000000000100000000101000000001000000001011001100011000000000011110010 010010000000002011100201 TULP2

000000000100000010101000001001000000001011001100011000000000010110010 000010000000002011100201 These data indicate that the TULP2 gene is most tightly linked (with lod>3) at 3.05 cR to framework marker WI-9028, which maps within the reported linked interval for 19q rod cone retinal dystrophy. The gene for rod cone dystrophy maps between D19S212 and D19S214.

It is evident from the above results that a novel member of the tubby gene family has been characterized. TULP2 is expressed in the testes and retina, but not in other adult tissue. Genomic mapping data indicate that the gene is closely associated with the locus for cone- rod retinal dystrophy, a disease causing early chorioretinal atrophy of the central and peripheral retina.

Figure 2 shows a comparison of the intron-exon structure of human TULPl and TULP2. The intron exon boundaries were determined by comparison of the cDNA sequence to the corresponding genomic sequence obtained by direct sequencing of bacterial artificial chromosomes encompassing the TULP2 or TULPl genomic locus. The intron exon structure is highly conserved at the sequences encoding the carboxy terminal portion of these molecules, and highly divergent over sequences encoding the amino terminal portion. These are sequences that are highly conserved in the TULP family across divergent species. Loss of function mutations that have been identified in TULPl map to the conserved regions.

Isolation of TULP3 cDNA In order to isolate a sequence tagged site for TULP3 from genomic DNA, degenerate primers from the highly conserved C-terminus of the TULP family were prepared and used to amplify anonymous human genomic DNA. Primers Mand-F [SEQ ID NO: 66] (5'-GCITCIGTIAAGAACTTYCAGMT-3' and Mand-R [SEQ ID NO: 67] (5'-CTKSWIAIISMIATIGCRAAIGCYTG-3' ) were used under standard reaction conditions.

Ramping PCR conditions were used: 95°C for 2 min, then 5 cycles of 95°C for 5 sec, 40°C for 10 sec, 72°C for 40 se , followed by 30 cycles at 95°C for 5 sec, 50°C for 10 se , 72°C for 40 sec, followed by an final extension at 72°C for 7 min. The products obtained from this reaction were subcloned and sequenced according to standard protocols. The new sequences corresponding to new TULP family members were then used to design primers for RACE (rapid amplification of cDNA ends) amplification of retina cDNA, as described below.

In order to detect retinal expression, an adaptor ligated human retinal double-stranded cDNA library (Marathon-Ready cDNA, Clontech) was amplified using a kit for Marathon cDNA amplification for 5'- and 3'-RACE (Clontech) . For amplification, 0.2 ng of cDNA was subjected to 5' Marathon RACE using a Tth-XL amplification kit (Perkin-Elmer) with the primers Ap-1 [SEQ ID NO:49] (5'-CCATCCTAATACGACTCACTATAGGGC-3' , Clontech) and the h5.7Rl primer [SEQ ID NO:50] (5'- AATCCAGTGTGAACACGTCAT-3' ) . PCR reactions were performed in a MJ Research PTC-100 cycler with the following program: 37 cycles of 94°C for 5 sec, 54°C for 10 sec, 72°C for 2min., followed by a final extension at 72°C for 7 min.

For the secondary, nested, PCR reaction a 1/50 dilution of the first 5' RACE reaction was prepared and the Marathon RACE reaction was again performed using 2 ul of the diluted product, the Tth-XL amplification kit (Perkin-Elmer), substituting the Ap2 [SEQ ID NO:51] (5'-ACTCACTATAGGGCTCGAGCGGC-3', Clontech) and the h5.7R2 [SEQ ID NO:52] (5 '-CACGTCCAAACTGCATGACT-3' ) primers.

PCR reactions were performed in a MJ Research PTC-100 cycler with the following program: 27 cycles of 94°C for 5 sec, 54°C for 10 sec, 72°C for 2mm., followed by a final extension at 72°C for 7 min.The resulting product was run on a 1.2% agarose gel, stained with EtBr, and a ~1.3 kb band was excised. The DNA was isolated from the agarose using a QIAquick gel extraction kit (Qiagen) and recovered in 50 ul TE buffer. The 3' RACE reaction was similarly performed. Thus the 3'Marathon RACE reaction was performed on 0.2 ng of cDNA using the Tth-XL amplification kit (Perkin-Elmer), along with the Apl primer [SEQ ID NO: 51] (5'-CCATCCTAATACGACTCACTATAGGGC-3' , Clontech) and the h5.7-F5 primer [SEQ ID NO:53] (5'-GCCCCCGTCTGGAACAGTG-3' ) . PCR reactions were performed in a MJ Research PTC-100 cycler with the following program: 37 cycles of 94°C for 5 sec, 54°C for 10 sec, 72°C for 2mιn., followed by a final extension at 72°C for 7 min. For the secondary, 'nested' , PCR reaction a 1/50 dilution of reaction 1 was prepared and the 3' Marathon RACE reaction was performed using 2 ul of the diluted product in a 20 ul reaction of the Tth-XL amplification kit (Perkm-Elmer), along with the Ap2 primer [SEQ ID NO:54] (5'-ACTCACTATAGGGCTCGAGCGGC- 3', Clontech) and the h5.7-f5 primer [SEQ ID NO:55] (5'- GCCCCCGTCTGGAACAGTG-3' ) . The PCR reaction were again performed in the MJResearch PTC-100 cycler with the following program: 27 cycles of 94°C for 5 sec, 54°C for 10 sec, 72 C for 2mιn., followed by a final extension at 72^CC for 7 mm. The resulting product was run on a 1.2% agarose gel, stained with EtBr and a ~500 bp band was excised and weight. DNA was isolated using the QIAquick gel extraction kit.

The DNA sequence was obtained by directly sequencing the 5' and 3' RACE products by automated sequencing on an ABI 480 sequencing system using the h5.7 F5 and h5.7 R2 primers.

Characterization of TUB Splice Variants Western analysis demonstrates that TUB protein is expressed in a variety of human tissues, including brain, colon, heart, skeletal muscle and stomach. TUB function is therefore not restricted in neuronal tissues. The pattern of protein expression is consistent with the pattern of mRNA expression observed by Northern blot analysis. Western blot analysis also indicates that multiple protein products observed in both neuronal and non-neuronal tissues, ranging n s ze from 36 kDa to 98 kDa. Using 5' RACE PCR, a series of alternative spliced forms of human tubby were identified, which can account for these alternative protein products, and which will have different biochemical activities. There are 6 alternative 5' ends for the TUB transcript, which lead to different amino acid sequences of the N terminus. The predicted amino acid sizes for each TUB protein form are listed, along with the SEQ ID NO of the appropriate 5' RACE product. Forms 1-4 are identical in their 3' end sequence from residue 69 to 561 [SEQ ID NO:10], and vary in the 5' sequence as shown. Forms 5 and 6 are spliced such that translation initiation occurs at an internal methionine at residue 102 [SEQ ID NO:10] and leading to a predicted protein of 460 amino acids [SEQ ID NO:8]. The alternative splicing form has been observed in both mouse (tub) and human ( TUB) transcripts.

Form Length AA Protein SEQ NO cDNA SEQ NO

Form 1 561 aa SEQ ID NO: 10 SEQ ID NO: 9

Form 2 518 aa SEQ ID NO: 58 SEQ ID NO: 57

Form 3 512 aa SEQ ID NO: 60 SEQ ID NO: 59

Form 4 506 aa SEQ ID NO: 62 SEQ ID NO: 61

Form 5 460 aa SEQ ID NO: 8 SEQ ID NO: 63

Form 6 460 aa SEQ ID NO: 8 SEQ ID NO: 64

Subcellular localisation directed bv alternative splicing of TUB Clontech vector pEGFP-C was used as the source of green fluorescent protein (GFP) . In all the constructs described herein the

GFP protein was tagged at the amino terminus of the chimeric protein.

Electroporation was used to obtain a transient transfection of Cos7 cell with these expression plasmids. After 8-24 hours of transfection, the cells were fixed with 4% paraformaldehyde and examined using a fluorescence microscope to determine the subcellular localisation of the construct.

construct length GFP Localization Protein SEQ ID NO (aa)

TUB 561 561 nuclear SEQ ID NO: 10

TUB N 285 nuclear SEQ ID NO: 10 residues 1-285

TUB del3 422 cytoplasmic SEQ ID NO: 10 residues 140-561

TUB C 276 cytoplasmic SEQ ID NO: 10 residues 286-561

GFP only cytoplasmic

Taken together these data define a 139 amino acid sequence (SEQ ID NO:10, residues 1-139), capable of nuclear localisation. The domain is common to TUB 561 and TUB N, and is absent from TUB del3 and TUB C. The specific amino acid sequences within this domain which are necessary for nuclear localisation remain to be defined, although the motif [SEQ ID NO:65] KKKRQ has previously been shown to direct nuclear transport.

A distinct (predominantly) cytoplasmic location for TUB 506 [SEQ ID NO: 62] is indicated by GFP assays described above, and by immunohistochemistry in mouse brain sections, where cytoplasmic rather than nuclear staining is obvious. The major form of mouse tubby protein in adult brain has been previously shown to be homologous to SEQ ID NO: 62.

Immunohistochemistry method:

Mouse adult brain section was obtained using standard procedure. After deparaffinization and hydration of the tissue section, slides were blocked with 3% normal goat serum. The primary antiserum from rabbit used for this study was raised against recombinant human TUB fragment (exons 7 to 12) . After overnight incubation with primary antibody at 4°C, the slides were washed several times and incubated with biotinylated anti-rabbit-IgG for 30 min at room temperature. Slides were washed again and incubated with fluorescein streptavidin for another 30 min at room temperature. After that, the slides were washed and mounted with anti-fade mounting medium containing 200ng/ml DAPI.

All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

SEQUENCE LISTING

(1) GENERAL INFORMATION

(i) APPLICANT: Sequana Therapeutics, Inc. and The Jackson Laborator

(ii) TITLE OF THE INVENTION: Family of Genes Associated with Neurosensory Defects

(iii) NUMBER OF SEQUENCES: 67

(iv) CORRESPONDENCE ADDRESS:

(A) ADDRESSEE: Fish and Richardson, P.C.

(B) STREET: 2200 Sand Hill Road (C) CITY: Menlo Park

(D) STATE: CA

(E) COUNTRY: U.S.A.

(F) ZIP: 94025

(v) COMPUTER READABLE FORM: (A) MEDIUM TYPE: Diskette

(B) COMPUTER: IBM Compatible

(C) OPERATING SYSTEM: DOS

(D) SOFTWARE: FastSEQ for Windows Version 2.0

(vi) CURRENT APPLICATION DATA: (A) APPLICATION NUMBER:

(B) FILING DATE: April 10, 1997

(viii) ATTORNEY/AGENT INFORMATION:

(A) NAME: Sherwood, Pamela J.

(B) REGISTRATION NUMBER: 36,677 (C) REFERENCE/DOCKET NUMBER: 08723/002WO1

(ix) TELECOMMUNICATION INFORMATION:

(A) TELEPHONE: 415 322 5070

(B) TELEFAX: 415 854-0875

(2) INFORMATION FOR SEQ ID NO: 1 : (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 2119 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: double

(D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:l:

ATCAGCCCAA GATGGAGGCA GGCTAGTTTA TCACTACCTG TATCTTATCT GCTAGCCAAT 60

GGTACTAAAA CCTATGGCTC AGTGTCCCTC TTCCCAACCA GGAAATGTGG AAGACAGTGG 120

GAAAGGAAGG ACCGTGCTCG TGGAAAACAG CCTCTGACCC CAGACACAAC TGTATGGAAA 180 GTCCAGGGCT GTGTGACAGT TCCTGTGACA GGAAAACACC TCCCCGTGTG GCACCAGGCA 240

GTGAGATGTC CCTAGACATT TTCATTGGCA CCGAGGAAGG CATGTTCTTT GGTATGCTTA 300

GCCGAGACCA ACACCTGGAA TGATACCAGG TGGCTGCCTC TGACCCCAAC ACTGTGCTTG 360 GAAAGAATGT AGCCTGTGAC TTCTAGTAAA AGTGTCCTAG ATGATGAGGG CAGCAACCTG 420

AGGCAGCAGA AGCTCGACCG GCAGCGGGCC CTGTTGGAAC AGAAGCAGAA GAAGAAGCGC 480

CAAGAGCCCT TGATGGTACA GGCCAATGCA GATGGACGGC CCCGGAGTCG GCGAGCCCGG 540

CAGTCAGAGG AGCAAGCCCC CCTGGTGGAG TCCTACCTCA GCAGCAGTGG CAGCACCAGC 600 TACCAAGTTC AAGAGGCCGA CTCGATTGCC AGTGTACAGC TGGGAGCCAC CCGCCCACCA 660

GCACCAGCCT CAGCCAAGAA ATCCAAGGGA GCGGCTGCAT CTGGGGGCCA GGGTGGAGCC 720

CCTAGGAAGG AGAAGAAGGG AAAGCATAAA GGCACCAGCG GGCCAGCAAC TCTGGCAGAA 780

GACAAGTCTG AGGCCCAAGG CCCAGTGCAG ATCTTGACTG TGGGACAGTC AGACCACGAC 840

AAGGATGCGG GAGAGACAGC AGCCGGCGGG GGCGCACAGC CCAGTGGGCA GGACCTCCGT 900 GCCACGATGC AGAGGAAGGG CATCTCCAGC AGCATGAGCT TTGACGAGGA CGAGGATGAG 960

GATGAAAACA GCTCCAGCTC CTCCCAGCTA AACAGCAACA CCCGCCCTAG TTCTGCCACT 1020

AGCAGAAAGT CCATCCGGGA GGCAGCTTCA GCCCCCAGCC CAGCCGCCCC AGAGCCACCA 1080

GTGGATATTG AGGTCCAGGA TCTAGAGGAG TTTGCACTGA GGCCAGCCCC ACAAGGGATC 1140

ACCATCAAAT GCCGCATCAC TCGGGACAAG AAGGGGATGG ACCGCGGCAT GTACCCCACC 1200 TACTTTCTGC ACCTAGACCG TGAGGATGGC AAGAAGGTGT TCCTCCTGGC GGGCAGGAAG 1260

AGAAAGAAGA GTAAAACTTC CAATTACCTC ATCTCTGTGG ACCCAACAGA CTTGTCTCGG 1320

GGAGGCGATA GCTATATCGG GAAGTTGCGG TCCAACCTGA TGGGCACCAA GTTCACCGTT 1380

TATGACAATG GCGTCAACCC TCAGAAGGCA TCCTCTTCCA CGCTGGAAAG CGGAACCTTG 1440

CGCCAGGAGC TGGCAGCGGT GTGCTATGAG ACAAATGTCC TAGGCTTCAA GGGACCTCGG 1500 AAGATGAGTG TGATCGTCCC AGGCATGAAC ATGGTTCATG AGAGAGTCTG TATCCGCCCC 1560

CGCAATGAAC ATGAGACCCT GTTAGCACGC TGGCAGAACA AGAACACGGA GAGCATCATT 1620

GAGCTGCAGA ACAAGACGCC AGTCTGGAAT GATGACACAC AGTCCTATGT ACTTAACTTC 1680

CACGGCCGTG TCACACAGGC TTCTGTGAAG AACTTCCAGA TCATCCACGG CAATGACCCG 1740

GACTACATCG TCATGCAGTT TGGCCGGGTA GCAGAAGATG TGTTCACCAT GGATTACAAC 1800 TACCCACTGT GTGCACTGCA GGCCTTTGCC ATTGCTCTGT CCAGCTTTGA CAGCAAGCTG 1860

GCCTGCGAGT AGAGGCCCCC ACTGCCTTTA GGTGGCCCAG TCCGGAGTGG AGCTTGCCTG 1920

CCTGCCAAGA CAGCCCTGCC TACCCTCTGT TCATAGGCCC TCTATGGGCT TTCTGGCCTT 1980

ACCAACCAGA GACTGGCTGC TCTGCCTCTG CTGCTGAAGC AGGGGGGACA GCAAATGGGT 2040

ATGACAGGAG AAGAATATTT CTGTGCCCCA AGGTCAACAA CACACATGCC CAGTCCTGGA 2100 AAAAAAAAAA AAAAAAAAA 2119

(2) INFORMATION FOR SEQ ID NO:2:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 459 amino acids

(B) TYPE: amino acid (C) STRA DEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: protein

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:

Met Val Gin Ala Asn Ala Asp Gly Arg Pro Arg Ser Arg Arg Ala Arg 1 5 10 15

Gin Ser Glu Glu Gin Ala Pro Leu Val Glu Ser Tyr Leu Ser Ser Ser

20 25 30

Gly Ser Thr Ser Tyr Gin Val Gin Glu Ala Asp Ser lie Ala Ser Val 35 40 45 Gin Leu Gly Ala Thr Arg Pro Pro Ala Pro Ala Ser Ala Lys Lys Ser 50 55 60

Lys Gly Ala Ala Ala Ser Gly Gly Gin Gly Gly Ala Pro Arg Lys Glu 65 70 75 80

Lys Lys Gly Lys His Lys Gly Thr Ser Gly Pro Ala Thr Leu Ala Glu 85 90 95

Asp Lys Ser Glu Ala Gin Gly Pro Val Gin He Leu Thr Val Gly Gin

100 105 HO

Ser Asp His Asp Lys Asp Ala Gly Glu Thr Ala Ala Gly Gly Gly Ala 115 120 125 Gin Pro Ser Gly Gin Asp Leu Arg Ala Thr Met Gin Arg Lys Gly He 130 135 140

Ser Ser Ser Met Ser Phe Asp Glu Asp Glu Asp Glu Asp Glu Asn Ser 145 150 155 160

Ser Ser Ser Ser Gin Leu Asn Ser Asn Thr Arg Pro Ser Ser Ala Thr 165 170 175

Ser Arg Lys Ser He Arg Glu Ala Ala Ser Ala Pro Ser Pro Ala Ala

180 185 190

Pro Glu Pro Pro Val Asp He Glu Val Gin Asp Leu Glu Glu Phe Ala 195 200 205 Leu Arg Pro Ala Pro Gin Gly He Thr He Lys Cys Arg He Thr Arg 210 215 220

Asp Lys Lys Gly Met Asp Arg Gly Met Tyr Pro Thr Tyr Phe Leu His 225 230 235 240

Leu Asp Arg Glu Asp Gly Lys Lys Val Phe Leu Leu Ala Gly Arg Lys 245 250 255

Arg Lys Lys Ser Lys Thr Ser Asn Tyr Leu He Ser Val Asp Pro Thr

260 265 270

Asp Leu Ser Arg Gly Gly Asp Ser Tyr He Gly Lys Leu Arg Ser Asn 275 280 285 Leu Met Gly Thr Lys Phe Thr Val Tyr Asp Asn Gly Val Asn Pro Gin 290 295 300

Lys Ala Ser Ser Ser Thr Leu Glu Ser Gly Thr Leu Arg Gin Glu Leu 305 310 315 320

Ala Ala Val Cys Tyr Glu Thr Asn Val Leu Gly Phe Lys Gly Pro Arg 325 330 335

Lys Met Ser Val He Val Pro Gly Met Asn Met Val His Glu Arg Val

340 345 350

Cys He Arg Pro Arg Asn Glu His Glu Thr Leu Leu Ala Arg Trp Gin 355 360 365 Asn Lys Asn Thr Glu Ser He He Glu Leu Gin Asn Lys Thr Pro Val 370 375 380

Trp Asn Asp Asp Thr Gin Ser Tyr Val Leu Asn Phe His Gly Arg Val 385 390 395 400

Thr Gin Ala Ser Val Lys Asn Phe Gin He He His Gly Asn Asp Pro 405 410 415

Asp Tyr He Val Met Gin Phe Gly Arg Val Ala Glu Asp Val Phe Thr

420 425 430

Met Asp Tyr Asn Tyr Pro Leu Cys Ala Leu Gin Ala Phe Ala He Ala 435 440 445 Leu Ser Ser Phe Asp Ser Lys Leu Ala Cys Glu 450 455

(2) INFORMATION FOR SEQ ID NO:3:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 2434 base pairs (B) TYPE: nucleic acid

(C) STRANDEDNESS: double

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 3: CCTCTCCCGA GCGCTGCACC GCGCACAGAC AACCGTTCTG GGAGCCCGCG GCCGGGGCCC 60

TGGCGTGCAG AGAGGGCCTC GGCGGGGCCC AGCGGTCGGG CCGGGGAGGA TGCGGCCCGG 120

GGCGGCCCGA GAGTTGAGCA GGGTCCCCGC GCCAGCCCCG AGCGGTCCCG GCCACCGGAG 180

CCGCAGCCGC CGCCCCGCCC CCGGGAGACA TGACTTCCAA GCCGCATTCC GACTGGATTC 240

CTTACAGTGT CCTAGATGAT GAGGGCAGCA ACCTGAGGCA GCAGAAGCTC GACCGGCAGC 300 GGGCCCTGTT GGAACAGAAG CAGAAGAAGA AGCGCCAAGA GCCCTTGATG GTACAGGCCA 360 ATGCAGATGG ACGGCCCCGG AGTCGGCGAG CCCGGCAGTC AGAGGAGCAA GCCCCCCTGG 420

TGGAGTCCTA CCTCAGCAGC AGTGGCAGCA CCAGCTACCA AGTTCAAGAG GCCGACTCGA 480

TTGCCAGTGT ACAGCTGGGA GCCACCCGCC CACCAGCACC AGCCTCAGCC AAGAAATCCA 540

AGGGAGCGGC TGCATCTGGG GGCCAGGGTG GAGCCCCTAG GAAGGAGAAG AAGGGAAAGC 600

ATAAAGGCAC CAGCGGGCCA GCAACTCTGG CAGAAGACAA GTCTGAGGCC CAAGGCCCAG 660

TGCAGATCTT GACTGTGGGA CAGTCAGACC ACGACAAGGA TGCGGGAGAG ACAGCAGCCG 720

GCGGGGGCGC ACAGCCCAGT GGGCAGGACC TCCGTGCCAC GATGCAGAGG AAGGGCATCT 780

CCAGCAGCAT GAGCTTTGAC GAGGACGAGG ATGAGGATGA AAACAGCTCC AGCTCCTCCC 840

AGCTAAACAG CAACACCCGC CCTAGTTCTG CCACTAGCAG AAAGTCCATC CGGGAGGCAG 900

CTTCAGCCCC CAGCCCAGCC GCCCCAGAGC CACCAGTGGA TATTGAGGTC CAGGATCTAG 960

AGGAGTTTGC ACTGAGGCCA GCCCCACAAG GGATCACCAT CAAATGCCGC ATCACTCGGG 1020

ACAAGAAGGG GATGGACCGC GGCATGTACC CCACCTACTT TCTGCACCTA GACCGTGAGG 1080

ATGGCAAGAA GGTGTTCCTC CTGGCGGGCA GGAAGAGAAA GAAGAGTAAA ACTTCCAATT 1140

ACCTCATCTC TGTGGACCCA ACAGACTTGT CTCGGGGAGG CGATAGCTAT ATCGGGAAAT 1200

TGCGGTCCAA CCTGATGGGC ACCAAGTTCA CCGTTTATGA CAATGGCGTC AACCCTCAGA 1260

AGGCATCCTC TTCCACGCTG GAAAGCGGAA CCTTGCGCCA GGAGCTGGCA GCGGTGTGCT 1320

ATGAGACAAA TGTCCTAGGC TTCAAGGGAC CTCGGAAGAT GAGTGTGATC GTCCCAGGCA 1380

TGAACATGGT TCATGAGAGA GTCTGTATCC GCCCCCGCAA TGAACATGAG ACCCTGTTAG 1440

CACGCTGGCA GAACAAGAAC ACGGAGAGCA TCATTGAGCT GCAGAACAAG ACGCCAGTCT 1500

GGAATGATGA CACACAGTCC TATGTACTTA ACTTCCACGG CCGTGTCACA CAGGCTTCTG 1560

TGAAGAACTT CCAGATCATC CACGGCAATG ACCCGGACTA CATCGTCATG CAGTTTGGCC 1620

GGGTAGCAGA AGATGTGTTC ACCATGGATT ACAACTACCC ACTGTGTGCA CTGCAGGCCT 1680

TTGCCATTGC TCTGTCCAGC TTTGACAGCA AGCTGGCCTG CGAGTAGAGG CCCCCACTGC 1740

CTTTAGGTGG CCCAGTCCGG AGTGGAGCTT GCCTGCCTGC CAAGACAGCC CTGCCTACCC 1800

TCTGTTCATA GGCCCTCTAT GGGCTTTCTG GCCTTACCAA CCAGAGACTG GCTGCTCTGC 1860

CTCTGCTGCT GAAGCAGGGG GGACAGCAAA TGGGTATGAC AGGAGAAGAA TATTTCTGTG 1920

CCCCAAGGTC AACACACATG CCCAGTCCTG GGTCAGTCCC CTGCTGCAGT GGTGTTATCA 1980

CACCGGAAAG CCTCTTCACC TGGAGGTACA GAGGGAGAGG AAGCACAAGC CTGGCTGCTG 2040

TGGYTCAGCC ATCCACTCAG CCTACGAGTC AGAGACAGTG GGTGTCCCKG GAAGCRGGGG 2100

TACAGTGAGT GTGTGTGTAT GTACAGGGCA CTCAAGCTGT ATGTAGAAAA AGCTCTGGTG 2160

GTCAGCAGAA AGCACTCCCR CTTCAAAAGG GCCCATTAGG CCCAAAGGGG GTTAGGAGTG 2220

GTAGGGATAG GTGCGTGGCA GGTCCCTGCT AGGATTGCAG GGGCCTGGCC ATGTGTATTA 2280

GCTGGAGGCT TAGAATGCTA GCTCATTTGT TGCTACAGAT TTGCCCAGTG CTTGCAYACG 2340

TAAGAACCCA GCTCTCAAGG CCAAATATCT GAKTGGATGG GGATGATAGG AGTCATCCAG 2400

TAGACTCCCT ACATCAGGGC TCTCAGCAGC CCCA 2434

(2) INFORMATION FOR SEQ ID NO:4:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 505 amino acids

(B) TYPE: amino acid (C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: protein

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 4:

Met Thr Ser Lys Pro His Ser Asp Trp He Pro Tyr Ser Val Leu Asp 1 5 10 15

Asp Glu Gly Ser Asn Leu Arg Gin Gin Lys Leu Asp Arg Gin Arg Ala

20 25 30

Leu Leu Glu Gin Lys Gin Lys Lys Lys Arg Gin Glu Pro Leu Met Val 35 40 45 Gin Ala Asn Ala Asp Gly Arg Pro Arg Ser Arg Arg Ala Arg Gin Ser 50 55 60

Glu Glu Gin Ala Pro Leu Val Glu Ser Tyr Leu Ser Ser Ser Gly Ser 65 70 75 80

Thr Ser Tyr Gin Val Gin Glu Ala Asp Ser He Ala Ser Val Gin Leu 85 90 95 Gly Ala Thr Arg Pro Pro Ala Pro Ala Ser Ala Lys Lys Ser Lys Gly

100 105 110

Ala Ala Ala Ser Gly Gly Gin Gly Gly Ala Pro Arg Lys Glu Lys Lys 115 120 125 Gly Lys His Lys Gly Thr Ser Gly Pro Ala Thr Leu Ala Glu Asp Lys 130 135 140

Ser Glu Ala Gin Gly Pro Val Gin He Leu Thr Val Gly Gin Ser Asp 145 150 155 160

His Asp Lys Asp Ala Gly Glu Thr Ala Ala Gly Gly Gly Ala Gin Pro 165 170 175

Ser Gly Gin Asp Leu Arg Ala Thr Met Gin Arg Lys Gly He Ser Ser

180 185 190

Ser Met Ser Phe Asp Glu Asp Glu Asp Glu Asp Glu Asn Ser Ser Ser 195 200 205 Ser Ser Gin Leu Asn Ser Asn Thr Arg Pro Ser Ser Ala Thr Ser Arg 210 215 220

Lys Ser He Arg Glu Ala Ala Ser Ala Pro Ser Pro Ala Ala Pro Glu 225 230 235 240

Pro Pro Val Asp He Glu Val Gin Asp Leu Glu Glu Phe Ala Leu Arg 245 250 255

Pro Ala Pro Gin Gly He Thr He Lys Cys Arg He Thr Arg Asp Lys

260 265 270

Lys Gly Met Asp Arg Gly Met Tyr Pro Thr Tyr Phe Leu His Leu Asp 275 280 285 Arg Glu Asp Gly Lys Lys Val Phe Leu Leu Ala Gly Arg Lys Arg Lys 290 295 300

Lys Ser Lys Thr Ser Asn Tyr Leu He Ser Val Asp Pro Thr Asp Leu 305 310 315 320

Ser Arg Gly Gly Asp Ser Tyr He Gly Lys Leu Arg Ser Asn Leu Met 325 330 335

Gly Thr Lys Phe Thr Val Tyr Asp Asn Gly Val Asn Pro Gin Lys Ala

340 345 350

Ser Ser Ser Thr Leu Glu Ser Gly Thr Leu Arg Gin Glu Leu Ala Ala 355 360 365 Val Cys Tyr Glu Thr Asn Val Leu Gly Phe Lys Gly Pro Arg Lys Met 370 375 380

Ser Val He Val Pro Gly Met Asn Met Val His Glu Arg Val Cys He 385 390 395 400

Arg Pro Arg Asn Glu His Glu Thr Leu Leu Ala Arg Trp Gin Asn Lys 405 410 415

Asn Thr Glu Ser He He Glu Leu Gin Asn Lys Thr Pro Val Trp Asn

420 425 430

Asp Asp Thr Gin Ser Tyr Val Leu Asn Phe His Gly Arg Val Thr Gin 435 440 445 Ala Ser Val Lys Asn Phe Gin He He His Gly Asn Asp Pro Asp Tyr 450 455 460

He Val Met Gin Phe Gly Arg Val Ala Glu Asp Val Phe Thr Met Asp 465 470 475 480

Tyr Asn Tyr Pro Leu Cys Ala Leu Gin Ala Phe Ala He Ala Leu Ser 485 490 495

Ser Phe Asp Ser Lys Leu Ala Cys Glu 500 505

(2) INFORMATION FOR SEQ ID NO:5:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 480 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: double

(D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: I

ACTTCCAGAT CATCCACGGC AATGACCTTG AGTGTTGCCA CTCCCTGTTT TTGATGTTGT 60 ACGCATGGTG CCCAGCCCCC ACCCCACCCC CAATCCCCTG ATCTGGTCCA TATCAGCCAG 120 TGATGGGATG TGGGTATATG GCTTTTGTTA GAACTTTCTA ACTGTAGTGA TCTAGAGTCC 180 TGCCCCTAGT GCCCTGCATG TCTGGGGCTT GGGAATACCC TTTAAATGGA TGTCTTTTCT 240 CTCCTGGGCC CTGCTGTCTG TGTGCATCTC CCCCCTTCAC CCTCTTGCTT CATAATGTTT 300 CTCTTGAACC TTTGTTTTGT TCATCCTTTC GATCTCTTTG GCATTTCTGC TTTCTCCTTC 360 CCTCTTGTGG CCCATGTCTT ACCTGGTCTC CCTGTCTCCA CCAATTCTTG CTTGGTGCAT 420 GCCACAGCGG ACTACATCGT CATGCAGTTT GGCCGGGTAG CAGAAGATGT GTTCACCATG 480

(2) INFORMATION FOR SEQ ID NO: 6:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 33 amino acids

(B) TYPE: amino acid (C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: protein

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 6:

Asn Phe Gin He He His Gly Asn Asp Leu Glu Cys Cys His Ser Leu 1 5 10 15

Phe Leu Met Leu Tyr Ala Trp Cys Pro Ala Pro Thr Pro Pro Pro He

20 25 30

Pro

(2) INFORMATION FOR SEQ ID NO: 7:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1426 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: double

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:7:

CAGAAGAAGA AGCGCCAGGA GCCCCTGATG GTGCAGGCCA ATGCAGATGG GCGGCCCCGG 60

AGCCGGCGGG CCCGGCAGTC AGAGGAACAA GCCCCCCTGG TGGAGTCCTA CCTCAGCAGC 120 AGTGGCAGCA CCAGCTACCA AGTTCAAGAG GCCGACTCAC TCGCCAGTGT GCAGCTGGGA 180

GCCACGCGCC CAACAGCACC AGCTTCAGCC AAGAGAACCA AGGCGGCAGC TACAGCAGGG 240

GGCCAGGGCG GCGCCGCTAG GAAGGAGAAG AAGGGAAAGC ACAAAGGCAC CAGCGGGCCA 300

GCAGCACTGG CAGAAGACAA GTCTGAGGCC CAAGGCCCAG TGCAGATTCT GACTGTGGGC 360

CAGTCAGACC ACGCCCAGGA CGCAGGGGAG ACGGCAGCTG GTGGGGGCGA ACGGCCCAGC 420 GGGCAGGATC TCCGTGCCAC GATGCAGAGG AAGGGCATCT CCAGCAGCAT GAGCTTTGAC 480

GAGGATGAGG AGGATGAGGA GGAGAATAGC TCCAGCTCCT CCCAGCTAAA TAGTAACACC 540

CGCCCCAGCT CTGCTACTAG CAGGAAGTCC GTCAGGGAGG CAGCCTCAGC CCCTAGCCCA 600

ACAGCTCCAG AGCAACCAGT GGACGTTGAG GTCCAGGATC TTGAGGAGTT TGCACTGAGG 660

CCGGCCCCCC AGGGTATCAC CATCAAATGC CGCATCACTC GGGACAAGAA AGGGATGGAC 720 CGGGGCATGT ACCCCACCTA CTTTCTGCAC CTGGACCGTG AGGATGGGAA GAAGGTGTTC 780

CTCCTGGCGG GAAGGAAGAG AAAGAAGAGT AAAACTTCCA ATTACCTCAT CTCTGTGGAC 840

CCAACAGACT TGTCTCGAGG AGGGGACAGC TATATCGGGA AACTGCGGTC CAACTTGATG 900

GGCACCAAGT TCACTGTTTA TGACAATGGA GTCAACCCTC AGAAGGCCTC ATCCTCCACT 960 TTGGAAAGTG GAACCTTACG TCAGGAGCTG GCAGCTGTGT GCTACGAGAC AAACGTCTTA 1020

GGCTTCAAGG GGCCTCGGAA GATGAGCGTG ATTGTCCCAG GCATGAACAT GGTCCATGAG 1080

AGAGTCTCTA TCCGCCCCCG CAACGAGCAT GAGACACTGC TAGCACGCTG GCAGAATAAG 1140

AACACGGAGA GTATCATCGA GCTGCAAAAC AAGACACCTG TCTGGAATGA TGACACACAG 1200 TCCTATGTAC TCAACTTCCA TGGGCGCGTC ACACAGGCCT CCGTGAAGAA CTTCCAGATC 1260

ATCCATGGCA ATGACCCGGA CTACATCGTG ATGCAGTTTG GCCGGGTAGC AGAGGATGTG 1320

TTCACCATGG ATTACAACTA CCCGCTGTGT GCACTGCAGG CCTTTGCCAT TGCCCTGTCC 1380

AGCTTCGACA GCAAGCTGGC GTGCGAGTAG AGGCCTCTTC GTGCCC 1426

(2) INFORMATION FOR SEQ ID NO: 8: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 460 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 8:

Met Val Gin Ala Asn Ala Asp Gly Arg Pro Arg Ser Arg Arg Ala Arg

1 5 10 15

Gin Ser Glu Glu Gin Ala Pro Leu Val Glu Ser Tyr Leu Ser Ser Ser 20 25 30

Gly Ser Thr Ser Tyr Gin Val Gin Glu Ala Asp Ser Leu Ala Ser Val

35 40 45

Gin Leu Gly Ala Thr Arg Pro Thr Ala Pro Ala Ser Ala Lys Arg Thr 50 55 60 Lys Ala Ala Ala Thr Ala Gly Gly Gin Gly Gly Ala Ala Arg Lys Glu 65 70 75 80

Lys Lys Gly Lys His Lys Gly Thr Ser Gly Pro Ala Ala Leu Ala Glu

85 90 95

Asp Lys Ser Glu Ala Gin Gly Pro Val Gin He Leu Thr Val Gly Gin 100 105 110

Ser Asp His Ala Gin Asp Ala Gly Glu Thr Ala Ala Gly Gly Gly Glu

115 120 125

Arg Pro Ser Gly Gin Asp Leu Arg Ala Thr Met Gin Arg Lys Gly He

130 135 140 Ser Ser Ser Met Ser Phe Asp Glu Asp Glu Glu Asp Glu Glu Glu Asn

145 150 155 160

Ser Ser Ser Ser Ser Gin Leu Asn Ser Asn Thr Arg Pro Ser Ser Ala

165 170 175

Thr Ser Arg Lys Ser Val Arg Glu Ala Ala Ser Ala Pro Ser Pro Thr 180 185 190

Ala Pro Glu Gin Pro Val Asp Val Glu Val Gin Asp Leu Glu Glu Phe

195 200 205

Ala Leu Arg Pro Ala Pro Gin Gly He Thr He Lys Cys Arg He Thr

210 215 220 Arg Asp Lys Lys Gly Met Asp Arg Gly Met Tyr Pro Thr Tyr Phe Leu

225 230 235 240

His Leu Asp Arg Glu Asp Gly Lys Lys Val Phe Leu Leu Ala Gly Arg

245 250 255

Lys Arg Lys Lys Ser Lys Thr Ser Asn Tyr Leu He Ser Val Asp Pro 260 265 270

Thr Asp Leu Ser Arg Gly Gly Asp Ser Tyr He Gly Lys Leu Arg Ser

275 280 285

Asn Leu Met Gly Thr Lys Phe Thr Val Tyr Asp Asn Gly Val Asn Pro 290 295 300 Gin Lys Ala Ser Ser Ser Thr Leu Glu Ser Gly Thr Leu Arg Gin Glu 305 310 315 320

Leu Ala Ala Val Cys Tyr Glu Thr Asn Val Leu Gly Phe Lys Gly Pro

325 330 335

Arg Lys Met Ser Val He Val Pro Gly Met Asn Met Val His Glu Arg 340 345 350

Val Ser He Arg Pro Arg Asn Glu His Glu Thr Leu Leu Ala Arg Trp

355 360 365

Gin Asn Lys Asn Thr Glu Ser He He Glu Leu Gin Asn Lys Thr Pro

370 375 380 Val Trp Asn Asp Asp Thr Gin Ser Tyr Val Leu Asn Phe His Gly Arg

385 390 395 400

Val Thr Gin Ala Ser Val Lys Asn Phe Gin He He His Gly Asn Asp

405 410 415

Pro Asp Tyr He Val Met Gin Phe Gly Arg Val Ala Glu Asp Val Phe 420 425 430

Thr Met Asp Tyr Asn Tyr Pro Leu Cys Ala Leu Gin Ala Phe Ala He

435 440 445

Ala Leu Ser Ser Phe Asp Ser Lys Leu Ala Cys Glu 450 455 460 (2) INFORMATION FOR SEQ ID NO: 9:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 3268 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: double (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 9:

CTTGAGGATT CAGTCTGGTC CTGAAGGGTT TGGGGGGAGA CTGCGACCAG AAGATGTTTC 60

CATGTCCTAA TTAATGGGTG ATGGTGGTTG TTAGTCTGAC TGTTGCCACG GTGATGAAGG 120 GAGACATCCA AGTGCTGGTT TCAGTACTGA GGCGAATACA GGGAATTTCA ACAGGCTCCA 180

GGTCTTACTA TGCAGCCTGA AGTGGGACCA TCCCTTAAAC CCACTCCATC CTGTGGCCAC 240

GATGGGGGCC AGGACACCTT TGCCTTCTTT CTGGGTTTCT TTCTTTGCCG AGACAGGGAT 300

TTTGTTCCCA GGAGGCACTC CCTGGCCCAT GGGATCTCAG CATTCAAAGC AGCACAGGAA 360

ACCTGGGCCC CTGAAACGGG GCCACCGAAG AGATCGGAGA ACAACCAGGA GGAAGTACTG 420 GAAGGAAGGA AGGGAGATCG CTCGTGTCTT AGATGATGAG GGCAGAAACC TGAGGCAGCA 480

GAAGCTTGAT CGGCAGCGGG CCCTGCTGGA GCAGAAGCAG AAGAAGAAGC GCCAGGAGCC 540

CCTGATGGTG CAGGCCAATG CAGATGGGCG GCCCCGGAGC CGGCGGGCCC GGCAGTCAGA 600

GGAACAAGCC CCCCTGGTGG AGTCCTACCT CAGCAGCAGT GGCAGCACCA GCTACCAAGT 660

TCAAGAGGCC GACTCACTCG CCAGTGTGCA GCTGGGAGCC ACGCGCCCAA CAGCACCAGC 720 TTCAGCCAAG AGAACCAAGG CGGCAGCTAC AGCAGGGGGC CAGGGCGGCG CCGCTAGGAA 780

GGAGAAGAAG GGAAAGCACA AAGGCACCAG CGGGCCAGCA GCACTGGCAG AAGACAAGTC 840

TGAGGCCCAA GGCCCAGTGC AGATTCTGAC TGTGGGCCAG TCAGACCACG CCCAGGACGC 900

AGGGGAGACG GCAGCTGGTG GGGGCGAACG GCCCAGCGGG CAGGATCTCC GTGCCACGAT 960

GCAGAGGAAG GGCATCTCCA GCAGCATGAG CTTTGACGAG GATGAGGAGG ATGAGGAGGA 1020 GAATAGCTCC AGCTCCTCCC AGCTAAATAG TAACACCCGC CCCAGCTCTG CTACTAGCAG 1080

GAAGTCCGTC AGGGAGGCAG CCTCAGCCCC TAGCCCAACA GCTCCAGAGC AACCAGTGGA 1140

CGTTGAGGTC CAGGATCTTG AGGAGTTTGC ACTGAGGCCG GCCCCCCAGG GTATCACCAT 1200

CAAATGCCGC ATCACTCGGG ACAAGAAAGG GATGGACCGG GGCATGTACC CCACCTACTT 1260

TCTGCACCTG GACCGTGAGG ATGGGAAGAA GGTGTTCCTC CTGGCGGGAA GGAAGAGAAA 1320 GAAGAGTAAA ACTTCCAATT ACCTCATCTC TGTGGACCCA ACAGACTTGT CTCGAGGAGG 1380

GGACAGCTAT ATCGGGAAAC TGCGGTCCAA CTTGATGGGC ACCAAGTTCA CTGTTTATGA 1440

CAATGGAGTC AACCCTCAGA AGGCCTCATC CTCCACTTTG GAAAGTGGAA CCTTACGTCA 1500

GGAGCTGGCA GCTGTGTGCT ACGAGACAAA CGTCTTAGGC TTCAAGGGGC CTCGGAAGAT 1560

GAGCGTGATT GTCCCAGGCA TGAACATGGT CCATGAGAGA GTCTCTATCC GCCCCCGCAA 1620 CGAGCATGAG ACACTGCTAG CACGCTGGCA GAATAAGAAC ACGGAGAGTA TCATCGAGCT 1680 GCAAAACAAG ACACCTGTCT GGAATGATGA CACACAGTCC TATGTACTCA ACTTCCATGG 1740

GCGCGTCACA CAGGCCTCCG TGAAGAACTT CCAGATCATC CATGGCAATG ACCCGGACTA 1800

CATCGTGATG CAGTTTGGCC GGGTAGCAGA GGATGTGTTC ACCATGGATT ACAACTACCC 1860

GCTGTGTGCA CTGCAGGCCT TTGCCATTGC CCTGTCCAGC TTCGACAGCA AGCTGGCGTG 1920

CGAGTAGAGG CCTCTTCGTG CCCTTTGGGG TTGCCCAGCC TGGAGCGGAG CTTGCCTGCC 1980

TGCCTGTGGA GACAGCCCTG CCTATCCTCT GTATATAGGC CTTCCGCCAG ATGAAGCTTT 2040

GGCCCTCAGT GGGCTCCCCT GGCCCAGCCA GCCAGGAACT GGCTCCTTTG CCTCTGCTAC 2100

TGAGCAGGGG AGTAGTGGAG AGCGGGTGGG TGGGTGTGAA GGGATGAGAA TAATTCTTTC 2160

CATGCCACGA GATCAACACA CACTCCCACC CTTGGGGTAG TAGTGTGTTG TAGTCGTACT 2220

TACCAAGCTG AGCAACCTCT TCAGCTGGGA AGGCCGCAAG AGGCATAGAG GGAGAGGAAG 2280

CACACTGCAG GGCTGCTGTG GCCCAGTCGT CCGCTCAGCC AAGGAGTCAG ATGGCAATGG 2340

GTACTCCAGC AGGTAGGGGC ACAGTGAATG TGTGTATGTA TGAAGGCCAC ATCAACTTTA 2400

TGTAGCAAAG GGCTTGGTGG CCAAGCCTGG CCCTTAAACA ACTGCAGAAA GCCCTTCAAC 2460

TTCAGAAGGC CTCACTCAAG CCTGAGAGAA GTTGGGAGGG TGGTGGGGAC AGGTAAGTGG 2520

CAGGACCCTG TCAGGATTGC AGGTGCCTGG CTTGCTGTGG CTATGGGAAT CAGCTGGTGG 2580

CTAGGTTTCT AGCGCATTTG ATTTCTCCAG GTTTGCTGTG TCTCACAGAG GCAGTAGGAA 2640

CCCAGCTCTC AGGGCTGTCT TGGTGGATGG GCCCTGCAAG ACACAGGCTC AGCATGCAGA 2700

AGTGCATGAA CAGGGTCCCT GGATCAGGGT TGTTCTGGGA GTCCTGTCAG CTTCCCCAGG 2760

AGCTCTCTGC TGAGCAGCCC AGCACAACCC CCAGGAAACA CAAATGGGGT CCAGGTCACC 2820

AGCCTGACTG CACACAGCTA GGCATGCCTG GGAATCCTGC TGCCAGAGAA CCATTCCCAA 2880

GCCATGGCAT GCTCCTTGAA GAATCTCTCC TCTCTCTCTC TCTCTGGAAA GACCCAACTT 2940

CCTCACTGCT GTCAGCCAAG TCATGGTTGG TAACCATGTA GGTTCTTGGG AGGGAATGGG 3000

ACAGGGTGAA TAAAGCAGGG AATATTTCCG GAATTCCACA AGAGATCAGC AGTGGCAGGA 3060

CCCTTAGGAA TCTAGTACAA CCTTGTTGCT TTAGGTGAGT CACACTCAGA AAATGGGGCT 3120

TGCCCTGGGT CACCTAGCTG GTTAATGGCA GCATTCAGTA ACTTCAAGTT CTCTTGATTT 3180

CTTTGTTCCC ACTGTCCCCC AAGAAACTAG TATCTCTGGC CTCCTGGGGC CCATTCTGCA 3240

TGCCCTCCCC ACTTCCCCCC CGGAATTC 3268

(2) INFORMATION FOR SEQ ID NO: 10:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 561 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 10:

Met Gly Ala Arg Thr Pro Leu Pro Ser Phe Trp Val Ser Phe Phe Ala

1 5 10 15

Glu Thr Gly He Leu Phe Pro Gly Gly Thr Pro Trp Pro Met Gly Ser 20 25 30 Gin His Ser Lys Gin His Arg Lys Pro Gly Pro Leu Lys Arg Gly His 35 40 45

Arg Arg Asp Arg Arg Thr Thr Arg Arg Lys Tyr Trp Lys Glu Gly Arg

50 55 60

Glu He Ala Arg Val Leu Asp Asp Glu Gly Arg Asn Leu Arg Gin Gin 65 70 75 80

Lys Leu Asp Arg Gin Arg Ala Leu Leu Glu Gin Lys Gin Lys Lys Lys

85 90 95

Arg Gin Glu Pro Leu Met Val Gin Ala Asn Ala Asp Gly Arg Pro Arg 100 105 110 Ser Arg Arg Ala Arg Gin Ser Glu Glu Gin Ala Pro Leu Val Glu Ser 115 120 125

Tyr Leu Ser Ser Ser Gly Ser Thr Ser Tyr Gin Val Gin Glu Ala Asp 130 135 140

Ser Leu Ala Ser Val Gin Leu Gly Ala Thr Arg Pro Thr Ala Pro Ala 145 150 155 160 Ser Ala Lys Arg Thr Lys Ala Ala Ala Thr Ala Gly Gly Gin Gly Gly

165 170 175

Ala Ala Arg Lys Glu Lys Lys Gly Lys His Lys Gly Thr Ser Gly Pro 180 185 190 Ala Ala Leu Ala Glu Asp Lys Ser Glu Ala Gin Gly Pro Val Gin He 195 200 205

Leu Thr Val Gly Gin Ser Asp His Ala Gin Asp Ala Gly Glu Thr Ala

210 215 220

Ala Gly Gly Gly Glu Arg Pro Ser Gly Gin Asp Leu Arg Ala Thr Met 225 230 235 240

Gin Arg Lys Gly He Ser Ser Ser Met Ser Phe Asp Glu Asp Glu Glu

245 250 255

Asp Glu Glu Glu Asn Ser Ser Ser Ser Ser Gin Leu Asn Ser Asn Thr 260 265 270 Arg Pro Ser Ser Ala Thr Ser Arg Lys Ser Val Arg Glu Ala Ala Ser 275 280 285

Ala Pro Ser Pro Thr Ala Pro Glu Gin Pro Val Asp Val Glu Val Gin

290 295 300

Asp Leu Glu Glu Phe Ala Leu Arg Pro Ala Pro Gin Gly He Thr He 305 310 315 320

Lys Cys Arg He Thr Arg Asp Lys Lys Gly Met Asp Arg Gly Met Tyr

325 330 335

Pro Thr Tyr Phe Leu His Leu Asp Arg Glu Asp Gly Lys Lys Val Phe 340 345 350 Leu Leu Ala Gly Arg Lys Arg Lys Lys Ser Lys Thr Ser Asn Tyr Leu 355 360 365

He Ser Val Asp Pro Thr Asp Leu Ser Arg Gly Gly Asp Ser Tyr He

370 375 380

Gly Lys Leu Arg Ser Asn Leu Met Gly Thr Lys Phe Thr Val Tyr Asp 385 390 395 400

Asn Gly Val Asn Pro Gin Lys Ala Ser Ser Ser Thr Leu Glu Ser Gly

405 410 415

Thr Leu Arg Gin Glu Leu Ala Ala Val Cys Tyr Glu Thr Asn Val Leu 420 425 430 Gly Phe Lys Gly Pro Arg Lys Met Ser Val He Val Pro Gly Met Asn 435 440 445

Met Val His Glu Arg Val Ser He Arg Pro Arg Asn Glu His Glu Thr

450 455 460

Leu Leu Ala Arg Trp Gin Asn Lys Asn Thr Glu Ser He He Glu Leu 465 470 475 480

Gin Asn Lys Thr Pro Val Trp Asn Asp Asp Thr Gin Ser Tyr Val Leu

485 490 495

Asn Phe His Gly Arg Val Thr Gin Ala Ser Val Lys Asn Phe Gin He 500 505 510 He His Gly Asn Asp Pro Asp Tyr He Val Met Gin Phe Gly Arg Val 515 520 525

Ala Glu Asp Val Phe Thr Met Asp Tyr Asn Tyr Pro Leu Cys Ala Leu

530 535 540

Gin Ala Phe Ala He Ala Leu Ser Ser Phe Asp Ser Lys Leu Ala Cys 545 550 555 560

Glu

(2) INFORMATION FOR SEQ ID NO: 11:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 5995 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: double

(D) TOPOLOGY: linear (ii) MOLECULE TYPE: Genomic DNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:11:

CGATAGAGTG GTAGGGAGAC CCTGCCGAAC AGATAATTAG AGGGTGCCAA TATGATCTGG 60

GGGGGAACCT GGGAGACAGG GAGCTCCAGA GGCACCGCCC CTCGCCTGCC CGCTTCCCTG 120

TCGCTTCCAC ACCCTGGGGC CCATCGTGCC CCACTTCCTC CAAGCCCCAA GCCTTTGCAA 180

ACAGAACAAA AGCCGTTTCC TTGGTTCCCT TTTGTACGTC TGAGTTCAGG GGTCCGTTTC 240

AGGGCCTGGA CTCCGGGAGA CTCCGGGAAA CTCCGGCGCC CGAAGACAGA GCTGCATTCC 300

TGCTGTGCCG CCACAAGATG GCACTCTCTA GGTGTCCGCC CCAGTTTGAG CACTCCGGGA 360

GTTTCTGACA CTTGCTGGCC TTTCGCCCAG TTTCAGCCTG AAGATTGTGG TCAGACACAC 420

TCTGAATCCC ACCAGGCTTG ATTAGCTTTG CCTGCCCCCT GAGGCAGCTC ATGGACTTCT 480

TCAGACTCTG TAGTTCAGGA CATATTGACC CCTTCTGAAG GGGCCCTCAG GAACTGCCTG 540

CAGTGTAATT ACCTGCCTGC TTATACTCCT CCCCACCAGG CACTCCTGAG AGCGGGACCG 600

TCTTATTCTC CTCGGGGCCA CCTGCCCCAA CCCAGGGCCT GGCACGGCAG AGATGGCAGA 660

GGTGTTTGGT GGGGTGTAAT GTGTAAACAA CAGAGTGCTG CTGTCGTCAT TCATCCCACC 720

ATAGTTTGTC TGGTGAATGC ATTTTTAGTG TCAAGCTGCC TGAAGGAGAA GCCAGGGATA 780

AAGACCCAAG CTCAGAATGT ATCCTGGGGA GAGGGATTGG TTCACAGAGA GAAGCTGTCT 840

TGCAGCCTTT CCCCCTCTGG CCTGGTTCTG GCTGTTGCCA GCATTCTAGG AGTTCTCTAG 900

ACGGGCTGAA ACGCACCGCA GGGATACAGG GAGGGCCGGA GAATAGGCGT TTGTTTCCAG 960

GTAGAATTTT GGGGCATACC CGGCCTTGTC TGGGAGCAAT CAGGGACCAG AGGCAAGGGC 1020

TGCGATGGGC TCTGGGGCCT ACTGTGGCCT CATCCCTCTC ACCTGGCCCC AGCTCAGGCC 1080

ATTCCAAGAG CCTCCCAGCC TAACAGCAAC GTGTGGCTAT CCAAGGGTCC CAGACAGAGG 1140

ATTGGAGGGC TGCACCTGTG TTTAGGGGAC AGCCACCCCT CCCCCTAAGC ACCTGCTCTG 1200

ACAGCATGGG ATGATGTCAA CAAGGGACTT CCATGAAGCC CAAGGGGGAA GGACAGTGGG 1260

AGTGGGGTCT GAGGTCTGGA CTCTGCTTGA AGATTGACAA TGATGGGTGG GAGTCCCTCA 1320

CCCACTGTAA GCTCTAGGAA GAGGGTGAGC ATTCCTGTTG ATACTGTGGC CCATTGTGTT 1380

GGCAGAGTCC AGGCCAGTTT GTGCTCTTGG TGTGACCCCA GGAGGGAGTC CTTTGCTGGA 1440

TCATCTACCT CATGGGCTGG TACTGACATG CAGGTGCGAT TTCCCTGCCT AAAACAGGCT 1500

CCAGAGTAAG ACTGGCATCG CTCACCAGGG TAATTATTGG TTTGGGTTCA ATTTCCATTC 1560

AAAACAGTAA TCCCAGCCTG AGCTGGGTGT CAGATCTGAA GGTTGATTAT TAGTAACATT 1620

TATCAACAGC CTCTCTCAGC TTCAGGCAAT TACAGCTCAT CTGCCATTCC TGCTCCCAGT 1680

CATGCAAACT TGCCAGCTTC TTCCCTGCCC ACCCCCTCCA TTCCCCTCTC CCCTTCTTCT 1740

CCCATCTCCT CCCCTTAGCA GACAACTGAC GGAGGGCAGG AGGTGGGTGC CACCTTATGA 1800

CTCACTATCA CCCTGTATGG AGGGGGTCCA TGTGCATGCT AGGCACCTGT GCTCCCCAGC 1860

AGCAATATTC ATGTTGCAGT CTTGTGAAAT CTGAATCTGA TTCTATCAGA ACTGAGGAGA 1920

ATCTGTGAAG GGGACAGATG GGAACCCATG TCTCCCGGCT CCTTGTCGCA TGATGCGTTT 1980

TCAATGGCAC TGTGCTCCTT CCTGCTCCTG ACTCAGTCTG TCCCTCCCCT CCAGGGCTGA 2040

GACTAGGGGA GGCTAGAAAG ACATTGACCT CAAGTGCAAC ATTCAAAGGA CCTCGAACAA 2100

GCTCAGTAAT TAAGATAAAT GATATTTCAA TATAGTATTT TTTTAAATCA AAATGAATGC 2160

AAAGCACCTA CAACAAAATC AAACCTTTAA TAAAGACAAG ATACAACACT GGATTTGCAG 2220

GCCTTGTATT GGCCTCACTT GCCTTACCCT AACTCCAGTC TTGTTTATCA TGGACAGTTT 2280

TGCTTTGATT TGCTGGAAGT ATTAAATTTC TTGGCTGCTG AGTTTTTTGG CAAATCTTTA 2340

AATTCTGCGC CTCAGGCGAG AGCTTTATTC AGCTTACCCT GGTGCTGGCC CCACTGCTCT 2400

CACTTCCCGC TGGGCCCTAA CCTCCTGCTC CCTTCAGCTC TTACTGCCTA CTGCCTCAGG 2460

CAGGGTGGCT CAGCTTCTCT CTTCGCAGGT GCCCAGGGCA GCAGGGGACC CAAAGGGCCC 2520

CTCCATGGGC TGTCTTCCAG GGTGCCCATC CTTCATTCCA TCCCACTGGA CCCTGCTTCA 2580

GCCGTCAGAC ACCTCAGGGA GGGCCTGCAG GTTGCCAGAG TAACTGCTGT GATAACTGG: 2640

AGGACAGAAC ATGCTGGTCT TGCTCTGCTC GTAGAATCAC GTCCAGCCAG GGCTGGATGA 2700

GTGCAAGCAG GCACGCCTGA CAGCGTCCCT GACACGCTGA TCCAAAACGT CACTGGACAT 2760

GCATGGAGGT GGAGAACATT CCATGTACCC ACATTCCTCT AGGGGGACGA CAGCATGAGG 2820

CTGGAGGAAA ACTGTGGTGA TCTGTTTGTG ACAGGGAGGT GAGACGCTGA AGTAGACATG 2880

GATGCTTCCT AACCAGCCTT CCGCAGAGGG TAGGTCTCAT TCGCTGAAGG GCTTCTGTTC 2940

TGCTGAGCAG GGTCTGTCAG TAGGGGGGCA CACCTGTCTC CAGAGAATAC CCTCCTCCTG 3000

TCCTCCCCTG GCTGTGCTCC ACTAGCCTAA AAGGTAAACA GACATTTTAG AAAGATCAGT 3060

GTTGAAGGGG TACCCAAGAT GCCAAATTAT ATCTGGGACT TGAGACACTG TTATGTCGAG 3120

GTCCAGGCCT AGGCCAGCTG GTCACAGTGT CCAGATGCCT GTCACGGTGG GAGGCCTGAG 3180

GGTCTCAGGG GACATGTATC AGAAGCACCT CTGCCCTGCC TGTTCCACTC TGTAATCTCC 3240

CTTCTGAGCC CCTACTGCAG CACAGAGCCA GCTGGTCATC TAGCCTGGCA GTAGTAAGTC 3300

ATTCTATTTT CCTGCAGATA GGAATACATG GTTCCTGTTC CTCCTATGCA CTCTGCCACT 3360 TAAATTCCCC TCTCTGAGTC CTAGGTTCCC CTTTTGTGAA ATATCAATGA TAGCATCCTT 3420

CTTAGAAGGC TGTGCTCACC ATTCAGTGCA CTAATGCAAA GCACTGTGAC CGACTGAAGA 3480

GTCATGTTCT GTGGGGCCAT GGAGGACAGA ACTAGGACTG AAGGGAGGTG TGTTTGAGCT 3540

TTAGGTGAAG CAGCAATGGC CAACTACAAA GATGGAGGGA CCGCTCTGGG AAGAGCAAAC 3600 ACCCTGATGC TCAGAGTGTG CATGAGGAGG TTTCATAATC ACCATCCAGC AGCTTAGCCT 3660

CAAAAGGGCT GCCTGCCCCA GGGAGCTATG ACCCTTGAGA GATGCAGTTT ATCCAGCCCT 3720

GAGGTTCTGT TTGACCATCT TTCCCCGGTT GTCCTCCAGG GGGTCATGGC ACAAGTCTCA 3780

GTAGCACGGG CCCCATGGTC CAGCCTTAAG GTAAGAATGG ACCTCCCTGG AGGAAGCTGG 3840

CTTCATCTAC AGTTGATAAG TTCACCTTTT TTCCTGGTCC ACTTTCCTTG GTTTAACCCT 3900 GTGACCAAAC CTGAGAGCTT TGGCAGGAAG GAAACCAGGG AGGATGTTGT GCTTGAGAAA 3960

GTGCTGGCCT GAGCATTGGC TTTGAGATGT CCTTTTACTC TGACTGGAGG GTCTCATTCC 4020

ACCTGTAGCA AGACTAAAGA CACCTGAAAG AGAGTTTCTG GGAGATGGAG GATGAGGTCT 4080

CCAGTTGCAG GTGCATCACA CGTCCACTTC CCCACCTGGC AGGTGCCGGC ATGCAGGATG 4140

TCTGTGCGTG TGCCCCTTGC ACTGACTCCC TTGAGGCTGG CTGTGCAGCT TTGGGGCATG 4200 TGTCCAAGCA GAGAGAATGG AAGACTCCAT ATTGGGAGCC TTGGCTTTGA CCTTTCCTTT 4260

CTCTGAGCCT GATTTTCCCA ACAGTGTTAT GGGAGGGGAA GGATGAGATG CGCTTCTCAG 4320

CTGATGTCCG TGATTCTTCT GTTTTCTGGA GGCCATGAGT GTTAACAGAA TGTGTTCACT 4380

TTTGCACCCT TCTTCCATGA CCACTTACAG TCTGTCTGCT TAGCAGATGA GGGGTCTGGG 4440

TCTCCAGCGT CCATTTGGGG TGGGGTCAGC AATGTCCAGC TTTGCATCTG GGTATCACTT 4500 TTCCTTCTGA TACTTGAAAT TGGATTCTGA AGATTCCTAA TTATTGTTCC AAGTTCTCAT 4560

TGAAAATCTG GGTGTAATTT TTACAAGAGC ATGGCTGAGG ATGGACATGG AGGGGAAGTA 4620

GTGGGGCTGG AGGGAGGGAA GGGACAGACA GAAGGTGATG TTGTCATTAG GAGTTAAAGC 4680

CAGGGCCTGG TAGTAGATAA GGCTGGACAG TTGGCAGGAT CATCGGGCGG ACTAAAGTAG 4740

CTTAGATTCT GTCCAGAGGA AGTGGGGGTC TTCTGAAGGG TTTAAGTAGG CTGGGAGGAC 4800 ATGATCTTAG GAAGCTCACT CTGGTGTCAG TTGCAGGATG GATTTGAGAG GAGCAAGTTA 4860

GGTGTAGATG CCCATGATGA TGCCAAGATC TGGGCAACAG ACAGGAAGGC CCTAGCTCAG 4920

AAGTGGCTCT AGGGAAGGTG AGGTGCATAG AATTGAGAGA TGCTCAGTAG ATGGCATGAG 4980

CAGTGCTTGA TGATTGTCTG GGTTGGTGGA GGAAGGTGGA CAGGGAAAAG CAGAAAGCTA 5040

CGATGGTGCC TCAAGGGGCT GAGTGATGTC ACTCACAGAG ACAGAATGTA TAGAGTGAAT 5100 GTTCAGACTC ACAGGAAGTC CAAAACTACA TACCCCAACG TGAGGTGCTG TGGGACATCC 5160

GGGGTGCAGG GTCCAGAGAG CAGGTAGGTA GAGTTTAGAA GAGGGCTGGG TCCACAATGC 5220

AGCCTTGGAT GTTCTCAATG TAAGAGTTGT GGGAGATGAA GCCTTGTGAG TGGATGGGAA 5280

CACCCAGGTG CATTTCAGGT GAAGCAAGGG GACAAGAGGC TGAGGACACA GACAAGCAAA 5340

TCCTAGATCT TCCATCAGTC CCTAGAAGGC ACGATGTGTG CCCCTCCCAG CACACAGCCT 5400 GAGCCCTAGC ACAGAGCTGG CCGCAGAGAG GGCAGCAGTG AATGTGTCCT CGGTGGTTCC 5460

TCCAGATGGG GCCTTTGTCC GCAGTGCACT TGTCTCTGCC TGGGTTGCTA TAGTAACCCA 5520

CAGATGCAGA GAGACTTGGC CTCCGTGTTG CCATGGAAAC CAGCAATTGG GTGTCCCTGT 5580

GTGGCATGGC CACTGAGACC TTGAGGATTC AGTCTGGTCC TGAAGGGTTT GGGGGGAGAC 5640

TGCGACCAGA AGATGTTTCC ATGTCCTAAT TAATGGGTGA TGGTGGTTGT TAGTCTGACT 5700 GTTGCCACGG TGATGAAGGG AGACATCCAA GTGCTGGTTT CAGTACTGAG GCGAATACAG 5760

GGAATTTCAA CAGGCTCCAG GTCTTACTAT GCAGCCTGAA GTGGGACCAT CCCTTAAACC 5820

CACTCCATCC TGTGGCCACG ATGGGGGCCA GGACACCTTT GCCTTCTTTC TGGGTTTCTT 5880

TCTTTGCCGA GACAGGGATT TTGTTCCCAG GAGGCACTCC CTGGCCCATG GGATCTCAGC 5940

ATTCAAAGCA GCACAGGAAA CCTGGGCCCC TGAAACGGGG CCACCGAAGA GATCG 5995 (2) INFORMATION FOR SEQ ID NO: 12:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 2115 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: double (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 12:

AGAATTCAGC GGCCGCTGAA TTCTAGCAAA GGCACCATGC CTCTGCGGGA TGAAACCCTC 60

CGAGAGGTGT GGGCCTCTGA CAGTGGGCAT GAAGAAGAAA GCCTGAGCCC GGAGGCCCCG 120 CGGCGCCCCA AACAGCGACC CGCCCCGGCA CAGAGGCTAA GGAAGAAGAG GACGGAGGCC 180 CCCGAATCCC CCTGCCCCAC GGGATCCAAG CCCCGGAAGC CCGGAGCTGG GCGGAGGGGG 240

AGGCCGCGGG AGGAGCCTTC CCCAGACCCA GCCCAGGCCC GGGCGCCGCA GACGGTCTAC 300

GCCAGGTTCC TCAGGGACCC CGAGGCCAAG AAGCGCGACC CCCGGGAAAC CTTTCTGGTA 360

GCCCGTGCCC CAGACGCGGA GGACGAGGAG GAGGAGGAAG AGGAGGACGA GGAGGACGAG 420 GAAGAGGAGG CAGAGGAAAA GAAAGAGAAA ATCCTTCTGC CTCCCAAGAA GCCCCTGAGA 480

GAGAAGAGCT CCGCAGACCT GAAGGAGAGG AGGGCCAAGG CCCAGGGCCC AAGGGGAGAC 540

CTGGGAAGCC CTGACCCCCC ACCGAAACCT CTGCGTGTTA GGAATAAGGA AGCTCCAGCA 600

GGGGAGGGGA CCAAGATGAG AAAGACCAAG AAGAAAGGGT CTGGGGAGGC CGACAAGGAC 660

CCCTCAGGGA GCCCAGCCAG TGCGAGGAAG AGCCCAGCAG CCATGTTTCT GGTTGGGGAA 720 GRCAGTCCTG ACAAGAAAGC CCTGAAGAAG AAAGGCACTC CCAAAGGCGC GAGGAAGGAG 780

GAAGAAGAGG AGGAGGAGGC AGCTACGGTG ATAAAGAACA GCAATCAAAA GGGCAAAGCC 840

AAAGGAAAAG GCAAAAAGAA AGCGAAGGAG GAGAGGGCCC CGTCTCCCCC CGTGGAGGTG 900

GACGAACCCC GGGAGTTTGT GCTCCGGCCT GCCCCCCAGG GCCGCACGGT GCGCTGCCGG 960

CTGACCCGGG ACAAAAAGGG CATGGATCGA GGCATGTATC CCTCCTACTT CCTGCACCTG 1020 GACACGGAGA AGAAGGTGTT CCTCTTGGCT GGCAGGAAAC GAAAACGGAG CAAGACAGCC 1080

AATTACCTCA TCTCCATCGA CCCTACCAAT CTGTCCCGAG GAGGGGAGAA TTTCATCGGG 1140

AAGCTGAGGT CCAACCTCCT GGGGAACCGC TTCACGGTCT TTGACAACGG GCAGAACCCA 1200

CAGCGTGGGT ACAGCACTAA TGTGGCAAGC CTTCGGCAGG AGCTGGCAGC TGTGATCTAT 1260

GAAACCAACG TGCTGGGCTT CCGTGGCCCC CGGCGCATGA CCGTCATCAT TCCTGGCATG 1320 AGTGCGGAGA ACGAGAGGGT CCCCATCCGG CCCCGAAATG CTAGTGACGG CCTGCTGGTG 1380

CGCTGGCAGA ACAAGACGCT GGAGAGCCTC ATAGAACTGC ACAACAAGCC ACCTGTCTGG 1440

AACGATGACA GTGGCTCCTA CACCCTCAAC TTCCAAGGCC GGGTCACCCA GGCCTCAGTC 1500

AAGAACTTCC AGATTGTCCA CGCTGATGAC CCCGACTATA TCGTGCTGCA GTTCGGCCGC 1560

GTGGCGGAGG ACGCCTTCAC CCTAGACTAC CGGTACCCGC TGTGCGCCCT GCAGGCCTTC 1620 GCCATCGCCC TCTCCAGTTT CGACGGGAAG CTGGCTTGCG AGTGACCCCA GCAGCCCCTC 1680

AGCGCCCCCA GAGCCCGTCA GCGTGGGGGA AAGGATTCAG TGGAGGCTGG CAGGGTCCCT 1740

CCAGCAAAGC TCCCGCGGAA AACTGCTCCT GTGTCGGGGC TGACCTCTCA CTGCCTCTCG 1800

GTGACCTCCG TCCTCTCCCC AGCCTGGCAC AGGCCGAGGC AGGAGGAGCC CGGACGGCGG 1860

GTAGGACGGA GATGAAGAAC ATCTGGAGTT GGAGCCGCAC ATCTGGTTTC GGAGTTCGCC 1920 TGCGCCGCTG TGCCCCCCTC CTCCCCGCGC CCCAGTCAAT TCCTGTCCGG GAGCAGTAGT 1980

CATTGTTGTT TTAACCTCCC CTCTCCCCGG GACCGCGCTA GGGCTCCGAG GAGCTGGGGC 2040

GGGCTAGGGG AGGGGGTAGG TGATGGGGGA CGAGGGCCAG GCACCCACAT CCCCAATAAA 2100

GCCGCGTCCT TGGCA 2115

(2) INFORMATION FOR SEQ ID NO: 13': (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 542 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:13:

Met Pro Leu Arg Asp Glu Thr Leu Arg Glu Val Trp Ala Ser Asp Ser

1 5 10 15

Gly His Glu Glu Glu Ser Leu Ser Pro Glu Ala Pro Arg Arg Pro Lys 20 25 30

Gin Arg Pro Ala Pro Ala Gin Arg Leu Arg Lys Lys Arg Thr Glu Ala

35 40 45

Pro Glu Ser Pro Cys Pro Thr Gly Ser Lys Pro Arg Lys Pro Gly Ala 50 55 60 Gly Arg Arg Gly Arg Pro Arg Glu Glu Pro Ser Pro Asp Pro Ala Gin 65 70 75 80

Ala Arg Ala Pro Gin Thr Val Tyr Ala Arg Phe Leu Arg Asp Pro Glu

85 90 95

Ala Lys Lys Arg Asp Pro Arg Glu Thr Phe Leu Val Ala Arg Ala Pro 100 105 110 Asp Ala Glu Asp Glu Glu Glu Glu Glu Glu Glu Asp Glu Glu Asp Glu

115 120 125

Glu Glu Glu Ala Glu Glu Lys Lys Glu Lys He Leu Leu Pro Pro Lys

130 135 140 Lys Pro Leu Arg Glu Lys Ser Ser Ala Asp Leu Lys Glu Arg Arg Ala

145 150 155 160

Lys Ala Gin Gly Pro Arg Gly Asp Leu Gly Ser Pro Asp Pro Pro Pro

165 170 175

Lys Pro Leu Arg Val Arg Asn Lys Glu Ala Pro Ala Gly Glu Gly Thr 180 185 190

Lys Met Arg Lys Thr Lys Lys Lys Gly Ser Gly Glu Ala Asp Lys Asp

195 200 205

Pro Ser Gly Ser Pro Ala Ser Ala Arg Lys Ser Pro Ala Ala Met Phe

210 215 220 Leu Val Gly Glu Xaa Ser Pro Asp Lys Lys Ala Leu Lys Lys Lys Gly

225 230 235 240

Thr Pro Lys Gly Ala Arg Lys Glu Glu Glu Glu Glu Glu Glu Ala Ala

245 250 255

Thr Val He Lys Asn Ser Asn Gin Lys Gly Lys Ala Lys Gly Lys Gly 260 265 270

Lys Lys Lys Ala Lys Glu Glu Arg Ala Pro Ser Pro Pro Val Glu Val

275 280 285

Asp Glu Pro Arg Glu Phe Val Leu Arg Pro Ala Pro Gin Gly Arg Thr

290 295 300 Val Arg Cys Arg Leu Thr Arg Asp Lys Lys Gly Met Asp Arg Gly Met

305 310 315 320

Tyr Pro Ser Tyr Phe Leu His Leu Asp Thr Glu Lys Lys Val Phe Leu

325 330 335

Leu Ala Gly Arg Lys Arg Lys Arg Ser Lys Thr Ala Asn Tyr Leu He 340 345 350

Ser He Asp Pro Thr Asn Leu Ser Arg Gly Gly Glu Asn Phe He Gly

355 360 365

Lys Leu Arg Ser Asn Leu Leu Gly Asn Arg Phe Thr Val Phe Asp Asn

370 375 380 Gly Gin Asn Pro Gin Arg Gly Tyr Ser Thr Asn Val Ala Ser Leu Arg

385 390 395 400

Gin Glu Leu Ala Ala Val He Tyr Glu Thr Asn Val Leu Gly Phe Arg

405 410 415

Gly Pro Arg Arg Met Thr Val He He Pro Gly Met Ser Ala Glu Asn 420 425 430

Glu Arg Val Pro He Arg Pro Arg Asn Ala Ser Asp Gly Leu Leu Val

435 440 445

Arg Trp Gin Asn Lys Thr Leu Glu Ser Leu He Glu Leu His Asn Lys

450 455 460 Pro Pro Val Trp Asn Asp Asp Ser Gly Ser Tyr Thr Leu Asn Phe Gin

465 470 475 480

Gly Arg Val Thr Gin Ala Ser Val Lys Asn Phe Gin He Val His Ala

485 490 495

Asp Asp Pro Asp Tyr He Val Leu Gin Phe Gly Arg Val Ala Glu Asp 500 505 510

Ala Phe Thr Leu Asp Tyr Arg Tyr Pro Leu Cys Ala Leu Gin Ala Phe

515 520 525

Ala He Ala Leu Ser Ser Phe Asp Gly Lys Leu Ala Cys Glu 530 535 540 (2) INFORMATION FOR SEQ ID NO: 14:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1734 base pairs

(B) TYPE: nucleic acid (C) STRANDEDNESS: double

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 14:

GGAATCCTCC CTCCCTCTGA GCCGTCTTTC TTCTCCTCCC TATTTCGCAG ATATCCCGAG 60

ATTAGGTCCC CAGCTTCCAA AGAGAGGATC AGAATGTCTC AGGATAATGA CACATTGATG 120

AGAGACATCC TGGGGCATGA GCTCGCTGCT ATGAGGCTGC AGAAGCTJGGA ACAGCAGCGG 180

CGGCTGTTTG AAAAGAAGCA GCGACAGAAG CGCCAGGAGC TCCTCATGGT TCAGGCCAAT 240

CCTGACGCTT CCCCGTGGCT TTGGCGCTCT TGTCTGCGGG AGGAGCGCCT TTTAGGTGAC 300

AGAGGCCTTG GGAACCCTTT CCTCCGGAAG AAAGTGTCAG AGGCACATCT GCCCTCTGGC 360

ATCCACAGTG CCCTGGGCAC CGTGAGCTGT GGTGGAGACG GCAGGGGCGA GCGCGGCCTC 420

CCGACACCGC GGACAGAAGC AGTGTTCAGG AATCTCGGTC TCCAGTCCCC TTTCTTATCC 480

TGGCTCCCAG ACAATTCCGA TGCAGAATTG GAGGAAGTCT CCGTGGAGAA TGGTTCCGTC 540

TCTCCCCCAC CTTTTAAACA GTCTCCGAGA ATCCGACGCA AGGGTTGGCA AGCCCACCAA 600

CGACCTGGGA CCCGTGCAGA GGGTGAGAGT GACTCCCAGG ATATGGGAGA TGCACACAAG 660

TCACCCAATA TGGGACCAAA CCCTGGAATG GATGGTGACT GTGTATATGA AAACTTGGCC 720

TTCCAAAAGG AAGAAGACTT GGAAAAGAAG AGAGAGGCCT CTGAGTCTAC AGGGACGAAC 780

TCCTCAGCAG CACACAACGA AGAGTTGTCC AAGGCCCTGA AAGGCGAGGG TGGCACGGAC 840

AGCGACCATA TGAGGCACGA AGCCTCCTTG GCAATCCGCT CCCCCTGCCC TGGGCTGGAG 900

GAGGACATGG AAGCCTACGT GCTGCGGCCA GCGCTCCCGG GCACCATGAT GCAGTGCTAC 960

CTCACCCGTG ACAAGCACGG CGTGGACAAG GtGCTTGTTC CCCCTCTACT ACCTCTACCT 1020

GGAGACCTCT GACAGCCTGC AGCGCTTCCT CCTGGCTGGG CGAAAGAGAA GAAGGAGCAA 1080

AACTTCTAAT TACCTCATCT CCCTGGATCC TACACTCCTA TCTCGGGACG GGGACAATTT 1140

CGTGGGCAAA GTCAGATCCA ATGTCTTCAG CACCAAGTTC ACCATCTTTG ACAATGGGGT 1200

GAATCCTGAC CGGGAGCATT TAACCAGGAA TACTGCCCGG ATCAGACAGG AGCTGGGGGC 1260

TGTGTGTTAT GAGCCCAACG TCTTAGGATA CCTGGGGCCT CGGAAAATGA CTGTGATTCT 1320

CCCAGGAACC AACAGCCAGA ACCAGCGAAT CAATGTCCAG CCACTAAATG AACAGGAGTC 1380

GCTACTGAGT CGTTACCAAC GTGGGGACAA ACAAGGGTTG CTTTTGTTGC ACAACAAAAC 1440

CCCGTCGTGG GACAAGGAGA ACGGTGTCTA CACGCTCAAT TTCCATGGTC GAGTCACTCG 1500

GGCTTCGGTG AAGAACTTCC AAATCGTGGA TCCCAAACAC CAAGAACATC TGGTGCTCCA 1560

GTTCGGCCGA GTGGGCCCAG ACACATTCAC CATGGACTTC TGCTTTCCAT TTAGCCCGCT 1620

CCAGGCCTTC AGCATCTGCT TGTCCAGTTT CAATTAGAAG CTGGCTGTTG AATAACTCAA 1680

TAAAATACCA TACCCTTGCC AGCAAAAAAA AAAAAAAAAA AAAAAAAAAA AAAA 1734

(2) INFORMATION FOR SEQ ID NO: 15: (l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 520 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 15:

Met Ser Gin Asp Asn Asp Thr Leu Met Arg Asp He Leu Gly His Glu

1 5 10 15

Leu Ala Ala Met Arg Leu Gin Lys Leu Glu Gin Gin Arg Arg Leu Phe 20 25 30

Glu Lys Lys Gin Arg Gin Lys Arg Gin Glu Leu Leu Met Val Gin Ala

35 40 45

Asn Pro Asp Ala Ser Pro Trp Leu Trp Arg Ser Cys Leu Arg Glu Glu 50 55 60 Arg Leu Leu Gly Asp Arg Gly Leu Gly Asn Pro Phe Leu Arg Lys Lys 65 70 75 80

Val Ser Glu Ala His Leu Pro Ser Gly He His Ser Ala Leu Gly Thr 85 90 95

Val Ser Cys Gly Gly Asp Gly Arg Gly Glu Arg Gly Leu Pro Thr Pro

100 105 110

Arg Thr Glu Ala Val Phe Arg Asn Leu Gly Leu Gin Ser Pro Phe Leu 115 120 125

Ser Trp Leu Pro Asp Asn Ser Asp Ala Glu Leu Glu Glu Val Ser Val

130 135 140

Glu Asn Gly Ser Val Ser Pro Pro Pro Phe Lys Gin Ser Pro Arg He 145 150 155 160 Arg Arg Lys Gly Trp Gin Ala His Gin Arg Pro Gly Thr Arg Ala Glu

165 170 175

Gly Glu Ser Asp Ser Gin Asp Met Gly Asp Ala His Lys Ser Pro Asn

180 185 190

Met Gly Pro Asn Pro Gly Met Asp Gly Asp Cys Val Tyr Glu Asn Leu 195 200 205

Ala Phe Gin Lys Glu Glu Asp Leu Glu Lys Lys Arg Glu Ala Ser Glu

210 215 220

Ser Thr Gly Thr Asn Ser Ser Ala Ala His Asn Glu Glu Leu Ser Lys 225 230 235 240 Ala Leu Lys Gly Glu Gly Gly Thr Asp Ser Asp His Met Arg His Glu

245 250 255

Ala Ser Leu Ala He Arg Ser Pro Cys Pro Gly Leu Glu Glu Asp Met

260 265 270

Glu Ala Tyr Val Leu Arg Pro Ala Leu Pro Gly Thr Met Met Gin Cys 275 280 285

Tyr Leu Thr Arg Asp Lys His Gly Val Asp Lys Gly Leu Phe Pro Leu

290 295 300

Tyr Tyr Leu Tyr Leu Glu Thr Ser Asp Ser Leu Gin Arg Phe Leu Leu 305 310 315 320 Ala Gly Arg Lys Arg Arg Arg Ser Lys Thr Ser Asn Tyr Leu He Ser

325 330 335

Leu Asp Pro Thr Leu Leu Ser Arg Asp Gly Asp Asn Phe Val Gly Lys

340 345 350

Val Arg Ser Asn Val Phe Ser Thr Lys Phe Thr He Phe Asp Asn Gly 355 360 365

Val Asn Pro Asp Arg Glu His Leu Thr Arg Asn Thr Ala Arg He Arg

370 375 380

Gin Glu Leu Gly Ala Val Cys Tyr Glu Pro Asn Val Leu Gly Tyr Leu 385 390 395 400 Gly Pro Arg Lys Met Thr Val He Leu Pro Gly Thr Asn Ser Gin Asn

405 410 415

Gin Arg He Asn Val Gin Pro Leu Asn Glu Gin Glu Ser Leu Leu Ser

420 425 430

Arg Tyr Gin Arg Gly Asp Lys Gin Gly Leu Leu Leu Leu His Asn Lys 435 440 445

Thr Pro Ser Trp Asp Lys Glu Asn Gly Val Tyr Thr Leu Asn Phe His

450 455 460

Gly Arg Val Thr Arg Ala Ser Val Lys Asn Phe Gin He Val Asp Pro 465 470 475 480 Lys His Gin Glu His Leu Val Leu Gin Phe Gly Arg Val Gly Pro Asp

485 490 495

Thr Phe Thr Met Asp Phe Cys Phe Pro Phe Ser Pro Leu Gin Ala Phe

500 505 510

Ser He Cys Leu Ser Ser Phe Asn 515 520

(2) INFORMATION FOR SEQ ID NO: 16:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1482 base pairs (B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 16:

CGGAGAAGAG TGTGTAACGT GGTGGGGGCT TCNTCGGTGG CGGGCATGGA GGCTTCGCGC 60

TGCCGGCTCA GTCCCAGCGG CGACAGTGTC TTCCATGAAG AAATGATGAA GATGCGACAG 120

GCTAAGCTGG ATTATCAGAG GCTACTACTT GAGAAGAGGC AAAGGAAAAA GCGCCTTGAG 180

CCATTTATGG TGCAGCCCAA TCCAGAAGCC AGGCTACGTC GGGCAAAGCC AAGGGCCAGT 240

GATGAGCAGA CTCCCTTGGT GAACTGTCAT ACTCCCCACA GCAATGTCAT CTTACATGGT 300

ATTGATGGTC CAGCTGCTGT CCTGAAACCA GACGAAGTTC ATGCTCCATC AGTAAGCTCC 360

TCTGTTGTGG AAGAAGATGC TGAAAACACC GTGGATACTG CTTCCAAGCC AGGACTTCAG 420

GAGCGTCTCC AAAAGCATGA TATCTCTGAA AGTGTGAACT TCGATGAGGA GACTGATGGA 480

ATATCCCAGT CAGCATGTTT AGAAAGACCC AATTCTGCAT CAAGCCAGAA TTCAACCGAT 540

ACAGGCATTC CGGTTCTGCT ACTGCCGCCC AACCAGCTGA TAACCTTCCT GGGAGACATA 600

GACGACCTGG AGGACTTTGT GTTAGTCCCT GCCCCTCAAG GTGTCACAGT AAGATGTCGG 660

ATAATCCGGG ATAAAAGGGG AATGGATCGG GGTCTTTTTT CCCACCTACT ATATGTACTT 720

GGAAAAGAAG AAAA CAGAA GATATTTCTT CTTGCAGCTA GAAAGCGGAA AAAGAGCAAA 780

ACAGCCAACT ACCTTATCTC CATTGATCCA GTTGATTTAT CTCGTGAAGG AGAAAGTTAT 840

GTCGGCAAGC TTAGATCCAA CCTCATGGGG ACCAAGTTTA CAGTTTATGA CCGTGGCATC 900

TGCCCCATGA AGGGCCGGGG TTTGGTAGGA GCGGCCCACA CCCGGCAGGA GCTGGCTGCC 960

ATCTCCTATG AAACAAACGT ACTTGGATTT AAAGGTCCTA GGAAAATGTC TGTGATCATT 1020

CCTGGAATGA CACTGAATCA TAAGCAGATC CCCTATCAGC CACAAAACAA CCATGACAGT 1080

TTGCTCTCAA GGTGGCAGAA CAGAACTATG GAAAATCTGG TTGAGCTGCA CAACAAGGCC 1140

CCCGTCTGGA ACAGTGACAC TCAGTCCTAT GTCCTCAACT TCCGTGGCCG GGTCACTCAG 1200

GCGTCTGTGA AGAACTTCCA GCTAGTCCAC AAAAATGACC CTGATTATAT AGTCATGCAG 1260

TTTGGACGTG TGGCAGATGA CGTGTTCACA CTGGATTACA ACTACCCACT TTGTGCAGTA 1320

CAAGCCTTTG CCATCTCCCT TTCTAGCTTT GACAGTAAGC TGGCGTGTGA ATGAGAGAAC 1380

AGTCAGGCAG GGAGCCCTTC TCCCCACAGA GCTTTCAGGA GCAGACNTNG GCCGNCCGAC 1440

CTGCCAGGGC GGNCGCCAAA ACCCTATAGT GAGATTAATC CC 1482

(2) INFORMATION FOR SEQ ID NO: 17:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 442 amino acids

(B) TYPE: amino acid (C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: protein

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 17:

Met Glu Ala Ser Arg Cys Arg Leu Ser Pro Ser Gly Asp Ser Val Phe 1 5 10 ^• 15

His Glu Glu Met Met Lys Met Arg Gin Ala Lys Leu Asp Tyr Gin Arg

20 25 30

Leu Leu Leu Glu Lys Arg Gin Arg Lys Lys Arg Leu Glu Pro Phe Met 35 40 45 Val Gin Pro Asn Pro Glu Ala Arg Leu Arg Arg Ala Lys Pro Arg Ala 50 55 60

Ser Asp Glu Gin Thr Pro Leu Val Asn Cys His Thr Pro His Ser Asn 65 70 75 80

Val He Leu His Gly He Asp Gly Pro Ala Ala Val Leu Lys Pro Asp 85 90 95

Glu Val His Ala Pro Ser Val Ser Ser Ser Val Val Glu Glu Asp Ala 100 105 110 Glu Asn Thr Val Asp Thr Ala Ser Lys Pro Gly Leu Gin Glu Arg Leu

115 120 125

Gin Lys His Asp He Ser Glu Ser Val Asn Phe Asp Glu Glu Thr Asp

130 135 140 Gly He Ser Gin Ser Ala Cys Leu Glu Arg Pro Asn Ser Ala Ser Ser

145 150 155 160

Gin Asn Ser Thr Asp Thr Gly He Pro Val Leu Leu Leu Pro Pro Asn

165 170 175

Gin Leu He Thr Phe Leu Gly Asp He Asp Asp Leu Glu Asp Phe Val 180 185 190

Leu Val Pro Ala Pro Gin Gly Val Thr Val Arg Cys Arg He He Arg

195 200 205

Asp Lys Arg Gly Met Asp Arg Gly Leu Phe Ser His Leu Leu Tyr Val

210 215 220 Leu Gly Lys Glu Glu Asn Gin Lys He Phe Leu Leu Ala Ala Arg Lys

225 230 235 240

Arg Lys Lys Ser Lys Thr Ala Asn Tyr Leu He Ser He Asp Pro Val

245 250 255

Asp Leu Ser Arg Glu Gly Glu Ser Tyr Val Gly Lys Leu Arg Ser Asn 260 265 270

Leu Met Gly Thr Lys Phe Thr Val Tyr Asp Arg Gly He Cys Pro Met

275 280 285

Lys Gly Arg Gly Leu Val Gly Ala Ala His Thr Arg Gin Glu Leu Ala

290 295 300 Ala He Ser Tyr Glu Thr Asn Val Leu Gly Phe Lys Gly Pro Arg Lys

305 310 315 320

Met Ser Val He He Pro Gly Met Thr Leu Asn His Lys Gin He Pro

325 330 335

Tyr Gin Pro Gin Asn Asn His Asp Ser Leu Leu Ser Arg Trp Gin Asn 340 345 350

Arg Thr Met Glu Asn Leu Val Glu Leu His Asn Lys Ala Pro Val Trp

355 360 365

Asn Ser Asp Thr Gin Ser Tyr Val Leu Asn Phe Arg Gly Arg Val Thr

370 375 380 Gin Ala Ser Val Lys Asn Phe Gin Leu Val His Lys Asn Asp Pro Asp

385 390 395 400

Tyr He Val Met Gin Phe Gly Arg Val Ala Asp Asp Val Phe Thr Leu

405 410 415

Asp Tyr Asn Tyr Pro Leu Cys Ala Val Gin Ala Phe Ala He Ser Leu 420 425 430

Ser Ser Phe Asp Ser Lys Leu Ala Cys Glu 435 440

(2) INFORMATION FOR SEQ ID NO: 18:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1743 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: double

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:18:

GGCACGAGGG ACCGTGAGGG CCAAGAGGGC CAAGAAGTGG AGCGTCTCAG GAGAATGAAC 60

AGTGGAAGAA AGAGACCCTG GAGGATGAAT TCTCTGGCGT GAGGCTGCAG AAGCTAGAAC 120

AACAGCGACA GCTATTTGAG AAGAAGCAGC GCAGGAAACG CCAGGAGCCC CTCATGGTTC 180

AGGCCAATCC TGATGCTACC CTGAGGCACC GGCGACCAAG GCGCGGGGAG GAGCGCTTCC 240 AGAGTGACAG CAGCTGGGGC CTTGGTGTTG GGAGCCCTTT CCTCCAGGAG AACGTTCCGC 300 AGGCACATCT GCCCTCAGGG GCGCACAGTG CCCTTGTCAC CATGAGCTAT GTCGCAGATG 360

GGAGTGGTGA GCGGGCCCCC CTACTGTCAC CCCGAGGAGC AGTATACACT CGGGGCAACG 420

GCCCTGCGGT CCGTCATCAT CTTTGCTGGC TTCCAGACAG CTCCGATTCA GACGTGGAGG 480

AAGTGACCAT GGAAGACATC CCCGTCATCT CCCGACCTCC CCAGACGAAT CTGGCAAACC 540 TACGCAGGGG CTGGTTAGCC TCCCCAGGAC CCGGGATCAG TCAAGAAGAA AAAGAAGAAG 600

AGGTTGGATC CACGGATGCC AGAGTTGAAG ACAAGACACC CAGCCCAGAC CCAGACCCAG 660

ACCCTACCGT GAACTCTGAC GGAGATCATG GAGACCTGGC ACCCTGCAAG GTGGAAGAAA 720

ACACAGCCCA GAAGAATACA GAAACAGCCT CTGGCATCGG GGATGAAGAC CGGGAGAAGG 780

GAGAGGTCAC AGAGTCTACA GAGACAAACT ATGCCCCAGT GGCATCCAAG GTTTTGCAAG 840 GCGACGATGG TGACGCCAGC AACCACAATG CCTGGAACAT GACCTGCCCC CAGCCTCGCA 900

TTCCCGGCCC TCGGCTCGGG GAGGACATGG AAGCATACGT GTTGCTCCCT GCACCCCGAG 960

ACCACATGGT GCAGTGGCGC ATCGTCCGAA ACAAGCACGG GATGGACAAG GGGATGTTCC 1020

CTTCCTACTA CCTCTACCTG GAGGGCGAGG ATGGTGTAGC ACATTTCCTT CTGGCTGGGC 1080

GGAAAAGGAA AAGAAGCAAA ACTTCAAATT ATCTCATCTC CCTGGACCCC AAAGACATGT 1140 CTCGCAATGG GAGCAACTTT GTAGGCAAAG TTAGATCCAA TGTCTTGGGC ACGAAATTCA 1200

CCATCTTCGA TAATGGGGTG AACCCTGAGC GGAGTTACTG GGTTCCAGAC AGTGCCCGGA 1260

TCAGAGAGGA GCTGGGAGTC GTCTGTTATG AGACCAATGT CTTGGGATTC AGGGGGCCTC 1320

GGAAAATGAC TGTGATCCTT CCAGGAATGG ACAGCCGGAA GCAGAGGATG AAAGTCCAGC 1380

CACAAAATGA TCAGGATTCC ATATTGAGTC GCGTACAGAA GGGCGCTGGA CACGGGCTGC 1440 TTCTACTGCA GAACAAGGCC CCATCGTGGA GCGACGAAAG CGGCGCATAC GTACTCAATT 1500

TTCACGGTCG CGTCACGCGG GCTTCAGTCA AGAACTTCCA GATAGTGCAC CCGGATGAAC 1560

CCGACCACCT GGTGCTCCAG TTTGGCCGTG TGGCCCCAAA CATATTCACG ATGGATTTCC 1620

GATATCCTCT TTGCCCGCTC CAAGCCTTCG CCATCTGCTT ATCCAGTTTC GATGGGAAAC 1680

TGGCGTGTGA GTAACTGAAT AAAATACCAT CCCTCACCAA CTCTGAAAAA AAAAAAAAAA 1740 AAA 1743

(2) INFORMATION FOR SEQ ID NO: 19:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 506 amino acids

(B) TYPE: amino acid (C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: protein

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 19:

Met Val Gin Ala Asn Pro Asp Ala Thr Leu Arg His Arg Arg Pro Arg 1 5 10 15

Arg Gly Glu Glu Arg Phe Gin Ser Asp Ser Ser Trp Gly Leu Gly Val

20 25 30

Gly Ser Pro Phe Leu Gin Glu Asn Val Pro Gin Ala His Leu Pro Ser 35 40 45 Gly Ala His Ser Ala Leu Val Thr Met Ser Tyr Val Ala Asp Gly Ser 50 55 60

Gly Glu Arg Ala Pro Leu Leu Ser Pro Arg Gly Ala Val Tyr Thr Arg 65 70 75 80

Gly Asn Gly Pro Ala Val Arg His His Leu Cys Trp Leu Pro Asp Ser 85 90 95

Ser Asp Ser Asp Val Glu Glu Val Thr Met Glu Asp He Pro Val He

100 105 110

Ser Arg Pro Pro Gin Thr Asn Leu Ala Asn Leu Arg Arg Gly Trp Leu 115 120 125 Ala Ser Pro Gly Pro Gly He Ser Gin Glu Glu Lys Glu Glu Glu Val 130 135 140

Gly Ser Thr Asp Ala Arg Val Glu Asp Lys Thr Pro Ser Pro Asp Pro 145 150 155 160

Asp Pro Asp Pro Thr Val Asn Ser Asp Gly Asp His Gly Asp Leu Ala 165 170 175 Pro Cys Lys Val Glu Glu Asn Thr Ala Gin Lys Asn Thr Glu Thr Ala

180 185 190

Ser Gly He Gly Asp Glu Asp Arg Glu Lys Gly Glu Val Thr Glu Ser 195 200 205 Thr Glu Thr Asn Tyr Ala Pro Val Ala Ser Lys Val Leu Gin Gly Asp 210 215 220

Asp Gly Asp Ala Ser Asn His Asn Ala Trp Asn Met Thr Cys Pro Gin 225 230 235 240

Pro Arg He Pro Gly Pro Arg Leu Gly Glu Asp Met Glu Ala Tyr Val 245 250 255

Leu Leu Pro Ala Pro Arg Asp His Met Val Gin Trp Arg He Val Arg

260 265 270

Asn Lys His Gly Met Asp Lys Gly Met Phe Pro Ser Tyr Tyr Leu Tyr 275 280 285 Leu Glu Gly Glu Asp Gly Val Ala His Phe Leu Leu Ala Gly Arg Lys 290 295 300

Arg Lys Arg Ser Lys Thr Ser Asn Tyr Leu He Ser Leu Asp Pro Lys 305 310 315 320

Asp Met Ser Arg Asn Gly Ser Asn Phe Val Gly Lys Val Arg Ser Asn 325 330 335

Val Leu Gly Thr Lys Phe Thr He Phe Asp Asn Gly Val Asn Pro Glu

340 345 350

Arg Ser Tyr Trp Val Pro Asp Ser Ala Arg He Arg Glu Glu Leu Gly 355 360 365 Val Val Cys Tyr Glu Thr Asn Val Leu Gly Phe Arg Gly Pro Arg Lys 370 375 380

Met Thr Val He Leu Pro Gly Met Asp Ser Arg Lys Gin Arg Met Lys 385 390 395 400

Val Gin Pro Gin Asn Asp Gin Asp Ser He Leu Ser Arg Val Gin Lys 405 410 415

Gly Ala Gly His Gly Leu Leu Leu Leu Gin Asn Lys Ala Pro Ser Trp

420 425 430

Ser Asp Glu Ser Gly Ala Tyr Val Leu Asn Phe His Gly Arg Val Thr 435 440 445 Arg Ala Ser Val Lys Asn Phe Gin He Val His Pro Asp Glu Pro Asp 450 455 460

His Leu Val Leu Gin Phe Gly Arg Val Ala Pro Asn He Phe Thr Met 465 470 475 480

Asp Phe Arg Tyr Pro Leu Cys Pro Leu Gin Ala Phe Ala He Cys Leu 485 490 495

Ser Ser Phe Asp Gly Lys Leu Ala Cys Glu 500 505

(2) INFORMATION FOR SEQ ID NO:20:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 19 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: Other (xi) SEQUENCE DESCRIPTION: SEQ ID NO:20:

TTCACAAAAG CACACCTGG 19

(2) INFORMATION FOR SEQ ID NO:21: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 19 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:21:

GTCCCAAGGA TGGAGACCT 19

(2) INFORMATION FOR SEQ ID NO: 22:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:22:

TGGTGAGCAA AACAAGGAAC 20

(2) INFORMATION FOR SEQ ID NO: 23:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 19 base pairs (B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:23: TGGGGAAAGC AATTTCTGG 19

(2) INFORMATION FOR SEQ ID NO:24:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 19 base pairs

(B) TYPE: nucleic acid (C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 24: GCCTGTCAGC AAGGACCTT 19 (2) INFORMATION FOR SEQ ID NO:25:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 20 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:25: CCATGTCCCA AACAAGATGG , 20

(2) INFORMATION FOR SEQ ID NO:26: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 19 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:26:

ACCTGAGGCA GCAGAAGCT 19

(2) INFORMATION FOR SEQ ID NO: 27:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 19 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:27:

CAGCCAGTCT CTGGTTGGT 19

(2) INFORMATION FOR SEQ ID NO: 28:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 19 base pairs (B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:28: TGCAGAACAA GACGCCAGT 19

(2) INFORMATION FOR SEQ ID NO: 29:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 19 base pairs

(B) TYPE: nucleic acid (C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:29: GATGTTGTAC GCATGGTGC 19

(2) INFORMATION FOR SEQ ID NO: 30:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 19 base pairs (B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 30: TGGAGACAGG GAGACCAGG 19

(2) INFORMATION FOR SEQ ID NO: 31:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 19 base pairs

(B) TYPE: nucleic acid (C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 31: GATGGCAAGA AGGTGTTCC 19 (2) INFORMATION FOR SEQ ID NO: 32:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 19 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 32:

TCATTGCGGG GGCGGATAC 19

(2) INFORMATION FOR SEQ ID NO: 33: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 20 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 33: ATGGTGAAGG TCGGTGTGAA 20

(2) INFORMATION FOR SEQ ID NO: 34: (1) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 20 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 34:

ACCAGTAGAC TCCACGACAT 20

(2) INFORMATION FOR SEQ ID NO: 35: (l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 22 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear ( i) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:35:

CTTAAACCCA CTCCATCCTG TG 22

(2) INFORMATION FOR SEQ ID NO: 36:

(l) SEQUENCE CHARACTERISTICS: (A) LENGTH: 3 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: double

(D) TOPOLOGY: linear

(n) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 36: ggg

(2) INFORMATION FOR SEQ ID NO: 37:

(l) SEQUENCE CHARACTERISTICS: (A) LENGTH: 22 base pairs (B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(li) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 37: CTTAAACCCA CTCCATCCTG TG 22

(2) INFORMATION FOR SEQ ID NO: 38:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 22 base pairs

(B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (11) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 38: ATCTCCCTTC CTTCCTTCCA GT 22 (2) INFORMATION FOR SEQ ID NO: 39:

(I) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 19 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single (D) TOPOLOGY: linear

(II) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:39: TGCCTGGGAA TCCTGCTGC 19

(2) INFORMATION FOR SEQ ID NO: 40: (l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 19 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear ( i) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 40:

TCCTAAGGGT CCTGCCACT 19

(2) INFORMATION FOR SEQ ID NO: 41:

(l) SEQUENCE CHARACTERISTICS: (A) LENGTH: 19 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(li) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 41:

CGAAAACGGA GCAAGACAG 19

(2) INFORMATION FOR SEQ ID NO: 42:

(l) SEQUENCE CHARACTERISTICS: (A) LENGTH: 19 base pairs (B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 42:

TATGAGGCTC TCCAGCGTC 19

(2) INFORMATION FOR SEQ ID NO: 43:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 22 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 3:

TCTACAGAGA CAAACTATGC CC 22

(2) INFORMATION FOR SEQ ID NO: 44:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 22 base pairs (B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:44: GGAAATGTGC TACACCATCC TC 22

(2) INFORMATION FOR SEQ ID NO: 45:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 22 base pairs

(B) TYPE: nucleic acid (C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:45: CCACTAAATG AACAGGAGTC GC 22 (2) INFORMATION FOR SEQ ID NO: 46:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 22 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:46:

GAAACTGGAC AAGCAGATGC TG 22 (2) INFORMATION FOR SEQ ID NO: 47:

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 22 base pairs

(B) TYPE: nucleic acid (C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(li) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 47:

CCACTAAATG AACAGGAGTC GC 22 (2) INFORMATION FOR SEQ ID NO: 48:

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 22 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 48:

TTGGAAGTTC TTCACCGAAG CC 22

(2) INFORMATION FOR SEQ ID NO: 49: (l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 27 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 49:

CCATCCTAAT ACGACTCACT ATAGGGC 27

(2) INFORMATION FOR SEQ ID NO:50:

(l) SEQUENCE CHARACTERISTICS: (A) LENGTH: 21 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 50:

AATCCAGTGT GAACACGTCA T 21

(2) INFORMATION FOR SEQ ID NO: 51:

(l) SEQUENCE CHARACTERISTICS: (A) LENGTH: 23 base pairs (B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 51:

ACTCACTATA GGGCTCGAGC GGC 23

(2) INFORMATION FOR SEQ ID NO: 52:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 base pairs (B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:52: CACGTCCAAA CTGCATGACT 20

(2) INFORMATION FOR SEQ ID NO: 53:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 19 base pairs

(B) TYPE: nucleic acid (C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:53: GCCCCCGTCT GGAACAGTG 19 (2) INFORMATION FOR SEQ ID NO: 54:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 23 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: double (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 54:

ACTCACTATA GGGCTCGAGC GGC 23

(2) INFORMATION FOR SEQ ID NO: 55: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 19 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear (11) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:55:

GCCCCCGTCT GGAACAGTG 19 (2) INFORMATION FOR SEQ ID NO:56: (l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 2112 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: double

(D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 56:

GTCTTACTAT GCAGCCTGAA GTGGGACCAT CCCTTAAACC CACTCCATCC TGTGGCCACG 60

ATGGGGGCCA GGACACCTTT GCCTTCTTTC TGGGTTTCTT TCTTTGCCGA GACAGGGATT 120

TTGTTCCCAG GAGGCACTCC CTGGCCCATG GGATCTCAGC ATTCAAAGCA GCACAGGAAA 180 CCTGGGCCCC TGAAACGGGG CCACCGAAGA GATCGGAGAA CAACCAGGAG GAAGTACTGG 240

AAGGAAGGAA GGGAGATCGC TCGTGTCTTA GATGATGAGG GCAGAAACCT GAGGCAGCAG 300

AAGCTTGATC GGCAGCGGGC CCTGCTGGAG CAGAAGCAGA AGAAGAAGCG CCAGGAGCCC 360

CTGATGGTGC AGGCCAATGC AGATGGGCGG CCCCGGAGCC GGCGGGCCCG GCAGTCAGAG 420

GAACAAGCCC CCCTGGTGGA GTCCTACCTC AGCAGCAGTG GCAGCACCAG CTACCAAGTT 480 CAAGAGGCCG ACTCACTCGC CAGTGTGCAG CTGGGAGCCA CGCGCCCAAC AGCACCAGCT 540

TCAGCCAAGA GAACCAAGGC GGCAGCTACA GCAGGGGGCC AGGGTGGCGC CGCTAGGAAG 600

GAGAAGAAGG GAAAGCACAA AGGCACCAGC GGGCCAGCAG CACTGGCAGA AGACAAGTCT 660

GAGGCCCAAG GCCCAGTGCA GATTCTGACT GTGGGCCAGT CAGACCACGC CCAGGACGCA 720

GGGGAGACGG CAGCTGGTGG GGGCGAACGG CCCAGCGGGC AGGATCTCCG TGCCACGATG 780 CAGAGGAAGG GCATCTCCAG CAGCATGAGC TTTGACGAGG ATGAGGAGGA TGAGGAGGAG 840

AATAGCTCCA GCTCCTCCCA GCTAAATAGT AACACCCGCC CCAGCTCTGC TACTAGCAGG 900

AAGTCCGTCA GGGAGGCAGC CTCAGCCCCT AGCCCAACAG CTCCAGAGCA ACCAGTGGAC 960

GTTGAGGTCC AGGATCTTGA GGAGTTTGCA CTGAGGCCGG CCCCCCAGGG TATCACCATC 1020

AAATGCCGCA TCACTCGGGA CAAGAAAGGG ATGGACCGGG GCATGTACCC CACCTACTTT 1080 CTGCACCTGG ACCGTGAGGA TGGGAAGAAG GTGTTCCTCC TGGCGGGAAG GAAGAGAAAG 1140

AAGAGTAAAA CTTCCAATTA CCTCATCTCT GTGGACCCAA CAGACTTGTC TCGAGGAGGG 1200

GACAGCTATA TCGGGAAACT GCGGTCCAAC TTGATGGGCA CCAAGTTCAC TGTTTATGAC 1260

AATGGAGTCA ACCCTCAGAA GGCCTCATCC TCCACTTTGG AAAGTGGAAC CTTACGTCAG 1320

GAGCTGGCAG CTGTGTGCTA CGAGACAAAC GTCTTAGGCT TCAAGGGGCC TCGGAAGATG 1380 AGCGTGATTG TCCCAGGCAT GAACATGGTT CATGAGAGAG TCTCTATCCG CCCCCGCAAC 1440

GAGCATGAGA CACTGCTAGC ACGCTGGCAG AATAAGAACA CGGAGAGTAT CATCGAGCTG 1500

CAAAACAAGA CACCTGTCTG GAATGATGAC ACACAGTCCT ATGTACTCAA CTTCCATGGG 1560

CGCGTCACAC AGGCCTCCGT GAAGAACTTC CAGATCATCC ATGGCAATGA CCCGGACTAC 1620

ATCGTGATGC AGTTTGGCCG GGTAGCAGAG GATGTGTTCA CCATGGATTA CAACTACCCG 1680 CTGTGTGCAC TGCAGGCCTT TGCCATTGCC CTGTCCAGCT TCGACAGCAA GCTGGCGTGC 1740

GAGTAGAGGC CTCTTCGTGC CCTTTGGGGT TGCCCAGCCT GGAGCGGAGC TTGCCTGCCT 1800

GCCTGTGGAG ACAGCCCTGC CTATCCTCTG TATATAGGCC TTCCGCCAGA TGAAGCTTTG 1860

GCCCTCAGTG GGCTCCCTGG CCCAGCCAGC CAGGAACTGG CTCCTTTGGC TCTGCTACTG 1920

AGGCAGGGGA GTAGTGGAGA GCGGGTGGGT GGGTGTTGAA GGGATTGAGA ATTAATTCTT 1980 TCCATGCCAC GAGGATCAAC ACACACTCCC ACCCTTGGGT AGTAAGTGGT TGTTGTNAGT 2040

CGGTACTTAC CAAAGCTTGA GCAACCTCTT CCAAGCTTGG GAAAGGGCCG CAAAAAGGCA 2100

TTAGGAGGGG AG 2112

(2) INFORMATION FOR SEQ ID NO: 57:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 2368 base pairs

(B) TYPE: nucleic acid (C) STRANDEDNESS: double

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 57:

CCCGGGCAGT CCTAAGCCCA CTGTTTATTG TCGACCCAGT GCACTTGCTA GCGGACGGCA 60

GGATGAGATC CTCAGTCCCG CCTTGTACAC AGCTTGCTCT CTGTAGAGCA TCATACCGTC 120

ATGATAGAAA TAGTCTGACG GGCTCTTCTC TGAGTCTGTC CAGACAGCGT CCCAATGGAA 180

ACCAGCTGAA ACGCCCAAGG CTTCTTAAAA GCAGATCCTT CTGAAAACAG GCACGTGGCC 240

TGGGAACTCA GGGTTTCTCT TGAGAATTGT TACTCTAATC TCAGCTCCTG TGGGGGATTC 300

AGGGGTTTCC AGGTTATTTT GTGTCTCTCC CCACAACCAC CAGCAACACC CTCACACGTG 360

CGCACATACA GGTCACCCAC AGGCTCTCCT GCAGACACAT GTAGTCACAC TTCAGTCTCA 420

CATGGATTAG GGAGCTGTTT CCATCATGGA ACCAGGGACT GGGGCTGTGC TGACTGAGAA 480

GAGCTGCTGC GCCAGACAGA CGTCCAGGCT GGGGCACAGT GTCTTAGATG ATGAGGGCAG 540

AAACCTGAGG CAGCAGAAGC TTGATCGGCA GCGGGCCCTG CTGGAGCAGA AGCAGAAGAA 600

GAAGCGCCAG GAGCCCCTGA TGGTGCAGGC CAATGCAGAT GGGCGGCCCC GGAGCCGGCG 660

GGCCCGGCAG TCAGAGGAAC AAGCCCCCCT GGTGGAGTCC TACCTCAGCA GCAGTGGCAG 720

CACCAGCTAC CAAGTTCAAG AGGCCGACTC ACTCGCCAGT GTGCAGCTGG GAGCCACGCG 780

CCCAACAGCA CCAGCTTCAG CCAAGAGAAC CAAGGCGGCA GCTACAGCAG GGGGCCAGGG 840

TGGCGCCGCT AGGAAGGAGA AGAAGGGAAA GCACAAAGGC ACCAGCGGGC CAGCAGCACT 900

GGCAGAAGAC AAGTCTGAGG CCCAAGGCCC AGTGCAGATT CTGACTGTGG GCCAGTCAGA 960

CCACGCCCAG GACGCAGGGG AGACGGCAGC TGGTGGGGGC GAACGGCCCA GCGGGCAGGA 1020

TCTCCGTGCC ACGATGCAGA GGAAGGGCAT CTCCAGCAGC ATGAGCTTTG ACGAGGATGA 1080

GGAGGATGAG GAGGAGAATA GCTCCAGCTC CTCCCAGCTA AATAGTAACA CCCGCCCCAG 1140

CTCTGCTACT AGCAGGAAGT CCGTCAGGGA GGCAGCCTCA GCCCCTAGCC CAACAGCTCC 1200

AGAGCAACCA GTGGACGTTG AGGTCCAGGA TCTTGAGGAG TTTGCACTGA GGCCGGCCCC 1260

CCAGGGTATC ACCATCAAAT GCCGCATCAC TCGGGACAAG AAAGGGATGG ACCGGGGCAT 1320

GTACCCCACC TACTTTCTGC ACCTGGACCG TGAGGATGGG AAGAAGGTGT TCCTCCTGGC 1380

GGGAAGGAAG AGAAAGAAGA GTAAAACTTC CAATTACCTC ATCTCTGTGG ACCCAACAGA 1440

CTTGTCTCGA GGAGGGGACA GCTATATCGG GAAACTGCGG TCCAACTTGA TGGGCACCAA 1500

GTTCACTGTT TATGACAATG GAGTCAACCC TCAGAAGGCC TCATCCTCCA CTTTGGAAAG 1560

TGGAACCTTA CGTCAGGAGC TGGCAGCTGT GTGCTACGAG ACAAACGTCT TAGGCTTCAA 1620

GGGGCCTCGG AAGATGAGCG TGATTGTCCC AGGCATGAAC ATGGTTCATG AGAGAGTCTC 1680

TATCCGCCCC CGCAACGAGC ATGAGACACT GCTAGCACGC TGGCAGAATA AGAACACGGA 1740

GAGTATCATC GAGCTGCAAA ACAAGACACC TGTCTGGAAT GATGACACAC AGTCCTATGT 1800

ACTCAACTTC CATGGGCGCG TCACACAGGC CTCCGTGAAG AACTTCCAGA TCATCCATGG 1860

CAATGACCCG GACTACATCG TGATGCAGTT TGGCCGGGTA GCAGAGGATG TGTTCACCAT 1920

GGATTACAAC TACCCGCTGT GTGCACTGCA GGCCTTTGCC ATTGCCCTGT CCAGCTTCGA 1980

CAGCAAGCTG GCGTGCGAGT AGAGGCCTCT TCGTGCCCTT TGGGGTTGCC CAGCCTGGAG 2040

CGGAGCTTCC TGCCTGCCTG TGGAGACAGC CCTGCCTATC CTCTGTATAT AGGCCTTCCG 2100

CCAGATGAAG CTTTGGCCCT CAGTGGGCTC CCTGGCCCAG CCAGCCAGGA ACTGGCTCCT 2160

TTGGCTCTGC TACTGAGGCA GGGGAGTAGT GGAGAGCGGG TGGGTGGGTG TTGAAGGGAT 2220

TGAGAATTAA TTCTTTCCAT GCCACGAGGA TCAACACACA CTCCCACCCT TGGGTAGTAA 2280

GTGGTTGTTG TNAGTCGGTA CTTTACCAAA GCTTGAGCAA CCTCTTCCAA GCTTGGGAAA 2340

GGGCCGCAAA AAGGCATTAG GAGGGGAG 2368

(2) INFORMATION FOR SEQ ID NO: 58:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 518 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: protein

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:58: Met Glu Pro Gly Thr Gly Ala Val Leu Thr Glu Lys Ser Cys Cys Ala

1 5 10 15

Arg Gin Thr Ser Arg Leu Gly His Ser Val Leu Asp Asp Glu Gly Arg 20 25 30

Asn Leu Arg Gin Gin Lys Leu Asp Arg Gin Arg Ala Leu Leu Glu Gin 35 40 45

Lys Gin Lys Lys Lys Arg Gin Glu Pro Leu Met Val Gin Ala Asn Ala 50 55 60

Asp Gly Arg Pro Arg Ser Arg Arg Ala Arg Gin Ser Glu Glu Gin Ala

65 70 75 80

Pro Leu Val Glu Ser Tyr Leu Ser Ser Ser Gly Ser Thr Ser Tyr Gin 85 90 95

Val Gin Glu Ala Asp Ser Leu Ala Ser Val Gin Leu Gly Ala Thr Arg 100 105 110

Pro Thr Ala Pro Ala Ser Ala Lys Arg Thr Lys Ala Ala Ala Thr Ala 115 120 125

Gly Gly Gin Gly Gly Ala Ala Arg Lys Glu Lys Lys Gly Lys His Lys

130 135 140

Gly Thr Ser Gly Pro Ala Ala Leu Ala Glu Asp Lys Ser Glu Ala Gin

145 150 155 160

Gly Pro Val Gin He Leu Thr Val Gly Gin Ser Asp His Ala Gin Asp 165 170 175

Ala Gly Glu Thr Ala Ala Gly Gly Gly Glu Arg Pro Ser Gly Gin Asp

180 185 190

Leu Arg Ala Thr Met Gin Arg Lys Gly He Ser Ser Ser Met Ser Phe 195 200 205

Asp Glu Asp Glu Glu Asp Glu Glu Glu Asn Ser Ser Ser Ser Ser Gin 210 215 220

Leu Asn Ser Asn Thr Arg Pro Ser Ser Ala Thr Ser Arg Lys Ser Val

225 230 235 240

Arg Glu Ala Ala Ser Ala Pro Ser Pro Thr Ala Pro Glu Gin Pro Val 245 250 255

Asp Val Glu Val Gin Asp Leu Glu Glu Phe Ala Leu Arg Pro Ala Pro 260 265 270

Gin Gly He Thr He Lys Cys Arg He Thr Arg Asp Lys Lys Gly Met 275 280 285

Asp Arg Gly Met Tyr Pro Thr Tyr Phe Leu His Leu Asp Arg Glu Asp

290 295 300

Gly Lys Lys Val Phe Leu Leu Ala Gly Arg Lys Arg Lys Lys Ser Lys

305 310 315 320

Thr Ser Asn Tyr Leu He Ser Val Asp Pro Thr Asp Leu Ser Arg Gly 325 330 335

Gly Asp Ser Tyr He Gly Lys Leu Arg Ser Asn Leu Met Gly Thr Lys

340 345 350

Phe Thr Val Tyr Asp Asn Gly Val Asn Pro Gin Lys Ala Ser Ser Ser 355 360 365

Thr Leu Glu Ser Gly Thr Leu Arg Gin Glu Leu Ala Ala Val Cys Tyr 370 375 380

Glu Thr Asn Val Leu Gly Phe Lys Gly Pro Arg Lys Met Ser Val He

385 390 395 400

Val Pro Gly Met Asn Met Val His Glu Arg Val Ser He Arg Pro Arg 405 410 415

Asn Glu His Glu Thr Leu Leu Ala Arg Trp Gin Asn Lys Asn Thr Glu 420 425 430

Ser He He Glu Leu Gin Asn Lys Thr Pro Val Trp Asn Asp Asp Thr 435 440 445

Gin Ser Tyr Val Leu Asn Phe His Gly Arg Val Thr Gin Ala Ser Val

450 455 460

Lys Asn Phe Gin He He His Gly Asn Asp Pro Asp Tyr He Val Met

465 470 475 480 Gin Phe Gly Arg Val Ala Glu Asp Val Phe Thr Met Asp Tyr Asn Tyr

485 490 495

Pro Leu Cys Ala Leu Gin Ala Phe Ala He Ala Leu Ser Ser Phe Asp

500 505 510

Ser Lys Leu Ala Cys Glu 515

(2) INFORMATION FOR SEQ ID NO: 59:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1936 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: double

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:59:

GCGGAGCCCC GAGCGGAGCC GGAGGCGGCG ATGGAGGGAG TCAGCAGCCA CCGGACCCTG 60

TCTTACAGCC GCTGGAGCTA TGACAGTGTC TTAGATGATG AGGGCAGAAA CCTGAGGCAG 120

CAGAAGCTTG ATCGGCAGCG GGCCCTGCTG GAGCAGAAGC AGAAGAAGAA GCGCCAGGAG 180

CCCCTGATGG TGCAGGCCAA TGCAGATGGG CGGCCCCGGA GCCGGCGGGC CCGGCAGTCA 240

GAGGAACAAG CCCCCCTGGT GGAGTCCTAC CTCAGCAGCA GTGGCAGCAC CAGCTACCAA 300

GTTCAAGAGG CCGACTCACT CGCCAGTGTG CAGCTGGGAG CCACGCGCCC AACAGCACCA 360

GCTTCAGCCA AGAGAACCAA GGCGGCAGCT ACAGCAGGGG GCCAGGGTGG CGCCGCTAGG 420

AAGGAGAAGA AGGGAAAGCA CAAAGGCACC AGCGGGCCAG CAGCACTGGC AGAAGACAAG 480

TCTGAGGCCC AAGGCCCAGT GCAGATTCTG ACTGTGGGCC AGTCAGACCA CGCCCAGGAC 540

GCAGGGGAGA CGGCAGCTGG TGGGGGCGAA CGGCCCAGCG GGCAGGATCT CCGTGCCACG 600

ATGCAGAGGA AGGGCATCTC CAGCAGCATG AGCTTTGACG AGGATGAGGA GGATGAGGAG 660

GAGAATAGCT CCAGCTCCTC CCAGCTAAAT AGTAACACCC GCCCCAGCTC TGCTACTAGC 720

AGGAAGTCCG TCAGGGAGGC AGCCTCAGCC CCTAGCCCAA CAGCTCCAGA GCAACCAGTG 780

GACGTTGAGG TCCAGGATCT TGAGGAGTTT GCACTGAGGC CGGCCCCCCA GGGTATCACC 840

ATCAAATGCC GCATCACTCG GGACAAGAAA GGGATGGACC GGGGCATGTA CCCCACCTAC 900

TTTCTGCACC TGGACCGTGA GGATGGGAAG AAGGTGTTCC TCCTGGCGGG AAGGAAGAGA 960

AAGAAGAGTA AAACTTCCAA TTACCTCATC TCTGTGGACC CAACAGACTT GTCTCGAGGA 1020

GGGGACAGCT ATATCGGGAA ACTGCGGTCC AACTTGATGG GCACCAAGTT CACTGTTTAT 1080

GACAATGGAG TCAACCCTCA GAAGGCCTCA TCCTCCACTT TGGAAAGTGG AACCTTACGT 1140

CAGGAGCTGG CAGCTGTGTG CTACGAGACA AACGTCTTAG GCTTCAAGGG GCCTCGGAAG 1200

ATGAGCGTGA TTGTCCCAGG CATGAACATG GTTCATGAGA GAGTCTCTAT CCGCCCCCGC 1260

AACGAGCATG AGACACTGCT AGCACGCTGG CAGAATAAGA ACACGGAGAG TATCATCGAG 1320

CTGCAAAACA AGACACCTGT CTGGAATGAT GACACACAGT CCTATGTACT CAACTTCCAT 1380

GGGCGCGTCA CACAGGCCTC CGTGAAGAAC TTCCAGATCA TCCATGGCAA TGACCCGGAC 1440

TACATCGTGA TGCAGTTTGG CCGGGTAGCA GAGGATGTGT TCACCATGGA TTACAACTAC 1500

CCGCTGTGTG CACTGCAGGC CTTTGCCATT GCCCTGTCCA GCTTCGACAG CAAGCTGGCG 1560

TGCGAGTAGA GGCCTCTTCG TGCCCTTTGG GGTTGCCCAG CCTGGAGCGG AGCTTGCCTG 1620

CCTGCCTGTG GAGACAGCCC TGCCTATCCT CTGTATATAG GCCTTCCGCC AGATGAAGCT 1680

TTGGCCCTCA GTGGGCTCCC TGGCCCAGCC AGCCAGGAAC TGGCTCCTTT GGCTCTGCTA 1740

CTGAGGCAGG GGAGTAGTGG AGAGCGGGTG GGTGGGTGTT GAAGGGATTG AGAATTAATT 1800

CTTTCCATGC CACGAGGATC AACACACACT CCCACCCTTG GGTAGTAAGT GGTTGTTGTN 1860

AGTCGGTACT TTACCAAAGC TTGAGCAACC TCTTCCAAGC TTGGGAAAGG GCCGCAAAAA 1920

GGCATTAGGA GGGGAG 1936

(2) INFORMATION FOR SEQ ID NO: 60:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 512 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 60:

Met Glu Gly Val Ser Ser His Arg Thr Leu Ser Tyr Ser Arg Trp Ser 1 5 10 15 Tyr Asp Ser Val Leu Asp Asp Glu Gly Arg Asn Leu Arg Gin Gin Lys 20 25 30

Leu Asp Arg Gin Arg Ala Leu Leu Glu Gin Lys Gin Lys Lys Lys Arg

35 40 45

Gin Glu Pro Leu Met Val Gin Ala Asn Ala Asp Gly Arg Pro Arg Ser 50 55 60

Arg Arg Ala Arg Gin Ser Glu Glu Gin Ala Pro Leu Val Glu Ser Tyr 65 70 75 80

Leu Ser Ser Ser Gly Ser Thr Ser Tyr Gin Val Gin Glu Ala Asp Ser 85 90 95 Leu Ala Ser Val Gin Leu Gly Ala Thr Arg Pro Thr Ala Pro Ala Ser 100 105 110

Ala Lys Arg Thr Lys Ala Ala Ala Thr Ala Gly Gly Gin Gly Gly Ala

115 120 125

Ala Arg Lys Glu Lys Lys Gly Lys His Lys Gly Thr Ser Gly Pro Ala 130 135 140

Ala Leu Ala Glu Asp Lys Ser Glu Ala Gin Gly Pro Val Gin He Leu

145 150 155 160

Thr Val Gly Gin Ser Asp His Ala Gin Asp Ala Gly Glu Thr Ala Ala

165 170 175 Gly Gly Gly Glu Arg Pro Ser Gly Gin Asp Leu Arg Ala Thr Met Gin

180 185 190

Arg Lys Gly He Ser Ser Ser Met Ser Phe Asp Glu Asp Glu Glu Asp

195 200 205

Glu Glu Glu Asn Ser Ser Ser Ser Ser Gin Leu Asn Ser Asn Thr Arg 210 215 220

Pro Ser Ser Ala Thr Ser Arg Lys Ser Val Arg Glu Ala Ala Ser Ala

225 230 235 240

Pro Ser Pro Thr Ala Pro Glu Gin Pro Val Asp Val Glu Val Gin Asp

245 250 255 Leu Glu Glu Phe Ala Leu Arg Pro Ala Pro Gin Gly He Thr He Lys

260 265 270

Cys Arg He Thr Arg Asp Lys Lys Gly Met Asp Arg Gly Met Tyr Pro

275 280 285

Thr Tyr Phe Leu His Leu Asp Arg Glu Asp Gly Lys Lys Val Phe Leu 290 295 300

Leu Ala Gly Arg Lys Arg Lys Lys Ser Lys Thr Ser Asn Tyr Leu He

305 310 315 320

Ser Val Asp Pro Thr Asp Leu Ser Arg Gly Gly Asp Ser Tyr He Gly

325 330 335 Lys Leu Arg Ser Asn Leu Met Gly Thr Lys Phe Thr Val Tyr Asp Asn

340 345 350

Gly Val Asn Pro Gin Lys Ala Ser Ser Ser Thr Leu Glu Ser Gly Thr

355 360 365

Leu Arg Gin Glu Leu Ala Ala Val Cys Tyr Glu Thr Asn Val Leu Gly 370 375 380

Phe Lys Gly Pro Arg Lys Met Ser Val He Val Pro Gly Met Asn Met 385 390 395 400

Val His Glu Arg Val Ser He Arg Pro Arg Asn Glu His Glu Thr Leu 405 410 415 Leu Ala Arg Trp Gin Asn Lys Asn Thr Glu Ser He He Glu Leu Gin 420 425 430

Asn Lys Thr Pro Val Trp Asn Asp Asp Thr Gin Ser Tyr Val Leu Asn 435 440 445 Phe His Gly Arg Val Thr Gin Ala Ser Val Lys Asn Phe Gin He He

450 455 460

His Gly Asn Asp Pro Asp Tyr He Val Met Gin Phe Gly Arg Val Ala 465 470 475 480 Glu Asp Val Phe Thr Met Asp Tyr Asn Tyr Pro Leu Cys Ala Leu Gin

485 490 495

Ala Phe Ala He Ala Leu Ser Ser Phe Asp Ser Lys Leu Ala Cys Glu 500 505 510

(2) INFORMATION FOR SEQ ID NO:61: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1890 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: double

(D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:61:

GACATGACTT CCAAGCCGCA TTCCGACTGG ATTCCCTACA GTGTCTTAGA TGATGAGGGC 60

AGAAACCTGA GGCAGCAGAA GCTTGATCGG CAGCGGGCCC TGCTGGAGCA GAAGCAGAAG 120

AAGAAGCGCC AGGAGCCCCT GATGGTGCAG GCCAATGCAG ATGGGCGGCC CCGGAGCCGG 180 CGGGCCCGGC AGTCAGAGGA ACAAGCCCCC CTGGTGGAGT CCTACCTCAG CAGCAGTGGC 240

AGCACCAGCT ACCAAGTTCA AGAGGCCGAC TCACTCGCCA GTGTGCAGCT GGGAGCCACG 300

CGCCCAACAG CACCAGCTTC AGCCAAGAGA ACCAAGGCGG CAGCTACAGC AGGGGGCCAG 360

GGTGGCGCCG CTAGGAAGGA GAAGAAGGGA AAGCACAAAG GCACCAGCGG GCCAGCAGCA 420

CTGGCAGAAG ACAAGTCTGA GGCCCAAGGC CCAGTGCAGA TTCTGACTGT GGGCCAGTCA 480 GACCACGCCC AGGACGCAGG GGAGACGGCA GCTGGTGGGG GCGAACGGCC CAGCGGGCAG 540

GATCTCCGTG CCACGATGCA GAGGAAGGGC ATCTCCAGCA GCATGAGCTT TGACGAGGAT 600

GAGGAGGATG AGGAGGAGAA TAGCTCCAGC TCCTCCCAGC TAAATAGTAA CACCCGCCCC 660

AGCTCTGCTA CTAGCAGGAA GTCCGTCAGG GAGGCAGCCT CAGCCCCTAG CCCAACAGCT 720

CCAGAGCAAC CAGTGGACGT TGAGGTCCAG GATCTTGAGG AGTTTGCACT GAGGCCGGCC 780 CCCCAGGGTA TCACCATCAA ATGCCGCATC ACTCGGGACA AGAAAGGGAT GGACCGGGGC 840

ATGTACCCCA CCTACTTTCT GCACCTGGAC CGTGAGGATG GGAAGAAGGT GTTCCTCCTG 900

GCGGGAAGGA AGAGAAAGAA GAGTAAAACT TCCAATTACC TCATCTCTGT GGACCCAACA 960

GACTTGTCTC GAGGAGGGGA CAGCTATATC GGGAAACTGC GGTCCAACTT GATGGGCACC 1020

AAGTTCACTG TTTATGACAA TGGAGTCAAC CCTCAGAAGG CCTCATCCTC CACTTTGGAA 1080 AGTGGAACCT TACGTCAGGA GCTGGCAGCT GTGTGCTACG AGACAAACGT CTTAGGCTTC 1140

AAGGGGCCTC GGAAGATGAG CGTGATTGTC CCAGGCATGA ACATGGTTCA TGAGAGAGTC 1200

TCTATCCGCC CCCGCAACGA GCATGAGACA CTGCTAGCAC GCTGGCAGAA TAAGAACACG 1260

GAGAGTATCA TCGAGCTGCA AAACAAGACA CCTGTCTGGA ATGATGACAC ACAGTCCTAT 1320

GTACTCAACT TCCATGGGCG CGTCACACAG GCCTCCGTGA AGAACTTCCA GATCATCCAT 1380 GGCAATGACC CGGACTACAT CGTGATGCAG TTTGGCCGGG TAGCAGAGGA TGTGTTCACC 1440

ATGGATTACA ACTACCCGCT GTGTGCACTG CAGGCCTTTG CCATTGCCCT GTCCAGCTTC 1500

GACAGCAAGC TGGCGTGCGA GTAGAGGCCT CTTCGTGCCC TTTGGGGTTG CCCAGCCTGG 1560

AGCGGAGCTT GCCTGCCTGC CTGTGGAGAC AGCCCTGCCT ATCCTCTGTA TATAGGCCTT 1620

CCGCCAGATG AAGCTTTGGC CCTCAGTGGG CTCCCTGGCC CAGCCAGCCA GGAACTGGCT 1680 CCTTTGGCTC TGCTACTGAG GCAGGGGAGT AGTGGAGAGC GGGTGGGTGG GTGTTGA-.3G 1740

GATTGAGAAT TAATTCTTTC CATGCCACGA GGATCAACAC ACACTCCCAC CCTTGGGTAG 1800

TAAGTGGTTG TTGTNAGTCG GTACTTTACC AAAGCTTGAG CAACCTCTTC CAAGCTTGGG 1860

AAAGGGCCGC AAAAAGGCAT TAGGAGGGGA 1890

(2) INFORMATION FOR SEQ ID NO:62: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 506 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: single (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: protein

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 62:

Met Thr Ser Lys Pro His Ser Asp Trp He Pro Tyr Ser Val Leu Asp 1 5 10 15

Asp Glu Gly Arg Asn Leu Arg Gin Gin Lys Leu Asp Arg Gin Arg Ala

20 25 30

Glu Glu Gin Ala Pro Leu Val Glu Ser Tyr Leu Ser Ser Ser Gly Ser 65 70 75 80

Thr Ser Tyr Gin Val Gin Glu Ala Asp Ser Leu Ala Ser Val Gin Leu 85 90 95

Gly Ala Thr Arg Pro Thr Ala Pro Ala Ser Ala Lys Arg Thr Lys Ala

100 105 110

Ala Ala Thr Ala Gly Gly Gin Gly Gly Ala Ala Arg Lys Glu Lys Lys 115 120 125 Gly Lys His Lys Gly Thr Ser Gly Pro Ala Ala Leu Ala Glu Asp Lys 130 135 140

Ser Glu Ala Gin Gly Pro Val Gin He Leu Thr Val Gly Gin Ser Asp 145 150 155 160

His Ala Gin Asp Ala Gly Glu Thr Ala Ala Gly Gly Gly Glu Arg Pro 165 170 175

Ser Gly Gin Asp Leu Arg Ala Thr Met Gin Arg Lys Gly He Ser Ser

180 185 190

Ser Met Ser Phe Asp Glu Asp Glu Glu Asp Glu Glu Glu Asn Ser Ser 195 200 205 Ser Ser Ser Gin Leu Asn Ser Asn Thr Arg Pro Ser Ser Ala Thr Ser 210 215 220

Arg Lys Ser Val Arg Glu Ala Ala Ser Ala Pro Ser Pro Thr Ala Pro 225 230 235 240

Glu Gin Pro Val Asp Val Glu Val Gin Asp Leu Glu Glu Phe Ala Leu 245 250 255

Arg Pro Ala Pro Gin Gly He Thr He Lys Cys Arg He Thr Arg Asp

260 265 270

Lys Lys Gly Met Asp Arg Gly Met Tyr Pro Thr Tyr Phe Leu His Leu 275 280 285 Asp Arg Glu Asp Gly Lys Lys Val Phe Leu Leu Ala Gly Arg Lys Arg 290 295 300

Lys Lys Ser Lys Thr Ser Asn Tyr Leu He Ser Val Asp Pro Thr Asp 305 310 315 320

Leu Ser Arg Gly Gly Asp Ser Tyr He Gly Lys Leu Arg Ser Asn Leu 325 330 335

Met Gly Thr Lys Phe Thr Val Tyr Asp Asn Gly Val Asn Pro Gin Lys

340 345 350

Ala Ser Ser Ser Thr Leu Glu Ser Gly Thr Leu Arg Gin Glu Leu Ala 355 360 365 Ala Val Cys Tyr Glu Thr Asn Val Leu Gly Phe Lys Gly Pro Arg Lys 370 375 380

Met Ser Val He Val Pro Gly Met Asn Met Val His Glu Arg Val Ser 385 390 395 400

He Arg Pro Arg Asn Glu His Glu Thr Leu Leu Ala Arg Trp Gin Asn 405 410 415

Lys Asn Thr Glu Ser He He Glu Leu Gin Asn Lys Thr Pro Val Trp 420 425 430 Asn Asp Asp Thr Gin Ser Tyr Val Leu Asn Phe His Gly Arg Val Thr

435 440 445

Gin Ala Ser Val Lys Asn Phe Gin He He His Gly Asn Asp Pro Asp

450 455 460 Tyr He Val Met Gin Phe Gly Arg Val Ala Glu Asp Val Phe Thr Met

465 470 475 480

Asp Tyr Asn Tyr Pro Leu Cys Ala Leu Gin Ala Phe Ala He Ala Leu

485 490 495

Ser Ser Phe Asp Ser Lys Leu Ala Cys Glu 500 505

(2) INFORMATION FOR SEQ ID NO: 63:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 2109 base pairs

(B) TYPE: nucleic acid (C) STRANDEDNESS: double

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 63:

GTCTCTGTGT AAAATGGGTG CTGGACTCCT AAGGCCCACT GTGTTATTGT CGACCCAGGT 60 GCACGTGCTA GCGGACGGCA GGATGAGATC CTCAGGTCCC GCCTTGTAAC ACAGCTTGCT 120

CTCTGTTAGA GCCTCATACC AGTCACTGAT AGAAAATAGT TCTGACAGGG CTCTTCTCTG 180

AGTCTGTCCA GACAGCGTCC CAAATGGAAA CCAGCTGAAA CCGCCCAAGG CTTCTTAAAA 240

GCAGATCCTT CTGAAAACAG TGTCTTAGAT GATGAGGGCA GAAACCTGAG GCAGCAGAAG 300

CTTGATCGGC AGCGGGCCCT GCTGGAGCAG AAGCAGAAGA AGAAGCGCCA GGAGCCCCTG 360 ATGGTGCAGG CCAATGCAGA TGGGCGGCCC CGGAGCCGGC GGGCCCGGCA GTCAGAGGAA 420

CAAGCCCCCC TGGTGGAGTC CTACCTCAGC AGCAGTGGCA GCACCAGCTA CCAAGTTCAA 480

GAGGCCGACT CACTCGCCAG TGTGCAGCTG GGAGCCACGC GCCCAACAGC ACCAGCTTCA 540

GCCAAGAGAA CCAAGGCGGC AGCTACAGCA GGGGGCCAGG GTGGCGCCGC TAGGAAGGAG 600

AAGAAGGGAA AGCACAAAGG CACCAGCGGG CCAGCAGCAC TGGCAGAAGA CAAGTCTGAG 660 GCCCAAGGCC CAGTGCAGAT TCTGACTGTG GGCCAGTCAG ACCACGCCCA GGACGCAGGG 720

GAGACGGCAG CTGGTGGGGG CGAACGGCCC AGCGGGCAGG ATCTCCGTGC CACGATGCAG 780

AGGAAGGGCA TCTCCAGCAG CATGAGCTTT GACGAGGATG AGGAGGATGA GGAGGAGAAT 840

AGCTCCAGCT CCTCCCAGCT AAATAGTAAC ACCCGCCCCA GCTCTGCTAC TAGCAGGAAG 900

TCCGTCAGGG AGGCAGCCTC AGCCCCTAGC CCAACAGCTC CAGAGCAACC AGTGGACGTT 960 GAGGTCCAGG ATCTTGAGGA GTTTGCACTG AGGCCGGCCC CCCAGGGTAT CACCATCAAA 1020

TGCCGCATCA CTCGGGACAA GAAAGGGATG GACCGGGGCA TGTACCCCAC CTACTTTCTG 1080

CACCTGGACC GTGAGGATGG GAAGAAGGTG TTCCTCCTGG CGGGAAGGAA GAGAAAGAAG 1140

AGTAAAACTT CCAATTACCT CATCTCTGTG GACCCAACAG ACTTGTCTCG AGGAGGGGAC 1200

AGCTATATCG GGAAACTGCG GTCCAACTTG ATGGGCACCA AGTTCACTGT TTATGACAAT 1260 GGAGTCAACC CTCAGAAGGC CTCATCCTCC ACTTTGGAAA GTGGAACCTT ACGTCAGGAG 1320

CTGGCAGCTG TGTGCTACGA GACAAACGTC TTAGGCTTCA AGGGGCCTCG GAAGATGAGC 1380

GTGATTGTCC CAGGCATGAA CATGGTTCAT GAGAGAGTCT CTATCCGCCC CCGCAACGAG 1440

CATGAGACAC TGCTAGCACG CTGGCAGAAT AAGAACACGG AGAGTATCAT CGAGCTGCAA 1500

AACAAGACAC CTGTCTGGAA TGATGACACA CAGTCCTATG TACTCAACTT CCATGGGCGC 1560 GTCACACAGG CCTCCGTGAA GAACTTCCAG ATCATCCATG GCAATGACCC GGACTACATC 1620

GTGATGCAGT TTGGCCGGGT AGCAGAGGAT GTGTTCACCA TGGATTACAA CTACCCGCTG 1680

TGTGCACTGC AGGCCTTTGC CATTGCCCTG TCCAGCTTCG ACAGCAAGCT GGCGTGCGAG 1740

TAGAGGCCTC TTCGTGCCCT TTGGGGTTGC CCAGCCTGGA GCGGAGCTTG CCTGCCTGCC 1800

TGTGGAGACA GCCCTGCCTA TCCTCTGTAT ATAGGCCTTC CGCCAGATGA AGCTTTGGCC 1860 CTCAGTGGGC TCCCTGGCCC AGCCAGCCAG GAACTGGCTC CTTTGGCTCT GCTACTGAGG 1920

CAGGGGAGTA GTGGAGAGCG GGTGGGTGGG TGTTGAAGGG ATTGAGAATT AATTCTTTCC 1980

ATGCCACGAG GATCAACACA CACTCCCACC CTTGGGTAGT AAGTGGTTGT TGTNAGTCGG 2040

TACTTTACAA AGCTTGAGCA ACCTCTTCCA AGCTTGGGAA AGGGCCGCAA AAAGGCATTA 2100

GGAGGGGAG 2109 (2) INFORMATION FOR SEQ ID NO: 64:

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 2088 base pairs

(B) TYPE: nucleic acid (C) STRANDEDNESS: double

(D) TOPOLOGY: linear

(n) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 64:

TGGGCCAGGC CAAGACATGG TTCTAGAAAG CTTCTCCCAG GGAGCCAGGG ACTAAAGCCA 60 CTTGTAGAGA GTGTGCAGGG GTCTTAGAGA AAATATGCCT CAAACGGAAT GGCTTAAGCC 120

TGTTCCTGGG AAAGGTGGCC CAGGAAGGTA GAACTGTCTC TAGGAAATGA TCCTGTTCTA 180

GCAAGTGCCT AGGGCCCTGG CATCCTGCAA GGAGTGATTT GGCACTTGCC TCAGCCCAGT 240

GTCTTAGATG ATGAGGGCAG AAACCTGAGG CAGCAGAAGC TTGATCGGCA GCGGGCCCTG 300

CTGGAGCAGA AGCAGAAGAA GAAGCGCCAG GAGCCCCTGA TGGTGCAGGC CAATGCAGAT 360 GGGCGGCCCC GGAGCCGGCG GGCCCGGCAG TCAGAGGAAC AAGCCCCCCT GGTGGAGTCC 420

TACCTCAGCA GCAGTGGCAG CACCAGCTAC CAAGTTCAAG AGGCCGACTC ACTCGCCAGT 480

GTGCAGCTGG GAGCCACGCG CCCAACAGCA CCAGCTTCAG CCAAGAGAAC CAAGGCGGCA 540

GCTACAGCAG GGGGCCAGGG TGGCGCCGCT AGGAAGGAGA AGAAGGGAAA GCACAAAGGC 600

ACCAGCGGGC CAGCAGCACT GGCAGAAGAC AAGTCTGAGG CCCAAGGCCC AGTGCAGATT 660 CTGACTGTGG GCCAGTCAGA CCACGCCCAG GACGCAGGGG AGACGGCAGC TGGTGGGGGC 720

GAACGGCCCA GCGGGCAGGA TCTCCGTGCC ACGATGCAGA GGAAGGGCAT CTCCAGCAGC 780

ATGAGCTTTG ACGAGGATGA GGAGGATGAG GAGGAGAATA GCTCCAGCTC CTCCCAGCTA 840

AATAGTAACA CCCGCCCCAG CTCTGCTACT AGCAGGAAGT CCGTCAGGGA GGCAGCCTCA 900

GCCCCTAGCC CAACAGCTCC AGAGCAACCA GTGGACGTTG AGGTCCAGGA TCTTGAGGAG 960 TTTGCACTGA GGCCGGCCCC CCAGGGTATC ACCATCAAAT GCCGCATCAC TCGGGACAAG 1020

AAAGGGATGG ACCGGGGCAT GTACCCCACC TACTTTCTGC ACCTGGACCG TGAGGATGGG 1080

AAGAAGGTGT TCCTCCTGGC GGGAAGGAAG AGAAAGAAGA GTAAAACTTC CAATTACCTC 1140

ATCTCTGTGG ACCCAACAGA CTTGTCTCGA GGAGGGGACA GCTATATCGG GAAACTGCGG 1200

TCCAACTTGA TGGGCACCAA GTTCACTGTT TATGACAATG GAGTCAACCC TCAGAAGGCC 1260 TCATCCTCCA CTTTGGAAAG TGGAACCTTA CGTCAGGAGC TGGCAGCTGT GTGCTACGAG 1320

ACAAACGTCT TAGGCTTCAA GGGGCCTCGG AAGATGAGCG TGATTGTCCC AGGCATGAAC 1380

ATGGTTCATG AGAGAGTCTC TATCCGCCCC CGCAACGAGC ATGAGACACT GCTAGCACGC 1440

TGGCAGAATA AGAACACGGA GAGTATCATC GAGCTGCAAA ACAAGACACC TGTCTGGAAT 1500

GATGACACAC AGTCCTATGT ACTCAACTTC CATGGGCGCG TCACACAGGC CTCCGTGAAG 1560 AACTTCCAGA TCATCCATGG CAATGACCCG GACTACATCG TGATGCAGTT TGGCCGGGTA 1620

GCAGAGGATG TGTTCACCAT GGATTACAAC TACCCGCTGT GTGCACTGCA GGCCTTTGCC 1680

ATTGCCCTGT CCAGCTTCGA CAGCAAGCTG GCGTGCGAGT AGAGGCCTCT TCGTGCCCTT 1740

TGGGGTTGCC CAGCCTGGAG CGGAGCTTGC CTGCCTGCCT GTGGAGACAG CCCTGCCTAT 1800

CCTCTGTATA TAGGCCTTCC GCCAGATGAA GCTTTGGCCC TCAGTGGGCT CCCTGGCCCA 1860 GCCAGCCAGG AACTGGCTCC TTTGGCTCTG CTACTGAGGC AGGGGAGTAG TGGAGAGCGG 1920

GTGGGTGGGT GTTGAAGGGA TTGAGAATTA ATTCTTTCCA TGCCACGAGG ATCAACACAC 1980

ACTCCCACCC TTGGGTAGTA AGTGGTTGTT GTNAGTCGGT ACTTTACCAA AGCTTGAGCA 2040

ACCTCTTCAA GCTTGGGAAA GGGCCGCAAA AAGGCATTAG GAGGGGAG 2088

(2) INFORMATION FOR SEQ ID NO: 65: (l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 5 amino acids

(B) TYPE: ammo acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 65: Lys Lys Lys Arg Gin 1 5

(2) INFORMATION FOR SEQ ID NO: 66:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 23 base pairs (B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (ix) FEATURE: (A) NAME/KEY: Inosine

(B) LOCATION: Positions 3, 6, 9

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 66: GCNTCNGTNA AGAACTTYCA GMT 23

(2) INFORMATION FOR SEQ ID NO: 67: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 26 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA

(ix) FEATURE:

(A) NAME/KEY: Inosine

(B) LOCATION: Positions 6, 8, 9, 12, 15, 21

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 67: CTKSWNANNS MNATNGCRAA NGCYTG 26

Claims

WHAT IS CLAIMED IS:

1. A purified polypeptide composition comprising at least 50 weight % of the protein present as a mammalian TULP protein or a fragment thereof.

2. A purified polypeptide according to Claim 1, wherein said polypeptide comprises a loss of function mutation.

3. A purified polypeptide according to Claim 1, wherein said mammalian TULP protein is selected from the group consisting of SEQ ID NO:10; SEQ ID NO:13; SEQ ID N0:15; SEQ ID N0:17; SEQ ID N0:19; SEQ ID NO:58; SEQ ID NO:60; SEQ ID NO: 62.

4. A DNA molecule or fragment thereof of at least about 18 nucleotides as part of other than a naturally occurring chromosome, comprising a sequence encoding a protein according to any of claims 1 to 3, or a complement thereof.

5. A DNA molecule according to Claim 4, comprising a DNA sequence selected from the group consisting of SEQ ID NO: 9; SEQ ID NO:12; SEQ ID NO:14; SEQ ID N0:16; SEQ ID N0:18; SEQ ID NO:56; SEQ ID NO: 57; SEQ ID NO:59; SEQ ID NO: 61; SEQ ID NO: 63 and SEQ ID NO: 64.

6. An isolated DNA molecule according to any of claims 4 to 5, wherein said DNA molecule comprises a transcriptional initiation region

5' to said sequence encoding a mammalian TULP protein.

7. A cell comprising a DNA composition according to any of claims 4 to 6.

8. An array of oligonucleotides comprising one or more sequences according to any of claims 4 to 6.

9. An isolated DNA comprising the sequence 5 ' to a mammalian TULP gene and further comprising a transcriptional control region.

10. A polypeptide fragment according to any of claims 1 to 3, wherein said polypeptide is capable of directing nuclear localization.

11. A method for detecting a predisposition to neurosensory defects in an individual, the method comprising: analyzing a nucleic acid of said individual for the presence of a TULP sequence according to any of claims 4 to 6 for the presence of a predisposing polymorphism; wherein the presence of said predisposing polymorphism is indicative of an increased susceptibility to said neurosensory defect.

12. A non-human transgenic animal model for TULP gene function comprising one of: (a) a knockout of a TULP gene; or

(a) an exogenous and stably transmitted TULP gene sequence according to any of claims 4 to 6.

13. A method of screening for biologically active agents that modulate TULP function, the method comprising: combining a candidate biologically active agent with any one of:

(a) a polypeptide according to any of claims 1 to 3;

(b) a cell according to claim 7; or

(c) an animal according to claim 12; and determining the effect of said agent on TULP function.

14. A probe comprising: a DNA molecule according to any of claims 4 to 6; and a detectable label.

15. A method of reducing expression of a TULP protein in a cell, the method comprising: contacting said cell with anti-sense nucleic acids that are complementary to a nucleic acid encoding a polypeptide according to any of claims 1 to 3.