CA2458872C - Human ubiquitin-conjugating enzyme - Google Patents

Abstract

Disclosed is a pharmaceutical composition for treating prostate cancer, the pharmaceutical composition comprising an antibody against human TMP-2 protein together with a pharmaceutically acceptable carrier. In one embodiment, the antibody is conjugated to a therapeutic moiety which can be a cytotoxic agent or a radioisotope.

Description

1 ' HUMAN UBIQUITIN-CONJUGATING ENZYME

This is a divisional application of Canadian Patent Application Serial No. 2,200,371 filed on March 19, 1997.

TECHNICAL FIELD

The present invention relates to a gene useful as an indicator in the prophylaxis, diagnosis and treatment of diseases in humans. More particularly, it relates to a novel human gene analogous to rat, inouse, yeast, nematode and known human genes, among others, and utilizable, after cDNA analysis thereof, chromosome mapping of cDNA and function analysis of cDNA, in gene diagnosis using said gene and in developing a novel therapeutic method. It should be understood that the expression "the invention" and the like encompasses the subject matter of both the parent and the divisional applications.

BACKGROUND ART

The genetic information of a liviing thing has been accumulated as sequences (DNA) of four bases, namely A, C, G
and T, which exist in cell nuclei. Said genetic information has been preserved for line preservation and ontogeny of each individual living thing.

In the case of human being, the number of said bases is said to be about 3 billion (3 x 10g) and supposedly there are 50 to 100 thousand genes therein. Such genetic information serves to maintain biological phenomena in that regulatory proteins, structural proteins and enzymes are produced via such route that mRNA is transcribed from a gene (DNA) and then translated into a protein. Abnormalities in said route from _..;
- --= : -CA 02458872 2004-03-23 .,..:_,...-_---`-'._ gene to protein translation are considered to be causative of abnormalities of life supporting systems, for example in cell proliferation and differentiation, hence causative of various diseases.

As a result of gene analyses so far made, a number of genes which may be expected to serve as useful materials in drug development, have been found, for example genes for various receptors such as insulin receptor and LDL receptor, genes involved in cell proliferation and differentiation and genes for metabolic enzymes such as proteases, ATPase and superoxide dismutases.

However, analysis of human genes and studies of the functions of the genes analyzed and of the relations between the genes analyzed and various diseases have been just begun and many points remain unknown. Further analysis of novel genes, analysis of the functions thereof, studies of the relations between the genes analyzed and diseases, and studies for applying the genes analyzed to gene diagnosis or for medicinal purposes, for instance, are therefore desired in the relevant art.

If such a novel human gene as mentioned above can be provided, it will be possible to analyze the level of expression thereof in each cell and the structure and function thereof and, through expression product analysis and other studies, it may become possible to reveal the pathogenesis of a disease associated therewith, for example a genopathy or cancer, or diagnose and treat said disease, for instance. It is an object of the present invention to provide such a novel human gene.

For attaining the above object, the present inventors made intensive investigations and obtained the findings mentioned below. Based thereon, the present invention has now been completed.

DISCLOSURE OF INVENTION

Thus, the present inventors synthesized cDNAs based on mRNAs extracted from various tissues, inclusive of human fetal brain, adult blood vessels and placenta, constructed libraries by inserting them into vectors, allowing colonies of Escherichia coli transformed with said libraries to form on agar medium, picked up colonies at random and transferred to 96-well micro plates and registered a large number of human gene-containing E.
coli clones.

Each clone thus registered was cultivated on a small size, DNA was extracted and purified, the four base-specifically terminating extension reactions were carried out by the dideoxy chain terminator method using the cDNA extracted as a template, and the base sequence of the gene was determined over about 400 bases from the 5' terminus thereof using an automatic DNA sequencer. Based on the thus-obtained base sequence information, a novel family gene analogous to known genes of animal and plant species such as bacteria, yeasts, nematodes, mice and humans was searched for.

The method of the above-mentioned cDNA analysis is detailedly described in the literature by Fujiwara, one of the present inventors [Fujiwara, Tsutomu, Saibo Kogaku (Cell Engineering), 14, 645-654 (1995)].

Among this group, there are novel receptors, DNA
binding domain-containing transcription regulating factors, signal transmission system factors, metabolic enzymes and so forth. Based on the homology of the novel gene of the present invention as obtained by gene analysis to the genes analogous thereto, the product of the gene, hence the function of the protein, can approximately be estimated by analogy.
Furthermore, such functions as enzyme activity and binding ability can be investigated by inserting the candidate gene into an expression vector to give a recombinant.

The present invention provides a pharmaceutical composition for treating prostate cancer, the pharmaceutical composition comprising an antibody against human TMP-2 protein together with a pharmaceutically acceptable carrier.
In one embodiment, the antibody is conjugated to a therapeutic moiety which can be a cytotoxic agent or a radioisotope.

According to the present invention, there are provided a novel human gene characterized by containing a nucleotide sequence coding for an amino acid sequence defined by SEQ ID NO:1, :4, :7, :10, :13, :16, :19, :22, :25, :28, :31, :34, :37 or 40, a human gene characterized s._ _. --...._._.-..__ _ ... .: õ ... .

._..J

by containing the nucleotide sequence defined by SEQ ID
NO:2, :5, :8, :11, :14, :17, :20, :23, :26, :29, :32, :35, :38 or :41, respectively coding for the amino acid sequence mentioned above, and a novel human gene characterized by the nucleotide sequence defined by SEQ
ID NO:3, :6, :9, :12, :15, :18, :21, :24, :27, :30, :33, :36, :39 or :42.

The symbols used herein for indicating amino acids, peptides, nucleotides, nucleotide sequences and so on are those recommended by IUPAC and IUB or in "Guide-line for drafting specifications etc. including nucleotide sequences or amino acid sequences" (edited by the Japanese Patent Office), or those in conventional use in the relevant field of art.

As specific examples of such gene of the present invention,.there may be mentioned genes deducible from the DNA sequences of the clones designated as "GEN-501D08", "GEN-080G01", "GEN-025F07", "GEN-076C09", "GEN-331G07", "GEN-163D09", "GEN-078D05TA13", "GEN-423A12", "GEN-092E10", "GEN-428B12", "GEN-073E07", "GEN-093E05"
and "GEN-077A09" shown later herein in Examples 1 to 11.
The respective nucleotide sequences are as shown in the sequence listing.

These clones have an open reading frame comprising nucleotides (nucleic acid) respectively coding - - - :- --_ ----.: _ .;.:::,_ _., ,.~.~:h.. ...w ~. ~=.:1.~....__.: -.=-: ..:'= =CA 02458872 2004-03-23 ...._-_'--'---`

for the amino acids shown in the sequence listing. Their molecular weights were calculated at the values shown later herein in the respective examples. Hereinafter, these human genes of the present invention are sometimes referred to as the designation used in Examples 1 to 11.
In the following, the human gene of the present invention is described in further detail.

As mentioned above, each human gene of the present invention is analogous to rat, mouse, yeast, nematode and known human genes, among others, and can be uti.lized in human gene analysis based on the information about the genes analogous thereto and in studying the function of the gene analyzed and the relation between the gene analyzed and a disease. It is possible to use said gene in gene diagnosis of the disease associated therewith and in exploitation studies of said gene for medicinal purposes.

The gene of the present invention is represented in terms of a single-stranded DNA sequence, as shown under SEQ ID N0:2. It is to be noted, however, that the present invention also includes a DNA sequence complementary to such a single-stranded DNA sequence and a component comprising both. The sequence of the gene of the present invention as shown under SEQ ID NO:3n - 1 (where n is an integer of 1 to 14) is merely an example .. ..
...CA 02458872 2004-03-23 -.7 -of the codon combination encoding the respective amino acid residues. The gene of the present invention is not limited thereto but can of course have a DNA sequence in which the codons are arbitrarily selected and combined for the respective amino acid residues. The codon selection can be made in the conventional manner, for example taking into consideration the codon utilization frequencies in the host to be used [Nucl. Acids Res., 9, 43-74 (1981)].

The gene of the present invention further includes DNA sequences coding for functional equivalents derived from the amino acid sequence mentioned above by partial amino acid or amino acid sequence substitution, deletion or addition. These polypeptides may be produced by spontaneous modification (mutation) or may be obtained by posttranslational modification or by modifying the natural gene (of the present invention) by a technique of genetic engineering, for example by site-specific mutagenesis [Methods in Enzymology, 154, p. 350, 367-382 (1987); ibid., 100, p. 468 (1983); Nucleic Acids Research, 12, p. 9441 (1984); Zoku Seikagaku Jikken Koza (Sequel to Experiments in Biochemistry) 1, "Idensi Kenkyu-ho (Methods in Gene Research) II", edited by the Japan Biochemical Society, p. 105 (1986)] or synthesizing mutant DNAs by a chemical synthetic technique such as the . :. .. . . _ . . . -. . :; .
---=------- - ----------õ -.:.._...:.... .:. _.. - - - --- 'CA 02458872 2004-03-23 _ .__::. . . . _:...:.

phosphotriester method or phosphoamidite method [J. Am.
Chem. Soc., 89, p. 4801 (1967); ibid., 91, p. 3350 (1969); Science, 150, p. 178 (1968); Tetrahedron Lett., 22, p. 1859 (1981); ibid., 24, p. 245 (1983)], or by utilizing the techniques mentioned above in combination.
The protein encoded by the gene of the present invention can be expressed readily and stably by utilizing said gene, for example inserting it into a vector for use with a microorganism and cultivating the microorganism thus transformed.

The protein obtained by utilizing the gene of the present invention can be used in specific antibody production. In this case, the protein producible in large quantities by the genetic engineering technique mentioned above can be used as the component-to serve as an antigen. The antibody obtained may be polyclonal or monoclonal and can be advantageously used in the purification, assay, discrimination or identification of the corresponding protein.

The gene of the present invention can be readily produced based on the sequence information thereof disclosed herein by using general genetic engineering techniques [cf. e.g. Molecular Cloning, 2nd Ed., Cold Spring Harbor Laboratory Press (1989); Zoku Seikagaku Jikken Koza, "Idenshi Kenkyu-ho I, II and III", ..
....... -- --- c : .CA 02458872 2004-03-23 .... ----------- - ._ __ edited by the Japan Biochemical Society (1986)].

This can be achieved, for example, by selecting a desired clone from a human cDNA library (prepared in the conventional manner from appropriate cells of origin in which the gene is expressed) using a probe or antibody specific to the gene of the present invention (e.g. Proc.
Natl. Acad. Sci. USA, 78, 6613 (1981); Science, 222, 778 (1983)].

The cells of origin to be used in the above method are, for example, cells or tissues in which the gene in question is expressed, or cultured cells derived therefrom. Separation of total RNA, separation and purification of mRNA, conversion to (synthesis of) cDNA, cloning thereof and so on can be carried out by conventional methods. cDNA libraries are also commer-cially available and such cDNA libraries, for example various cDNA libraries available from Clontech Lab. Inc.
can also be used in the above method.

Screening of the gene of the present invention from these cDNA libraries can be carried out by the conventional method mentioned above. These screening methods include, for example, the method comprising selecting a cDNA clone by immunological screening using an antibody specific to the protein produced by the corresponding cDNA, the technique of plaque or colony -------._--. . _ ... _ ..:. . ,..... ..;. _ .._.. . . _ .
...:....:..___:.._.,._._ ..,_:... - ----------...._..._...__..::..__=CA
02458872 2004-03-23 ------ ---`-`---'--...1 _ .._::....,.. .
...............:...

hybridization using probes selectively binding to the.
desired DNA sequence, or a combination of these. As regards the probe to be used here, a DNA sequence chemically synthesized based on the information about the DNA sequence of the present invention is generally used.
It is of course possible to use the gene of the present invention or fragments thereof as the proble.

Furthermore, a sense primer and an antisense primer designed based on the information about the partial amino acid sequence of a natural extract isolated and purified from cells or a tissue can be used as probes for screening.

For obtaining the gene of the present invention, the technique of DNA/RNA amplification by the PCR method [Science, 230, 1350-1354 (1984)] can suitably be employed. Particularly when the full-length cDNA can hardly be obtained from the library, the RACE method (rapid amplification of cDNA ends; Jikken Igaku (Experimental Medicine), 12 (6), 35-38 (1994)], in particular the 5'RACE method [Frohman, M. A., et al., Proc. Natl. Acad. Sci. USA, 85, 8998-9002 (1988)] is preferably employed. The primers to be used in such PCR
method can be appropriately designed based on the sequence information of the gene of the present invention as disclosed herein and can be synthesized by a CA 02458872 2004-03-23 .. . . . :.......... ... -- - --.. __ .. _. _. _.. ..:
. , :. ;.., - ..-....
-il-conventional method.

The amplified DNA/RNA fragment can be isolated and purified by a conventional method as mentioned above, for example by gel electrophoresis.

The nucleotide sequence of the thus-obtained gene of the present invention or any of various DNA
fragments can be determined by a conventional method, for example the dideoxy method [Proc. Nati. Acad. Sci. USA, 74, 5463-5467 (1977)] or the Maxam-Gilbert method [Methods in Enzymology, 65, 499 (1980)]. Such nucleotide sequence determination can be readily performed using a commercially available sequence kit as well.

When the gene of the present invention is used and conventional techniques of recombinant DNA technology [see e.g. Science, 224, p. 1431 (1984); Biochem. Biophys.

Res. Comm., 130, p. 692 (1985); Proc. Natl. Acad. Sci.
USA, 80, p. 5990 (1983) and the references cited above]
are followed, a recombinant protein can be obtained.
More detailedly, said protein can be produced by constructing a recombinant DNA enabling the gene of the present invention to be expressed in host cells, introducing it into host cells for transformation thereof and cultivating the resulting transformant.

In that case, the host cells may be eukaryotic or prokaryotic. The eukaryotic cells include vertebrate c::. = - -' :_--= .____ . _ .. -_ 3 ._. -.. _ :. - -CA 02458872 2004-03-23 -------- ` --cells, yeast cells and so on, and the vertebrate cells include, but are not limited to, simian cells named COS
cells [Cell, 23, 175-182 (1981)], Chinese hamster ovary cells and a dihydrofolate reductase-deficient cell line derived therefrom [Proc. Natl. Acad. Sci. USA, 77, 4216-4220 (1980)] and the like, which are frequently used.

As regards the expression vector to be used with vertebrate cells, an expression vector having a promoter located upstream of the gene to be expressed, RNA splicing sites, a polyadenylation site and a transcription termination sequence can be generally used.
This may further have an origin of replication as necessary. As an example of said expression vector, there may be mentioned pSV2dhfr [Mol. Cell. Biol., 1, 854 (1981)], which has the SV40 early promoter. As for the eukaryotic microorganisms, yeasts are generally and frequently used and, among them, yeasts of the genus Saccharomyces can be used with advantage. As regards the expression vector for use with said yeasts and other eukaryotic microorganisms, pAM82 [Proc. Natl. Acad. Sci.
USA, 80, 1-5 (1983)], which has the acid phosphatase gene promoter, for instance, can be used.

Furthermore, a prokaryotic gene fused vector can be preferably used as the expression vector for the gene of the present invention. As specific examples of . - . . . . .. . _ .: _ . . . .
-- = .
....,,,......CA 02458872 2004-03-23 " --`------------`.:__.-..:~...~W:~....--' said vector, there may be mentioned pGEX-2TK and pGEX-4T-2 which have a GST domain (derived from S. japonicum) with a molecular weight of 26,000.

Escherichia coli and Bacillus subtilis are generally and preferably used as prokaryotic hosts. When these are used as hosts in the practice of the present invention, an expression plasmid derived from a plasmid vector capable of replicating in said host organisms and provided in this vector with a promoter and the SD (Shine and Dalgarno) sequence upstream of said gene for enabling the expression of the gene of the present invention and further provided with an initiation codon (e.g. ATG) necessary for the initiation of protein synthesis is preferably used. The Escherichia coli strain K12, among others, is preferably used as the host Escherichia coli, and pBR322 and modified vectors derived therefrom are generally and preferably used as the vector, while various known strains and vectors can also be used.
Examples of the promoter which can be used are the tryptophan (trp) promoter, lpp promoter, lac promoter and PL/PR promoter.

The thus-obtained desired recombinant DNA can be introduced into host cells for transformation by using various general methods. The transformant obtained can be cultured by a conventional method and the culture _ CA 02458872 2004-03-23 ...:..---=---.-_.. . .. ._;'.._ leads to expression and production of the desired protein encoded by the gene of the present invention. The medium to be used in said culture can suitably be selected from among various media in conventional use according to the host cells employed. The host cells can be cultured under conditions suited for the growth thereof.

In the above manner, the desired recombinant protein is expressed and produced and accumulated or secreted within the transformant cells or extracellularly or on the cell membrane.

The recombinant protein can be separated and purified as desired by various separation procedures utilizing the physical, chemical and other properties thereof [cf. e.g. "Seikagaku (Biochemistry) Data Book II", pages 1175-1259, lst Edition, lst Printing, published June 23, 1980 by Tokyo Kagaku Dojin; Bio-chemistry, 25 (25), 8274-8277 (1986); Eur. J. Biochem., 163, 313-321 (1987)]. Specifically, said=procedures include, among others, ordinary reconstitution treatment, treatment with a protein precipitating agent (salting out), centrifugation, osmotic shock treatment, sonication, ultrafiltration, various liquid chromato-graphy techniques such as molecular sieve chromatography (gel filtration), adsorption chromatography, ion exchange chromatography, affinity chromatography and high-.:.. :: :...: .. . : .. . .. _. .. ... -....
CA 02458872 2004-03-23 ---'--- -15-performance liquid chromatography (HPLC), dialysis and combinations thereof. Among them, affinity chromato-graphy utilizing a column with the desired protein bound thereto is particularly preferred.

Furthermore, on the basis of the sequence information about the gene of the present invention as revealed by the present invention, for example by utilizing part or the whole of said gene, it is possible to detect the expression of the gene of the present invention in various human tissues. This can be performed by a conventional method, for example by RNA
amplification by RT-PCR (reverse transcribed-polymerase chain reaction) [Kawasaki, E. S., et al., Amplification of RNA, in PCR Protocol, A guide to methods and applications, Academic Press, Inc., San Diego, 21-27 (1991)], or by northern blotting analysis [Molecular Cloning, Cold Spring Harbor Laboratory (1989)], with good results.

The primers to be used in employing the above-mentioned PCR method are not limited to any particular ones provided that they are specific to the gene of the present invention and enable the gene of the present invention alone to be specifically amplified. They can be designed or selected apropriately based on the gene information provided by the present invention. They can CA 02458872 2006-09-22 .

have a partial sequence comprising about 20 to 30 nucleotides according to the established practice.
Suitable examples are as shown in Examples 1 to 11.

Thus, the present invention also provides primers and/or probes useful in specifically detecting such novel gene.

By using the novel gene provided by the present invention, it is possible to detect the expression of said gene in various tissues, analyze the structure and function thereof and, further, produce the human protein encoded by said gene in the manner of genetic-enginnering. These make it possible to analyze the expression product, reveal the pathology of a disease associated therewith, for example a genopathy or cancer, and diagnose and treat the disease.

The following drawings are referred to in the examples.

Fig. 1 shows the result obtained by testing the P14 kinase activity of NPIK in Example 9. Fig. 2 shows TM
the effect of Triton X-100 and adenosine on NPIK
activity.

EXAMPLES
The following examples illustrate the present invention in further detail.

Example 1 _CA
: _ ... ...: . , .:...._... .. : . 02458872 2004-03-23 GDP dissociation stimulator gene (1) Cloning and DNA sequencing of GDP dissociation stimulator gene mRNAs extracted from the tissues of human fetal brain, adult blood vessels and placenta were purchased from Clontech and used as starting materials.

cDNA was synthesized from each mRNA and inserted into the vector ).ZAPII (Stratagene) to thereby construct a cDNA library (Otsuka GEN Research Institute, Otsuka Pharmaceutical Co., Ltd.) Human gene-containing Escherichia coli colonies were allowed to form on agar medium by the in vivo excision technique [Short, J. M., et al., Nucleic Acids Res., 16, 7583-7600 (1988)]. Colonies were picked up at random and human gene-containing Escherichia coli clones were registered on 96-well micro plates. The clones registered were stored at -80 C.

Each of the clones registered was cultured overnight in 1.5 ml of LB medium, and DNA was extracted and purified using a model PI-100 automatic plasmid extractor (Kurabo). Contaminant Escherichia coli RNA was decomposed and removed by RNase treatment. The DNA was dissolved to a final volume of 30 l. A 2- l portion was used for roughly checking the DNA size and quantity using a minigel, 7 pl was used for sequencing reactions and the - = -`CA 02458872 2004-03-23 .--- .......:....... -.-'.-...._=_----'----^-=-----._._.:a----.....- - -.................,.-,,.-remaining portion (21 l) was stored as plasmid DNA at 4 C.

This method, after slight changes in the program, enables extraction of the cosmid, which is useful also as a probe for FISH (fluorescence in situ hybridization) shown later in the examples.

Then, the dideoxy terminator method of Sanger et al. [Sanger, F., et al., Proc. Natl. Acad. Sci. USA, 74, 5463-5467 (1977)] using T3, T7 or a synthetic oligonucleotide primer or the cycle suquence method [Carothers, A. M., et al., Bio. Techniques, 7, 494-499 (1989)] comprising the dideoxy chain terminator method plus PCR method was carried out. These are methods of terminating the extension reaction specifically to the four bases using a small amount of plasmid DNA (about 0.1 to 0. 5pg ) as a template.

The sequence primers used were FITC
(fluorescein isothiocyanate)-labeled ones. Generally, about 25 cycles of reaction were performed using Taq polymerase. The PCR products were separated on a polyacrylamide urea gel and the fluorescence-labeled DNA
fragments were submitted to an automatic DNA sequencer (ALFTM DNA Sequencer; Pharmacia) for determining the sequence of about 400 bases from the 5' terminus side of cDNA.

Since the 3' nontranslational region is high in heterogeneity for each gene and therefore suited for discriminating individual genes from one another, sequencing was performed on the 3' side as well depending on the situation.

The vast sum of nucleotide sequence information obtained from the DNA sequencer was transferred to a 64-bit DEC 3400 computer for homology analysis by the computer. In the homology analysis, a data base TM
(GenBank, EMBL) was used for searching according to the UWGCG FASTA program [Pearson, W. R. and Lipman, D. J., Proc. Natl. Acad. Sci. USA, 85, 2444-2448 (1988)].

As a result of arbitrary selection by the above method and of cDNA sequence analysis, a clone designated as GEN-501D08 and having a 0.8 kilobase insert was found to show a high level of homology to the C terminal region of the human Ral guanine nucleotide dissociation stimulator (Ra1GDS) gene. Since Ra1GDS is considered to play a certain role in signal transmission pathways, the whole nucleotide sequence of the cDNA insert portion providing the human homolog was further determined.
Low-molecular GTPases play an important role in transmitting signals for a number of cell functions including cell proliferation, differentiation and transformation [Bourne, H. R. et al., Nature, 348, 125-_ :....: .., .
:...__:,.._.._-_ . _ .,.._. :.:e, ~ ....., -.:CA 02458872 2004-03-23 . . -= ---- -:._..... . _ .

132 (1990); Bourne et al., Nature, 349, 117-127 (1991)].
It is well known that, among them, those proteins encoded by the ras gene family function as molecular switches or, in other words, the functions of the ras gene family are regulated by different conditions of binding proteins such as biologically inactive GDP-binding proteins or active GDP-binding proteins, and that these two conditions are induced by GTPase activating proteins (GAPs) or GDS. The former enzymes induce GDP

10. binding by stimulating the hydrolysis of bound GTP and the latter enzyme induces the regular GTP binding by releasing bound GDP [Bogusuki, M. S. and McCormick, F., Nature, 366, 643-654 (1993)].

Ra1GDS was first discovered as a member of the ras gene family lacking in transforming activity and as a GDP dissociation stimulator specific to RAS (Chardin, P.
and Tavitian, A., EMBO J., 5, 2203-2208 (1986); Albright, C. F., et al., EMBO J., 12, 339-347 (1993)].

In addition to Ral, Ra1GDS was found to function, through interaction with these proteins, as an effector molecule for N-ras, H-ras, K-ras and Rap [Spaargaren, M. and Bischoff, J. R., Proc. Nati. Acad.
Sci. USA, 91, 12609-12613 (1994)].

The nucleotide sequence of the cDNA clone designated as GEN-501D08 is shown under SEQ ID NO:3, the ......, ...,_ ._-.. __..-._... .. ,-CA 02458872 2004-03-23 nucleotide sequence of the coding region of said clone under SEQ ID NO:2, and the amino acid sequence encoded by said nucleotide sequence under SEQ ID NO:l.

This cDNA comprises 842 nucleotides, including an open reading frame comprising 366 nucleotides and coding for 122 amino acids. The translation initiation codon was found to be located at the 28th nucleotide residue.

Comparison between the Ra1GDS protein known among conventional databases and the amino acid sequence deduced from said cDNA revealed that the protein encoded by this cDNA is homologous to the C terminal domain of human RalGDS. The amino acid sequence encoded by this novel gene was found to be 39.5% identical with the C

terminal domain of Ra1GDS which is thought to be necessary for binding to ras.

Therefore, it is presumable, as mentioned above, that this gene product might interact with the ras family proteins or have influence on the ras-mediated signal transduction pathways. However, this novel gene is lacking in the region coding for the GDS activity domain and the corresponding protein seems to be different in function from the GDS protein. This gene was named human Ra1GDS by the present inventors.

(2) Northern blot analysis The expression of the Ra1GDS protein mRNA in normal human tissues was evaluated by Northern blotting using, as a probe, the human cDNA clone labeled by the random oligonucleotide priming method.

The Northern blot analysis was carried out with a human MTN blot (Human Multiple Tissue Northern blot;
Clontech, Palo Alto, CA, USA) according to the manufac-, turer's protocol.

Thus, the PCR amplification product from the above GEN-501D08 clone was labeled with [32P]-dCTP
(random-primed DNA labeling kit, Boehringer-Mannheim) for use as a probe.

For blotting, hybridization was performed overnight at 42 C in a solution comprising 50$

formamide/5 x SSC/50 x Denhardt's.solution/0.1$ SDS
(containing 100 pg/ml denatured salmon sperm DNA). After washing with two portions of 2 x SSC/0.01$ SDS at room temperature, the membrane filter was further washed three times with 0.1 x SSC/0.05* SDS at 50 C for 40 minutes.

An X-ray film (Kodak) was exposed to the filter at -70 C
for 18 hours.

As a result, it was revealed that a 900-bp transcript had been expressed in all the human tissues tested. In addition, a 3.2-kb transcript was observed specifically in the heart and skeletal muscle. The : :
:. CA 02458872 2004 03 23 .. . :. : _ ... ... . ... .. .. .

expression of these transcripts differing in size may be due either to alternative splicing or to cross hybridization with homologous genes.

(3) Cosmid clone and chromosome localization by FISH
FISH was performed by screening a library of human chromosomes cloned in the cosmid vector pWE15 using, as a probe, the 0.8-kb insert of the cDNA clone [Sambrook, J., et al., Molecular Cloning, 2nd Ed., pp.
3.1-3.58, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York (1989)].

FISH for chromosome assignment was carried out by the method of Inazawa et al. which comprises G-banding pattern comparison for confirmation [Inazawa, J., et al., Genomics, 17, 153-162 (1993)].

For use as a probe, the cosmid DNA (0.5 pg) obtained from chromosome screening and corresponding to GEN-501D08 was labeled with biotin-16-dUTP by nick translation.

To eliminate the background noise due to repetitive sequences, 0.5 l of sonicated human placenta DNA (10 mg/mi) was added to 9.5 pl of the probe solution.
The mixture was denatured at 80 C for 5 minutes and admixed with an equal volume of 4 x SSC containing 20t dextransulfate. Then, a denatured slide was sown with the hybridization mixture and, after covering with CA 02458872 2004-03-23 :. :. , :.o_..__.......

paraffin, incubated in a wet chamber at 37 C for 16 to 18 hours. After washing with 50% formamide/2 x SSC at 37 C
for 15 minutes, the slide was washed with 2 x SSC for 15 minutes and further with 1 x SSC for 15 minutes.

The slide was then incubated in 4 x SSC supple-mented with "1g Block Ace" (trademark; Dainippon Pharma-ceutical) containing avidin-FITC (5 g/ml) at 37 C for 40 minutes. Then, the slide was washed with 4 x SSC for 10 minutes and with 4 x SSC containing 0.05% Triton X-100 for 10 minutes and immersed in an antifading PPD solution [prepared by adjusting 100 mg of PPD (Wako Catalog No.
164-015321) and 10 ml of PBS(-) (pH 7.4) to pH 8.0 with 0.5 M Na2C03/0.5 M NaHCO3 (9:1, v/v) buffer (pH 9.0) and adding glycerol to make a total volume of 100 ml]

containing 1% DABCO [1% DABCO (Sigma) in PBS(-):glycerol 1:9 (v:v)], followed by counter staining with DAPI (4,6-diamino-2-phenylindole; Sigma).

With more than 100 tested cells in the metaphase, a specific hybridization signal was observed on the chromosome band at 6p2l.3, without any signal on other chromosomes. It was thus confirmed that the RalGDS
gene is located on the chromosome 6p21.3.

By using the novel human RalGDS-associated gene of the present invention as obtained in this example, the expression of said gene in various tissues can be ................ .. . -..

detected and the human Ra1GDS protein can be produced in the manner of genetic engineering. These are expected to enable studies on the roles of the expression product protein and ras-mediated signals in transduction pathways as well as pathological investigations of diseases in which these are involved, for example cancer, and the diagnosis and treatment of such diseases. Furthermore, it becomes possible to study the development and progress of diseases involving the same chromosomal translocation of the Ra1GDS protein gene of the present invention, for example tonic spondylitis, atrial septal defect, pigmentary retinopathy, aphasia and the like.

Example 2 Cytoskeleton-associated protein 2 gene (CKAP2 gene) (1) Cytoskeleton-associated protein 2 gene cloning and DNA sequencing cDNA clones were arbitrarily chosen from a human fetal brain cDNA library in the same manner as in Example 1 were subjected to sequence analysis and, as a result, a clone having a base sequence containing the CAP-glycine domain of the human cytoskeleton-associated protein (CAP) gene and highly homologous to several CAP
family genes was found and named GEN-080G01.

Meanwhile, the cytoskeleton occurs in the cytoplasm and just inside the cell membrane of eukaryotic ..... .

cells and is a network structure comprising complicatedly entangled filaments. Said cytoskeleton is constituted of microtubules composed of tubulin, microfilaments composed of actin, intermediate filaments composed of desmin and vimentin, and so on. The cytoskeleton not only acts as supportive cellular elements but also isokinetically functions to induce morphological changes of cells by polymerization and depolymerization in the fibrous system. The cytoskeleton binds to intracellular organelles, cell membrane receptors and ion channels and thus plays an important role in intracellular movement and locality maintenance thereof and, in addition, is said to have functions in activity regulation and mutual information transmission. Thus it supposedly occupies a very important position in physiological activity regulation of the whole cell. In particular, the relation between canceration of cells and qualitative changes of the cytoskeleton attracts attention since cancer cells differ in morphology and recognition response from normal cells.

The activity of this cytoskeleton is modulated by a number of cytoskeleton-associated proteins (CAPs).
One group of CAPs is characterized by a glycine motif highly conserved and supposedly contributing to associ-ation with microtubules [CAP-GLY domain; Riehemann, K.

.. ..:_... _.. - --= ---. .______. _. _ - - -; _ -= ------ .CA 02458872 2004-03-23 . _ . '. .. -=-..... -:'r_.._ . .

and Song, C., Trends Biochem. Sci., 18, 82-83 (1993)].
Among the members of this group of CAPs, there are CLIP-170, 150 kDa DAP (dynein-associated protein, or dynactin), D. melanoyaster GLUED, S. cerevisiae BIKl, restin [Bilbe, G., et al., EMBO J., 11, 2103-2113 (1992)]; Hilliker, C., et al., Cytogenet. Cell Genet., 65, 172-176 (1994)] and C. elegans 13.5 kDa protein [Wilson, R., et al., Nature, 368, 32-38 (1994)]. Except for the last two proteins, direct or indirect evidences have suggested that they could interact with microtublues.

The above-mentioned CLIP-170 is essential for the in vitro binding of endocytic vesicles to microtubules and colocalizes with endocytic organelles (Rickard, J. E. and Kreis, T. E., J. Biol. Chem., 18, 82-83 (1990); Pierre, P., et al., Cell, 70, 887-900 (1992)].
The above-mentioned dynactin is one of the factors constituting the cytoplasmic dynein motor, which functions in retrograde vesicle transport [Schroer, T. A.
and Sheetz, M. P., J. Cell Biol., 115, 1309-1318 (1991)]

or probably in the movement of chromosomes during mitosis [Pfarr, C. M., et al., Nature, 345, 263-265 (1990);
Steuer, E. R., et al., Nature, 345, 266-268 (1990);
Wordeman, L., et al., J. Cell Biol., 114, 285-294 (1991)].

_:___.: -__. ., , _,,._ . . .. ..... . . ..:..:_.._ . _.. .. . . . - .

GLUED, the Drosouhila homolog of mammalian dynactin, is essential for the viability of almost all cells and for the proper organization of some neurons (Swaroop, A., et al., Proc. Nati. Acad. Sci. USA, 84, 6501-6505 (1987); Holzbaur, E. L. P., et al., Nature, 351, 579-583 (1991)].

BIK1 interacts with microtubules and plays an important role in spindle formation during mitosis in yeasts (Trueheart, J., et al., Mol. Cell. Biol., 7, 2316-2326 (1987); Berlin, V., et al., J. Cell Biol., 111, 2573-2586 (1990)].

At present, these genes are classified under the term CAP family (CAPs).

As a result of database searching, the above-mentioned cDNA clone of 463-bp (excluding the poly-A
signal) showed significant homology in nucleotide sequence with the restin and CLIP-170 encoding genes.
However, said clone was lacking in the 5' region as compared with the restin gene and, therefore, the technique of 5' RACE [Frohman, M. A., et al., Proc. Natl.
Acad. Sci. USA, 85, 8998-9002 (1988)] was used to isolate this missing segment.

(2) 5' RACE (5' rapid amplification of cDNA ends) A cDNA clone containing the 5' portion of the gene of the present invention was isolated for analysis by the 5' RACE technique using a commercial kit (5'-Rapid TM
AmpliFinder RACE kit, Clontech) according to the manufacturer's protocol with minor modifications, as follows.

The gene-specific primer P1 and primer P2 used here were synthesized by the conventional method and their nucleotide sequences are as shown'below in Table 1.
The anchor primer used was the one attached to the commercial kit.

Table 1 Primer Nucleotide sequence Primer PI 5'-ACACCAATCCAGTAGCCAGGCTTG-3' Primer P2 5'-CACTCGAGAATCTGTGAGACCTACATACATGACG-3' cDNA was obtained by reverse transcription of 0.1 pg of human fetal brain poly(A)+RNA by the random hexamer technique using reverse transcriptase (SuperscriptTM II, Life Technologies) and the cDNA was amplified by the first PCR using the Plprimer and anchor primer according to Watanabe et al. [Watanabe, T., et al., Cell Genet., in press).

Thus, to 0.1 pg of the above-mentioned cDNA
were added 2.5 mM dNTP/1 x Taq buffer (Takara Shuzo)/0.2 TM
pM P1 primer, 0.2 pM adaptor primer/0.25 unit ExTaq enzyme (Takara Shuzo) to make a total volume of 50 }il, followed by addition of the anchor primer. The mixture -. , .... . - ..
: .: CA 02458872 2004-03-23 :...- . - - - - ------, .

was subjected to PCR. Thus, 35 cycles of amplification were performed under the conditions: 94 C for 45 seconds, 60 C for 45 seconds, and 72 C for 2 minutes. Finally, the mixture was heated at 72 C for 5 minutes.

Then, 1 l of the 50-Nl first PCR product was subjected to amplification by the second PCR using the specific nested P2 primer and anchor primer.. The second PCR product was analyzed by 1.5$ agarose gel electrophoresis.

Upon agarose gel electrophoresis, a single band, about 650 nucleotides in size, was detected. The product from this band was inserted into a vector (pT7Blue(R)T-Vector, Novagen) and a plurality of clones with an insert having an appropriate size were selected.

Six of the 5' RACE clones obtained from the PCR
product had the same sequence but had different lengths.
By sequencing two overlapping cDNA clones, GEN-080G01 and GEN-080G0149, the protein-encoding sequence and 5' and 3' flanking sequences, 1015 nucleotides in total length, were determined. Said gene was named cytoskeleton-associated protein 2 gene (CKAP2 gene).

The nucleotide sequence obtained from the above-mentioned two overlapping cDNA clones GEN-080G01 and GEN-080G0149 is shown under SEQ ID N0:6, the nucleotide sequence of the coding region of said clone . .,..,., .. . . .. . -... .. _ .
CA 02458872 2004-03-23 - - - - -. ---.. - - -..

under SEQ ID NO:5, and the amino acid sequence encoded by said nucleotide sequence under SEQ ID N0:4.

As shown under SEQ ID NO:6, the CKAP2 gene had a relatively.GC-rich 5' noncoding region, with incomplete triplet repeats, (CAG)4(CGG)4(CTG)(CGG), occurring at nucleotides 40-69.

ATG located at nucleotides 274-276 is the presumable start codon. A stop codon (TGA) was situated at nucleotides 853-855. A polyadenylation signal (ATTAAA) was followed by 16 nucleotides before the poly(A) start. The estimated open reading frame comprises 579 nucleotides coding for 193 amino acid residues with a calculated molecular weight of 21,800 daltons.

The coding region was further amplified by RT-PCR, to eliminate the possibility of the synthetic sequence obtained being a cDNA chimera.

(2) Similarity of CKAP2 to other CAPs While sequencing of CKAP2 revealed homology with the sequences of restin and CLIP-170, the homologous region was limited to a short sequence corresponding to the CAP-GLY domain. On the amino acid level, the deduced CKAP2 was highly homologous to five other CAPs in this domain.

CKAP2 was lacking in such other motif ....... . . ,_.:;. _ . -----~

characteristics of some CAPs as the alpha helical rod and zinc finger motif. The alpha helical rod is thought to contribute to dimerization and to increase the micro-tubule binding capacity [Pierre, P., et al., Cell, 70, 887-900 (1992)]. The lack of the alpha helical domain might mean that CKAP2 be incapable of homo or hetero dimer formation.

Paralleling of the CAP-GLY domains of these proteins revealed that other conserved residues other than glycine residues are also found in CKAP2. CAPs having a CAP-GLY domain are thought to be associated with the activities of cellular organelles and the interactions thereof with microtubules. Since it contains a CAP-GLY domain, as mentioned above, CKAP2 is placed in the family of CAPs.

Studies with mutants of Glued have revealed that the Glued product plays an important role in almost all cells [Swaroop, A., et al., Proc. Natl. Acad. Sci.
USA, 84, 6501-6505 (1987)] and that it has other neuron-specific functions in neuronal cells [Meyerowitz, E. M.
and Kankel, D. R., Dev. Biol., 62, 112-142 (1978)].
These microtubule-associated proteins are thought to function in vesicle transport and mitosis. Because of the importance of the vesicle transport system in neuronal cells, defects in these components might lead to ,.:=;~_r_:__.. ._ ._. -_... _ w. _.-_ -. . . --- -. :.
,_ -_-_-----' ---- CA 02458872 2004-03-23 aberrant neuronal systems.

In view of the above, CKAP2 might be involved in specific neuronal functions as well as in fundamental cellular functions.

(3) Northern blot analysis The expression of human CKAP2 mRNA in normal human tissues was examined by Northern blotting.in the same manner as in Example 1 (2) using the GEN-080G01 clone (corresponding to nucleotides 553-1015) as a probe.

As a result, in all the eight tissues tested, namely human heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas, a 1.0 kb transcript agreeing in size with the CKAP2 cDNA was detected. Said 1.0 kb transcript was expressed at significantly higher levels in heart and brain than in the other tissues examined. Two weak bands, 3.4 kb and 4.6 kb, were also detected in all the tissues examined.

According to the Northern blot analysis, the 3.4 kb and 4.6 kb transcripts might possibly be derived from the same gene coding for the 1.0 kb CKAP2 by alternative splicing or transcribed from other related genes. These characteristics of the transcripts may indicate that CKAP2 might also code for a protein having a CAP-GLY domain as well as an alpha helix.

(4) Cosmid cloning and chromosomal localization by ;..._ ---------- - -----......... .. .:::._~. ,.... _ =

direct R-banding FISH

Two cosmids corresponding to the CKAP2 cDNA
were obtained. These two cosmid clones were subjected to direct R-banding FISH in the same manner as in Example 1 (3) for chromosomal locus mapping of CKAP2.

For suppressing the background due to repetitive sequences, a 20-fold excessive amount of human Cot-I DNA (BRL) was added as described by Lichter et al.
[Lichter, P., et al., Proc. Natl. Acad. Sci. USA, 87, 6634-6638 (1990)]. A Provia 100 film (Fuji ISO 100; Fuji Photo Film) was used for photomicrography.

As a result, CKAP2 was mapped on chromosome bands 19q13.11-q13.12.

Two autosomal dominant neurological diseases have been localized to this region by linkage analysis:
CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) between the DNA markers D19S221 and D19S222, and FHM (familial hemiplegic migraine) between D19S215 and D19S216. These two diseases may be allelic disorders in which the same gene is involved (Tournier-Lasserve, E., et al., Nature Genet., 3, 256-259 (1993); Joutel, A., et al., Nature Genet., 5, 40-45 (1993)].

Although no evidence is available to support CKAP2 as a candidate gene for FHM or CADASIL, it is . _,.., - . ..: r . . :...:.... .. . - - ...
. - . - . .--:.=,.. -. -:. . -:. . . ._:.-: . -._._:r_ ; =..---:_.-.--.- ----.. . :. .. - _ _ -. .

conceivable that its mutation might lead to some or other neurological disease.

By using the novel human CKAP2 gene of the present invention as obtained in this example, it is possible to detect the expression of said gene in various tissues or produce the human CKAP2 gene in the manner of genetic engineering. Through these, it becomes possible to analyze the functions of the human CKAP2 system or human CKAP2, which is involved in diverse activities essential to cells, as mentioned above, to diagnose various neurological diseases in which said system or gene is involved, for example familial migraine, and to screen out and evaluate a therapeutic or prophylactic drug therefor.

Example 3 OTK27 gene (1) OTK27 gene cloning and DNA sequencing As a result of sequence analysis of cDNA clones arbitraily selected from a human fetal brain cDNA library in the same manner as in Example 1 (1) and database searching, a cDNA clone, GEN-025F07, coding for a protein highly homologous to NHP2, a yeast nucleoprotein [Saccharomyces cerevisiae; Kolodrubetz, D. and Burgum, A., YEAST, 7, 79-90 (1991)], was found and named OTK27.

Nucleoproteins are fundamental cellular consti-õ;_ ._..
: .. . . . , :.. CA 02458872 2004-03-23 ~.

tuents of chromosomes, ribosomes and so forth and are thought to play an essential role in cell multiplication and viability. The yeast nucleoprotein NHP2, a high-mobility group (HMG)-like protein, like HMG, has reportedly a function essential for cell viability [Kolodrubetz, D. and Burgum, A., YEAST, 7, 79-90 (1991)].
The novel human gene, OTK27 gene, of the present invention, which is highly homologous to the above-mentioned yeast NHP2 gene, is supposed to be similar in function.

The nucleotide sequence of said GEN-025F07 clone was found to comprise 1493 nucleotides, as shown under SEQ ID NO:9, and contain an open reading frame comprising 384 nucleotides, as shown under SEQ ID NO:8, coding for an amino acid sequence comprising 128 amino acid residues, as shown under SEQ ID NO:7. The initiation codon was located at nucleotides 95-97 of the sequence shown under SEQ ID N0:9, and the termination codon at nucleotides 479-481.

At the amino acid level, the OTK27 protein was highly homologous (38%) to NHP2. It was 83% identical with the protein deduced from the cDNA from Arabidonsis thaliana; Newman, T., unpublished; GENEMBL Accession No.
T14197).

(2) Northern blot analysis _._..<_. : ~ .

For examining the expression of human OTK27 mRNA in normal human tissues, the insert in the OTK27 cDNA was amplified by PCR, the PCR product was purified and labeled with [32P]-dCTP (random-primed DNA labeling kit, Boehringer Mannheim), and Northern blotting was performed using the labeled product as a probe in the same manner as in Example 1 (2).

As a result of the Northern blot analysis, two bands corresponding to possible transcripts from this gene were detected at approximately 1.6 kb and 0.7 kb.
Both sizes of transcript were expressed in all normal adult tissues examined. However, the expression of the 0.7 kb transcript was significantly reduced in brain and was of higher levels in heart, skeletal muscle and testicle than in other tissues examined.

For further examination of these two transcripts, eleven cDNA clones were isolated from a testis cDNA library and their DNA sequences were determined in the same manner as in Example 1 (1).

As a result, in six clones, the sequences were found to be in agreement with that of the 0.7 kb transcript, with a poly(A) sequence starting at around the 600th nucleotide, namely at the 598th nucleotide in two of the six clones, at the 606th nucleotide in three clones, and at the 613th nucleotide in one clone.

. -. .... ,..... .
-----------------~.

In these six clones, the "TATAAA" sequence was recognized at nucleotides 583-588 as a probable poly(A) signal. The upstream poly(A) signal "TATAAA" of this gene was recognized as little influencing in brain and more effective in the three tissues mentioned above than in other tissues. The possibility was considered that the stability of each transcript vary from tissue to tissue.

Results of zoo blot analysis indicated that this gene is well conserved also in other vertebrates.
Since this gene is expressed ubiquitously in normal adult tissues and conserved among a wide range of species, the gene product is likely to play an important physiological role. The evidence that yeasts lacking in NHP2 are nonviable suggests that the human homolog may also be essential to cell viability.

(3) Chromosomal localization of OTK27 by direct R-banding FISH

One cosmid clone corresponding to the cDNA
OTK27 was isolated from a total human genomic cosmid library (5-genome equivalent) using the OTK27 cDNA insert as a probe and subjected to FISH in the same manner as in Example 1 (3) for chromosomal localization of OTK27.

As a result, two distinct spots were observed on the chromosome band 12q24.3.

~

The OTK27 gene of the present invention can be used in causing expression thereof and detecting the OTK27 protein, a human nucleoprotein, and thus can be utilized in the diagnosis and pathologic studies of various diseases in which said protein is involved and, because of its involvement in cell proliferation and differentiation, in screening out and evaluating therapeutic and preventive drugs for cancer.

Example 4 OTK18 gene (1) OTK18 gene cloning and DNA sequencing Zinc finger proteins are defined as constituing a large family of transcription-regulating proteins in eukaryotes and carry evolutionally conserved structural motifs [Kadonaga, J. T., et al., Cell, 51, 1079-1090 (1987); Klung, A. and Rhodes, D., Trends Biol. Sci., 12, 464-469 (1987); Evans, R. M. and Hollenberg, S. M., Cell, 52, 1-3 (1988)].

The zinc finger, a loop-like motif formed by the interaction between the zinc ion and two residues, cysteine and histidine residues, is involved in the sequence-specific binding of a protein to RNA or DNA.
The zinc finger motif was first identified within the amino acid sequence of the Xenopus transcription factor IIIA [Miller, J., et al., EMBO J., 4, 1609-1614 (1986)].

The C2H2 finger motif is in general tandemly repeated and contains an evolutionally conserved inter-vening sequence of 7 or 8 amino acids. This intervening stretch was first identified in the Kruppel segmentation gene of Drosophila [Rosenberg, U. B., et al., Nature, 319, 336-339 (1986)]. Since then, hundreds of C2H2 zinc finger protein-encoding genes have been found in vertebrate genomes.

As a result of sequence analysis of cDNA clones arbitrarily selected from a human fetal brain cDNA
library in the same manner as in Example 1 (1). and database searching, several zinc finger structure-containing clones were identified and, further, a clone having a zinc finger structure of the Kruppel type was f ound .

Since this clone lacked the 5' portion of the transcript, plaque hybridization was performed with a fetal brain cDNA library using, as a probe, an appro-ximately 1.8 kb insert in the cDNA clone, whereby three clones were isolated. The nucleotide sequences of these were determined in the same manner as in Example 1 (1).
Among the three clones, the one having the largest insert spans 3,754 nucleotides including an open reading frame of 2,133 nucleotides coding for 711 amino acids. It was found that said clone contains a novel . . .- ......- -- a ..... . _ .: _.. . _.
= -. ~.- _ =....._ ' ..-..:1'_. -. ' . - - - . . . - _--_- -- .. . .. . . .. .
. .. . . ._- _.. . _. .. . . ...._. .... . .- -. . =. -' ~

~

human gene coding for a peptide highly homologous in the zinc finger domain to those encoded by human ZNF41 and the Drosophila Kruppel gene. This gene was named OTK18 gene (derived from the clone GEN-076C09).

The nucleotide sequence of the cDNA clone of the OTK18 gene is shown under SEQ ID N0:12, the coding region-containing nucleotide sequence under SEQ ID NO:11, and the predicted amino acid sequence encoded by said OTK18 gene under SEQ ID NO:10.

It was found that the amino acid sequence of OTK18 as deduced from SEQ ID N0:12 contains 13 finger motifs on its carboxy side.

(2) Comparison with other zinc finger motif-containing genes Comparison among OTK18, human ZNF41 and the Drosophila Kruppel gene revealed that each finger motif is for the most part conserved in the consensus sequence CXECGKAFXQKSXLX2HQRXH.

Comparison of the consensus sequence of the zinc finger motifs of OTK18 with those of human ZNF41 and the Drosophila Kruppel gene revealed that the Kruppel type motif is well conserved in the OTK18-encoded protein. However, the sequence similarities were limited to zinc finger domains and no significant homologies were found with regard to other regions.

_ . - ..Y... .._ _. , __ . ..... ...t... . . . -; : - . . _. _,....... . _ ...-,. .
:-:.... .-r __......_"_ __'= ___...-- .- . _..._ ___ __ __ _ _ _ _ _...___ r.:_>-.. :. . .. . ...............w.,...._....,....._..L..rs._.._. ...-_ .. ._. _... _:__:_'____ ~= -The zinc finger domain interacts specifically with the target DNA, recognizing an about 5 bp sequence to thereby bind to the DNA helix [Rhodes, D. and Kiug, A., Cell, 46, 123-132 (1986)].

Based on the idea that, in view of the above, the multiple module (tandem repetitions of zinc finger) can interact with long stretches of DNA, it is presumable that the target DNA of this gene product containing 13 repeated zinc finger units would be a DNA fragment with a length of approximately 65 bp.
(3) Northern blot analysis Northern blot analysis was performed as described in Example 1 (2) for checking normal human tissues for expression of the human OTK18 mRNA therein by amplifying the insert of the OTK18 cDNA by PCR, purifying the PCR product, labeling the same with [32P]-dCTP
(random-primed DNA labeling kit, Boehringer Mannheim) and using an MTN blot with the labeled product as a probe.

The results of Northern blot analysis revealed that the transcript of OTK18 is approximately 4.3 kb long and is expressed ubiquitously in various normal adult tissues. However, the expression level in the liver and in peripheral blood lymphocytes seemed to be lower than in other organs tested. ' (4) Cosmid cloning and chromosomal localization by .., . ,...,........ ,,.. r. .. . . .-. ._.. _, ~.-:. -. . .::-:. .. --._. ., .
, . . .

direct R-banding FISH

Chromosomal localization of OTK18 was carried out as described in Example 1 (3).

As a result, complete twin spots were identified with 8 samples while 23 samples showed an incomplete signal or twin spots on either or both homologs. All signals appeared at the q13.4 band of chromosome 19. No twin spots were observed on any other chromosomes.

The results of FISH thus revealed that this gene is localized on chromosomal band 19q13.4. This region is known to contain many DNA segments that hybridize with oligonucleotides corresponding to zinc finger domains [Hoovers, J. M. N., et al., Genomics, 12, 254-263 (1992)]. In addition, at least one other gene coding for a zinc finger domain has been identified in this region [Marine, J.-C., et al., Genomics, 21, 285-286 (1994)].

Hence, the chromosome 19q13 is presumably a site of grouping of multiple genes coding for transcription-regulating proteins.

When the novel human OTK18 gene provided by this example is used, it becomes possible to detect expression of said gene in various tissues and produce the human OTK18 protein in the manner of genetic engineering. Through these, it is possible to analyze the functions of the human transcription regulating protein gene system or human transcription regulating proteins, which are deeply involved in diverse activities fundamental to cells, as mentioned above, to diagnose various diseases with which said gene is associated, for example malformation or cancer resulting from a developmental or differentiation anomaly, and mental or nervous disorder resulting from a developmental anomaly in the nervous system, and further to screen out and evaluate therapeutic or prophylactic drugs for these diseases.

ExamDle 5 Genes encoding human 26S proteasome constituent P42 protein and P27 protein (1) Cloning and DNA sequencing of genes respectively encoding human 26S proteasome constituent P42 protein and P27 protein Proteasome, which is a multifunctional protease, is an enzyme occurring widely in eukaryotes from yeasts to humans and decomposing ubiquitin-binding proteins in cells in an energy-dependent manner.
=Structurally, said proteasome is constituted of 20S
proteasome composed of various constituents with a molecular weight of 21 to 31 kilodaltons and a group of . .............. ...,.
_- -- ~ .., --.. _ - -- -- ------PA700 regulatory proteins composed of various constituents with a molecular weight of 30 to 112 kilodaltons and showing a sedimentation coefficient of 22S and, as a whole, occurs as a macromolecule with a molecular weight of about 2 million daltons and a sedimentation coefficient of 26S [Rechsteiner, M., et al., J. Biol. Chem., 268, 6065-6068 (1993); Yoshimura, T., et al., J. Struct. Biol., 111, 200-211 (1993);

Tanaka, K., et al., New Biologist, 4, 173-187 (1992)].
Despite structural and mechanical analyses thereof, the whole picture of proteasome is not yet fully clear. However, according to studies using yeasts and mice in the main, it reportedly has the functions mentioned below and its functions are becoming more and more elucidated.

The mechanism of energy-dependent proteolysis in cells starts with selection of proteins by ubiquitin binding. It is not 20S proteasome but 26S proteasome that has ubiquitin-conjugated protein decomposing activity which is ATP-dependent [Chu-Ping et al., J.
Biol. Chem., 269, 3539-3547 (1994)]. Hence, human 26S
proteasome is considered to be useful in elucidating the mechanism of energy-dependent proteolysis.

Factors involved in the cell cycle regulation are generally short in half-life and in many cases they are subject to strict quantitative control. In fact, it has been made clear that the oncogene products Mos, Myc, Fos and so forth can be decomposed by 26S proteasome in an energy- and ubiquitin-dependent manner [Ishida, N., et al., FEBS.Lett., 324, 345-348 (1993); Hershko, A. and Ciechanover, A., Annu. Rev. Biochem., 61, 761-807 (1992)] and the importance of proteasone in cell cycle control is being recognized.

Its importance in the immune system has also been pointed out. It is suggested that proteasome is positively involved in class I major histocompatible complex antigen presentation [Michalek, M. T., et al., Nature, 363, 552-554 (1993)] and it is further suggested that proteasome may be involved in Alzheimer disease, since the phenomena of abnormal accumulation of ubiquitin-conjugated proteins in the brain of patients with Alzheimer disease [Kitaguchi, N., et al., Nature, 361, 530-532 (1988)]. Because of its diverse functions such as those mentioned above, proteasome attracts attention from the viewpoint of its utility in the diagnosis and treatment of various diseases.

A main function of 26S proteasome is ubiquitin-conjugated protein decomposing activity. In particular, it is known that cell cycle-related gene products such as oncogene products and cyclins, typically c-Myc, are degraded via ubiquitin-dependent pathways. It has also been observed that the proteasome gene is expressed abnormally in liver cancer cells, renal cancer cells, leukemia cells and the like as compared with normal cells [Kanayama, H., et al., Cancer Res., 51, 6677-6685 (1991)]
and that proteasome is abnormally accumulated in tumor cell nuclei. Hence, constituents of proteasome are expected to be useful in studying the mechanism of such canceration and in the diagnosis or treatment of cancer.

Also, it is known that the expression of proteasome is induced by interferon y and so on and is deeply involved in antigen presentation in cells [Aki, M., et al., J. Biochem., 115, 257-269 (1994)]. Hence, constituents of human proteasome are expected to be useful in studying the mechanism of antigen presentation in the immune system and in developing immunoregulating drugs.

Furthermore, proteasome is considered to be deeply associated with ubiquitin abnormally accumulated in the brain of patients with Alzheimer disease. Hence, it is suggested that constituents of human proteasome should be useful in studying the cause of Alzheimer disease and in the treatment of said disease.

In addition to the utilization of expectedly multifunctional proteasome as such in the above manner, - - ......w......a....i..i-tY ..+rn+M1/~..-_...Jw.~ rO::i[Y.tl...'li-:J"'Yr'..n..._ w.-ww..w+='ru'.s.a _:::J s..'f._ lJY :ff1=f.1M/f=~r.r.r.J..-._v-.rw...._ ... .. .. ... .... ..: ... .. !Ti...-ir,.v....

it is probably possible to produce antibodies using constituents of proteasome as antigens and use such antibodies in diagnosing various diseases by immunoassay.

Its utility in this field of diagnosis is thus also a focus of interest.

Meanwhile, a protein having the characteristics of human 26S proteasome is disclosed, for example in Japanese Unexamined Patent Publication No. 292964/1993 and rat proteasome constituents are disclosed in Japanese Unexamined Patent Publication Nos. 268957/1993 and 317059/1993. However, no human 26S proteasome constituents are known. Therefore, the present inventors made_a further search for human 26S proteasome constituents and successfully obtained two novel human 26S proteasome constituents, namely human 26S proteasome constituent P42 protein and human S26 proteasome constituent P27 protein, and performed cloning and DNA
sequencing of the corresponding genes in the following manner.

(1) Purification of human 26S proteasome constituents P42 protein and P27 protein Human proteasome was purified using about 100 g of fresh human kidney and following the method of purify-ing human proteasome as described in Japanese Unexamined Patent Publication No. 292964/1993, namely by column TM
chromatography using BioGel A-1.5 m (5 x 90 cm, Bio-Rad), hydroxyapatite (1.5 x 15 cm, Bio-Rad) and Q-Sepharose (1.5 x 15 cm, Pharmacia) and glycerol density gradient centrifugation.

The thus-obtained human proteasome was subjected to reversed phase high performance liquid chromatography (HPLC) using a Hitachi model'L6200 HPLC
TM
system. A Shodex RS Pak D4-613 (0.6 x 15 cm, Showa Denko) was used and gradient elution was performed with the following two solutions:

First solution: 0.06% trifluoroacetic acid;
Second solution: 0.05$ trifluoroacetic acid, 70t acetonitrile.

An aliquot of each eluate fraction was subjected to 8.5$ SDS-polyacrylamide electrophoresis under conditions of reduction with dithiothreitol. The P42 protein and P27 protein thus detected were isolated and purified.

The purified P42 and P27 proteins were respec-tively digested with 1 pg of trypsin in 0.1 M Tris buffer (pH 7.8) containing 2 M urea at 37 C for 8 hours and the partial peptide fragments obtained were separated by reversed phase HPLC and their sequences were determined by Edman degradation. The results obtained are as shown below in Table 2.

....----- _ _ _ _ _ ....._v.._- ._. ....... .. ... ... . . _ _ --- - ._.-_._._._._... _ ____---------._, Table 2 Partial protein Amino acid sequence P42 (1) VLNISLW

(2) TLMELLNQMDGFDTLHR
(3) AVSDFVVSEYXMXA
(4) EVDPLVYNX
(5) HGEIDYEAIVK
(6) LSXGFNGADLRNVXTEAGMFAIXAD

(7) MIMATNRPDTLDPALLRPGXL

(8) IHIDLPNEQARLDILK

(9) ATNGPRYVVVG

(10) EIDGRLK

(11) ALQSVGQIVGEVLK

(12) ILAGPITK

(13) XXVIELPLTNPELFQG

(14) VVSSSLVDK

(15) ALQDYRK

(16) EHREQLK

(17) KLESKLDYKPVR

P27 (1) LVPTR

(2) AKEEEIEAQIK
(3) ANYEVLESQK
(4) VEDALHQLHAR
(5) DVDLYQVR
(6) QSQGLSPAQAFAK
(7) AGSQSGGSPEASGVTVSDVQE
(8) GLLGXNIIPLQR

Y- r ^<n inn+ av.- : . --.: -.:"= ="='-= :-' ' -. ==r _...- CA 02458872 2004-03-23 -...._ .. _.. ... ... _.- _. . .. 'rr ' w ~.:.. .

(2) cDNA library screening, clone isolation and cDNA
nucleotide sequence determination As mentioned in Example 1 (1), the present inventors have a database comprising about 30,000 cDNA
data as constructed based on large-scale DNA sequencing using human fetal brain, arterial blood vessel and placenta cDNA libraries.

Based on the amino acid sequences obtained as mentioned above in (1), computer searching was performed with the FASTA program (search for homology between said amino acid sequences and the amino acid sequences estimated from the database). As regards P42, a clone (GEN-331G07) showing identity with regard to two amino acid sequences [(2) and (7) shown in table 2] was screened out and, as regards P27, a clone (GEN-163D09) showing identity with regard to two amino acid sequences [(1) and (8) shown in Table 2] was found.

For each of these clones, the 5' side sequence was determined by 5' RACE and the whole sequence was determined, in the same manner as in Example 2 (2).

As a result, it was revealed that the above-mentioned P42 clone GEN-331G07 comprises a 1,566-nucleotide sequence as shown under SEQ ID N0:15, inclusive of a 1,167-nucleotide open reading frame as shown under SEQ ID N0:14, and that the amino acid sequence encoded thereby is the one shown under SEQ ID
N0:13 and comprises 389 amino acid residues.

The results of computer homology search revealed that the P42 protein is significantly homologous to the AAA (ATPase associated with a variety of cellular activities) protein family (e.g. P45, TBP1, TBP7, S4, MSS1, etc.). It was thus suggested that it is a new member of the AAA protein family.

As for the P27 clone GEN-163D09, it was revealed that it comprises a 1,128-nucleotide sequence as shown under SEQ ID NO:18, including a 669-nucleotide open reading frame as shown under SEQ ID NO:17 and that the amino acid sequence encoded thereby is the one shown under SEQ ID N0:16 and comprises 223 amino acid residues.

As regards the P27 protein, homology search using a computer failed to reveal any homologous gene among public databases. Thus, the gene in question is presumably a novel gene having an unknown function.

Originally, the above-mentioned P42 and P27 gene products were both purified as regulatory subunit components of proteasome complex. Therefore, these are expected to play an important role in various biological functions through proteolysis, for example a role in energy supply through decomposition of ATP and, hence, they are presumably useful not only in studying the ------------------------------ -------------.

function of human 26S proteasome but also in the diagnosis and treatment of various diseases caused by lowering of said biological functions, among others.

Example 6 BNAP gene (1) BNAP gene cloning and DNA sequencing The nucleosome composed of DNA and histone is a fundamental structure constituting chromosomes in eukaryotic cells and is well conserved over borders among species. This structure is closely associated with the processes of replication and transcription of DNA.
However, the nucleosome formation is not fully understood as yet. Only certain specific factors involved in nucleosome assembly (NAPs) have been identified. Thus, two acidic proteins, nucleoplasmin and N1, are already known to facilitate nucleosome construction [Kleinschmidt, J. A., et al., J. Biol. Chem., 260, 1166-1176 (1985); Dilworth, S. M., et al., Cell, 51, 1009-1018 (1987)].

A yeast gene, NAP-I, was isolated using a mono-clonal antibody and recombinant proteins derived therefrom were tested as to whether they have nucleosome assembling activity in vivo.

More recently, a mouse NAP-I gene, which is a mammalian homolog of the yeast NAP-I gene was cloned ._._ ------------.. ------ _-_---.-------- ---- ...... ........

(Okuda, A.; registered in database under the accession number D12618). Also cloned were a mouse gene, DN38 [Kato, K., Eur. J. Neurosci., 2, 704-711 (1990)] and a human nucleosome assembly protein (hNRP) [Simon, H. U., et al., Biochem. J., 297, 389-397 (1994)]. It was shown that the hNRP gene is expressed in many tissues and is associated with T lymphocyte proliferation.

The present inventors performed sequence analysis of cDNA clones arbitrarily chosen from a human fetal brain cDNA library in the same manner as in Example 1 (1), followed by searches among databases and, as a result, made it clear that a 1,125-nucleotide cDNA clone (free of poly(A)), GEN-078D05, is significantly homologous to the mouse NAP-I gene, which is a gene for a nucleosome assembly protein (NAP) involved in nucleosome construction, a mouse partial cDNA clone, DN38, and hNRP.
Since said clone GEN-078D05 was lacking in the 5' region, 5' RACE was performed in the same manner as in Example 2 (2) to obtain the whole coding region. For this 5' RACE, primers P1 and P2 respectively having the nucleotide sequences shown below in Table 3.

Table 3 Primer Nucleotide sequence Primer P1 5'-TTGAAGAATGATGCATTAGGAACCAC-3' Primer P2 5'-CACTCGAGTGGCTGGATTTCAATTTCTCCAGTAG-3' - . ..__ ....._...,..-._ .:. ..
------....-..... - ........ .. . .. . ..., : :: _-r,. . ,.~. ~~, ,~. ~~ _._.
.... ...

After the first 5' RACE, a single band corresponding to a sequence length of 1,300 nucleotides was obtained. This product was inserted into pT7Blue(R) T-Vector and several clones appropriate in insert size were selected.

Ten 5' RACE clones obtained from two independent PCR reactions were sequenced and the longest clone GEN-078D05TA13 (about 1,300 nucleotides long) was further analyzed.

Both strands of the two overlapping cDNA clones GEN-078D05 and GEN-078D05TA13 were sequenced, whereby it was confirmed that the two clones did not yet cover the whole coding region. Therefore, a further second 5' RACE
was carried out. For the second 5' RACE, two primers, P3 and P4, respectively having the sequences shown below in Table 4 were used.

Table 4 Primer Nucleotide sequence Primer P3 5'-GTCGAGCTAGCCATCTCCTCTTCG-3' Primer P4 5'-CATGGGCGACAGGTTCCGAGACC-3' A clone, GEN-078D0508, obtained by the second 5' RACE was 300 nucleotides long. This clone contained an estimable initiation codon and three preceding in-frame termination codons. From these three overlapping clones, it became clear that the whole coding region comprises 2,636 nucleotides. This gene was named brain-specific nucleosome assembly protein (BNAP) gene.

The BNAP gene contains a 1,518-nucleotide open reading frame shown under SEQ ID N0:20. The amino acid encoded thereby comprises 506 amino acid residues; as shown under SEQ ID N0:19, and the nucleotide sequence of the whole cDNA clone of BNAP is as shown under SEQ ID
NO:21.

As shown under SEQ ID NO:21, the 5' noncoding region of said gene was found to be generally rich in GC.
Candidate initiation codon sequences were found at nucleotides Nos. 266-268, 287-289 and 329-331. These three sequences all had well conserved sequences in the vicinity of the initiation codons [Kozak, M., J. Biol.

Chem., 266, 19867-19870 (1991)].

According to the scanning model, the first ATG
(nucleotides Nos. 266-268) of the cDNA clone may be the initiation codon. The termination codon was located at nucleotides Nos. 1784-1786.

The 3' noncoding redion was generally rich in AT and two polyadenylation signals (AATAAA) were located at nucleotides Nos. 2606-2611 and 2610-2615, respectively.
The longest open reading frame comprised 1,518 nucleotides coding for 506 amino acid residues and the calculated molecular weight of the BNAP gene product was 57,600 daltons.

Hydrophilic plots indicated that BNAP is very hydrophilic, like other NAPs.

For recombinant BNAP expression and purification and for eliminating the possibility that the BNAP gene sequence might give three chimera clones in the step of 5' RACE, RT-PCR was performed using a sequence comprising nucleotides Nos. 326-356 as a sense primer and a sequence comprising nucleotides Nos. 1758-1786 as an antisenses primer.

As a result, a single product of about 1,500 bp was obtained and it was thus confirmed that said sequence is not a chimera but a single transcript.

(2) Comparison between BNAP and NAPs The amino acid sequence deduced from BNAP
showed 46$ identity and 65% similarity to hNRP.

The deduced BNAP gene product had motifs characteristic of the NAPs already reported and of BNAP.
In general, half of the C terminus was well conserved in humans and yeasts.

The first motif (domain I) is KGIPDYWLI (corres ponding to amino acid residues Nos. 309-317). This was observed also in hNRP (KGIPSFWLT) and in yeast NAP-I

(KGIPEFWLT).

----=- - - --=--._~ .............. _,... > ...__.._...__..._~s__..=- CA
02458872 2004~ 03=23, .,........,.,-.Y-~---...M........,._,...w...,..<..,..Y..,....,.x..r.,~,....Rr The second motif (domain II) is ASFFNFFSPP
(corresponding to amino acid residues Nos. 437-446) and this was expressed as DSFFNFFAPP in hNRP and as ESFFNFFSP
in yeast NAP-I.

These two motifs were also conserved in the deduced mouse NAP-I and DN38 peptides. Both conserved motifs were each a hydrophilic cluster, and the Cys in position 402 was also found conserved.

Half of the N terminus had no motifs strictly conserved from yeasts to mammalian species, while motifs conserved among mammalian species were found.

For instance, HDLERKYA (corresponding to amino acid residues Nos. 130 to 137) and IINAEYEPTEEECEW
(corresponding to amino acid residues Nos. 150-164), which may be associated with mammal-specific functions, were found strictly conserved.

NAPs had acidic stretches, which are believed to be readily capable of binding to histone or other basic proteins. All NAPs had three acidic stretches but the locations thereof were not conserved.

BNAP has no such three acidic stretches but, instead, three repeated sequences (corresponding to amino acid residues Nos. 194-207, 208-221 and 222-235) with a long acidic cluster, inclusive of 41 amino acid residues out of 98 amino acid residues, the consensus sequence being ExxKExPEVKxEEK (each x being a nonconserved, mostly hydrophobic, residue).

Furthermore, it was revealed that the BNAP
sequence had several BNAP-specific motifs. Thus, an extremely serine-rich doamin (corresponding to amino acid residues Nos. 24-72) with 33 (67%) of 49 amino acid residues being serine residues was found in the N-terminus portion. On the nucleic acid level, they were reflected as incomplete repetitions of AGC.

Following this serine-rich region, there appeared a basic domain (corresponding to amino acid residues Nos. 71-89) comprising 10 basic amino acid residues among 19 residues.

BNAP is supposed to be localized in the nucleus. Two possible signals localized in the nucleus were observed (NLSs). The first signal was found in the basic domain of BNAP and its sequence YRKKR (corres-ponding to amino acid residues Nos. 75-79) was similar to NLS (GRKKR) of Tat of HIV-1. The second signal was located in the C terminus and its sequence KKYRK
(corresponding to amino acid residues Nos. 502-506) was similar to NLS (KKKRK) of,the large T antigen of SV40.
The presence of these two presumable NLSs suggested the localization of BNAP in the nucleus. However the possibility that other basic clusters might act as NLSs could not be excluded.

BNAP has several phosphorylation sites and the activity of BNAP may be controlled through phosphoryla-tion thereof.

(3) Northern blot analysis Northern blot analysis was performed as described in Example 1 (2). Thus, the clone GEN-078D05TA13 (corresponding to nucleotides Nos. 323 to 1558 in the BNAP gene sequence) was amplified by PCR, the PCR

product was purified and labeled with [32P]-dCTP (random-primed DNA labeling kit, Boehringer Mannheim), and the expression of BNAP mRNA in normal human tissues was examined using an MTN blot with the labeled product as a probe.

As a result of Northern blot analysis, a 3.0 kb transcript of BNAP was detected (8-hour exposure) in the brain among eight human adult tissues tested, namely heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas and, after longer exposure (24 hours), a dim band of the same size was detected in the heart.

BNAP was found equally expressed in several sites of brain tested whereas, in other tissues, no signal was detected at all even after 72 hours of exposure. hNRP mRNA was found expressed everywhere in _.. _. _. . _,. . ,__ - . - .. .., __... _. _ . . ... ,..,. : ...,. .,. _:_:
:;:::-:.:.:, =. ...._ .... . - -- ._ .. ___._.. ... . ....__--_._. .........
_. . _ _ .
... . . .... . = ..-.. . _ -. :. : .-.:..- .... : . . .. .... .-. - - .... -..
..... ...r.,...,._._:r.._ _...=_. . . ...:..: --=---' -_ the human tissues tested whereas the expression of BNAP
mRNA was tissue-specific.

(4) Radiation hubrid mapping Chromosomal mapping of the BNAP clone was performed by means of radiation hibrid mapping [Cox, D.
R., et al., Science, 250, 245-250 (1990)].

Thus, a total human genome radiation hybrid clone (G3RH) panel was purchased from Research Genetics, Inc., AL, USA and PCR was carried out for chromosomal mapping analysis according to the product manual using two primers, Al and A2, respectively having the nucleotide sequences shown in Table 5.

Table 5 Primer Nucleotide sequence Al primer 5'-CCTAAAAAGTGTCTAAGTGCCAGTT-3' A2 primer 5'-TCAGTGAAAGGGAAGGTAGAACAC-3' The results obtained were analyzed utilizing softwares usable on the Internet [Boehnke, M., et al., Am. J. Hum. Genet., 46, 581-586 (1991)].

As a result, the BNAP gene was found strongly linked to the marker DXS990 (LOD = 1000, cR8000 = -0.00).
Since DXS990 is a marker localized on the chromosome Xq21.3-q22, it was established that BNAP is localized to the chromosomal locus Xq21.3-q22 where genes involved in several signs or symptoms of X-chromosome-associated mental retardation are localized.

The nucleosome is not only a fundamental chromosomal structural unit characteristic of eukaryotes but also a gene expression regulating unit. Several results indicate that genes with high transcription activity are sensitive to nuclease treatment, suggesting that the chromosome structure changes with the transcription activity [Elgin, S. C. R., J. Biol. Chem., 263, 19259-19262 (1988)].

NAP-I has been cloned in yeast, mouse and human and is one of the factors capable of promoting nucleosome construction in vivo. In a study performed on their sequences, NAPs containing the epitope of the specific antibody 4A8 were detected in human, mouse, frog, Drosophila and yeast (Saccharomyces cerevisiae) [Ishimi, Y., et al., Eur. J. Biochem., 162, 19-24 (1987)].

In these experiments, NAPs, upon SDS-PAGE
analysis, electrophoretically migrated to positions corresponding to a molecular weight between 50 and 60 kDa, whereas the recombinant BNAP slowly migrated to a position of about 80 kDa. The epitope of 4A8 was shown to be localized in the second, well-conserved, hydrophobic motif. And, it was simultaneously shown that the triplet FNF is important as a part of the epitope (Fujii-Nakata, T., et al., J. Biol. Chem., 267, 20980-20986 (1992)].

BNAP also contained this consensus motif in domain II. The fact that domain II is markedly hydrophobic and the fact that domain II can be recognized by the immune system suggest that it is probably presented on the BNAP surface and is possibly involved in protein-protein interactions.

Domain I, too, may be involved in protein-protein interactions. Considering that these are conserved generally among NAPs, though to a relatively low extent, it is conceivable that they must be essential for nucleosome construction, although the functional meaning of the conserved domains is still unknown.

The hNRP gene is expressed in thyroid gland, stomach, kidney, intestine, leukemia, lung cancer, mammary cancer and so on [Simon, H. U., et al., Biochem.
J., 297, 389-397 (1994)]. Like that, NAPs are expressed everywhere and are thought to be playing an important role in fundamental nucleosome formation.

BNAP may be involved in brain-specific nucleosome formation and an insufficiency thereof may cause neurological diseases or mental retardation as a result of deviated functions of neurons.

BNAP was found strongly linked to a marker on the X-chromosome q21.3-q22 where sequences involved in ------ . . ,.=:-.
CA 02458872 2004-03--23 ~

several symptoms of X-chromosome-associated mental retardation are localized. This center-surrounding region of X-chromosome was rich in genes responsible for a-thalassemia, mental retardation (ATR-X) or some other forms of mental retardation [Gibbons, R. J., et al., Cell, 80, 837-845 (1995)]. Like the analysis of the ATR-X gene which seems to regulate the nucleosome structure, the present inventors suppose that BNAP may be involved in a certain type of X-chromosome-linked mental retardation.

According to this example, the novel BNAP gene is provided and, when said gene is used, it is possible to detect the expression of said gene in various tissues and to produce the BNAP protein by the technology of genetic engineering. Through these, it is possible to study the brain nucleosome formation deeply involved, as mentioned above, in variegated activities essential to cells as well as the functions of cranial nerve cells and to diagnose various neurological diseases or mental retardation in which these are involved and screen out and evaluate drugs for the treatment or prevention of such diseases.

Example 7 Human skeletal muscle-specific ubiquitin-conjugating enzyme gene (UBE2G gene) ~

The ubiquitin system is a group of enzymes essential for cellular processes and is conserved from yeast to human. Said system is composed of ubiquitin-activating enzymes (UBAs), ubiquitin-conjugating enzymes (UBCs), ubiquitin protein ligases (UBRs) and 26S
proteasome particles.

Ubiquitin is transferred from the above-mentioned UBAs to several UBCs, whereby it is activated.
UBCs transfer ubiquitins to target proteins with or without the participation of UBRs. These ubiquitin-conjugated target proteins are said to induce a number of cellular responses, such as protein degradation, protein modification, protein translocation, DNA repair, cell cycle control, transcription control, stress responses, etc. and immunological responses [Jentsch, S., et al., Biochim. Biophys. Acta, 1089, 127-139 (1991); Hershko, A.
and Ciechanover, A., Annu. Rev. Biochem., 61, 761-807 (1992); Jentsch, S., Annu. Rev. Genet., 26, 179-207 (1992); Ciechanover, A., Cell, 79, 13-21 (1994)].

UBCs are key components of this system and seem to have distinct substrate specificities and modulate different functions. For example, Saccharomyces cerevisiae UBC7 is induced by cadmium and involved in resistance to cadmium poisoning jJungmann, J., et al., Nature, 361, 369-371 (1993)]. Degradation of MAT-a2 is ~

also executed by UBC7 and UBC6 [Chen, P., et al., Cell, 74, 357-369 (1993)].

The novel gene obtained in this example is UBC7-like gene strongly expressed in human skeletal muscle. In the following, cloning and and DNA sequencing thereof are described.

(1) Cloning and DNA sequencing of human skeletal muscle-specific ubiquitin-conjugating enzyme gene (UBE2G
gene) Following the same procedure as in Example 1 (1), cDNA clones were arbitrarily selected from a human fetal brain cDNA library and subjected to sequence analysis, and database searches were performed. As a result, a cDNA clone, GEN-423A12, was found to have a significantly high level of homology to the genes coding for ubiquitin-conjugating enzymes (UBCs) in various species.

Since said GEN-423A12 clone was lacking in the 5' side, 5' RACE was performed in the same manner as in Example 2 (2) to obtain an entire coding region.

For said 5' RACE, two primers, P1 and P2, respectively having the nucleotide sequences shown in Table 6 were used.

..----_..~_:..__.. _-~,,::.-:.._, .. . .:..............:: ,,.,...,M:::-.r:.;:.
., ..._ _'.: --- ----._=._...__.._~:_. :.,._..._ .,. : . .

~

Table 6 Primer Nucleotide sequence P1 primer 5'-TAATGAATTTCATTTTAGGAGGTCGG-3' P2 primer 5'-ATCTTTTGGGAAAGTAAGATGAGCC-3' The 5' RACE product was inserted into pT7Blue(R) T-Vector and clones with an insert proper in size were selected.

Four of the 5' RACE clones obtained from two independent PCR reactions contained the same sequence but were different in length.

By sequencing the above clones, the coding sequence and adjacent 5'- and 3'-flanking sequences of the novel gene were determined.

As a result, it was revealed that the novel gene has a total length of 617 nucleotides. This gene was named human skeletal muscle-specific ubiquitin-conjugating enzyme gene (UBE2G gene).

To exclude the conceivable possibility that this sequence was a chimera clone, RT-PCR was performed in the same manner as in Example 6 (1) using the sense primer to amplify said sequence from the human fetal brain cDNA library. As a result, a single PCR product was obtained, whereby it was confirmed that said sequence is not a chimera one.

The UBE2G gene contains an open reading frame of 510 nucleotides, which is shown under SEQ ID N0:23, the amino acid sequence encoded thereby comprises 170 amino acid residues, as shown under SEQ ID N0:22, and the nucleotide sequence of the entire UBE2G cDNA is as shown under SEQ ID N0:24.

As shown under SEQ ID NO:24, the estimable initiation codon was located at nucleotides Nos. 19-21, corresponding to the first ATG triplet of the cDNA clone.
Since no preceding in-frame termination codon was found, it was deduced that this clone contains the entire open reading frame on the following grounds.

Thus, (a) the amino acid sequence is highly homologous to S. cerevisiae UBC7 and said initiation codon agrees with that of yeast-UBC7, supporting said ATG

as such. (b) The sequence AGGATGA is similar to the consensus sequence (A/G)CCATGG around the initiation codon [Kozak, M., J. Biol. Chem., 266, 19867-19870 (1991)].

(2) Comparison in amino acid sequence between UBE2G and UBCs Comparison in amino acid sequence between UBE2G
and UBCs suggested that the active site cystein capable of binding to ubiquitin should be the 90th residue cystein. The peptides encoded by these genes seem to belong to the same family.

-_ _,.,_ .A=-.. .. .... ._. _...__.. -___-_._.__ ~ r ,. =

(3) Northern blot analysis Northern blot analysis was carried out as des-cribed in Example 1 (2). Thus, the entire sequence of UBE2G was amplified by PCR, the PCR product was purified and labeled with [32P]-dCTP (random-primed DNA labeling kit, Boehringer Mannheim) and the expression of UBE2G
mRNA in normal human tissues using the labeled product as a probe. The membrane used was an MTN blot.

As a result of the Northern blot analysis, 4.4 kb, 2.4 kb and 1.6 kb transcripts could be detected in all 16 human adult tissues, namely heart, brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, spleen, thyroid gland, urinary bladder, testis, ovary, small intestine, large intestine and peripheral blood leukocye, after 18 hours of exposure. Strong expression of these transcripts was observed in skeletal muscle.
(4) Radiation hybrid mapping Chromosomal mapping of the UBE2G clone was per-formed by radiation hybrid mapping in the same manner as in Example 6 (4).

The primers Cl and C4 used in PCR for chromosomal mapping analysis respectively correspond to nucleotides Nos. 415-435 and nucleotides Nos. 509-528 in the sequence shown under SEQ ID NO:24 and their nucleotide sequences are as shown below in Table 7.

...._ -,..: ._- __.
.._. :.__- :- :.. ,:. .... - : : . . . . . ,_..__ _.~ - . _...------- ------- -- ----------- -------------Y _,. .
------.. .

Table 7 Primer Nucleotide sequence Cl primer 5'-GGAGACTCACCTGCTAATGTT-3' C4 primer 5'-CTCAAAAGCAGTCTCTTGGC-3' As a result, the UBE2G gene was found linked to the markers D1S446 (LOD = 12.52, cR8000 = 8.60) and D1S235 (LOD = 9.14, cR8000 = 22.46). These markers are localized to the chromosome bands 1q42.13-q42.3.

UBE2G was expressed strongly in skeletal muscle and very weakly in all other tissues examined. All other UBCs are involved in essential cellular functions, such as cell cycle control, and those UBCs are expressed ubiquitously. However, the expression pattern of UBE2G
might suggest a muscle-specific role thereof.

While the three transcripts differing in size were detected, attempts failed to identify which corresponds to the cDNA clone. The primary structure of the UBE2G product showed an extreme homology to yeast UBC7. On the other hand, nematode UBC7 showed strong homology to yeast UBC7. It is involved in degradation of .25 the repressor and further confers resistance to cadmium in yeasts. The similarities among these proteins suggest that they belong to the same family.

It is speculated that UBE2G is involved in degradation of muscle-specific proteins and that a defect _ _--------.___..~,-n.r.,.:,...........-._-_.._... _. ... _. _ .,.
.._,._...,.,......w___.._.._... _ , ._..- ... . .. . . .

~ .. r in said gene could lead to such diseases as muscular dystrophy. Recently, another proteolytic enzyme, calpain 3, was found to be responsible for limb-girdle muscular dystrophy type 2A [Richard, I., et al., Cell, 81, 27-40 (1995)]. At the present, the chromosomal location of UBE2G suggests no significant relationship with any hereditary muscular disease but it is likely that a relation to the gene will be unearthed by linkage analysis in future.

In accordance with this example, the novel UBE2G gene is provided and the use of said gene enables detection of its expression in various tissues and production of the UBE2G protein by the technology of genetic engineering. Through these, it becomes possible to study the degradation of muscle-specific proteins deeply involved in basic activities variegated and essential to cells, as mentioned above, and the functions of skeletal muscle, to diagnose various muscular diseases in which these are involved and further to screen out and evaluate drugs for the treatment and prevention of such diseases.

Example 8 TMP-2 gene (1) TMP-2 gene cloning and DNA sequencing Following the procedure of Example 1 (1), cDNA

...,..__. .... .., . ............... . ... . . . .... .....--=---- --_ _.. . .
. , . - . ... ... .

clones were arbitrarily selected from a human fetal brain cDNA library and subjected to sequence analysis, and database searches were performed. As a result, a clone (GEN-092E10) having a cDNA sequence highly homologous to a transmembrane protein gene (accession No.: U19878) was found out.

Membrane protein genes have so far been cloned in frog (Xenopus laevis) and human. These are considered to be a gene for a transmembrane type protein having a follistatin module and an epidermal growth factor (EGF) domain (accession No.: U19878).

The sequence information of the above protein gene indicated that the GEN-092E10 clone was lacking in the 5' region, so that the a.gt10 cDNA library (human fetal brain 5'-STRETCH PLUS cDNA; Clontech) was screened using the GEN-092E10 clone as a probe, whereby a cDNA
clone containing a further 5' upstream region was isolated.

Both strands of this cDNA clone were sequenced, whereby the sequence covering the entire coding region became clear. This gene was named TMP-2 gene.

The TMP-2 gene was found to contain an open reading frame of 1,122 nucleotides, as shown under SEQ ID
N0:26, encoding an amino acid sequence of 374 residues, as shown under SEQ ID N0:25. The nucleotide sequence of ,.._. .._ . ._ _,... _. ._ _ .......... ... .... .. . . _: _ _- _:,_w~x: - rr__ ;
~_._...._. ... _. -___ _.....<,.--... _ . - _~ : -:_. .... __ . : .. _ >.:. -CA 02458872 2004-03-23 ' _ _._....._ _ the entire TMP-2 cDNA clone comprises 1,721 nucleotides, as shown under SEQ ID N0:27.

As shown under SEQ ID NO:27, the 5' noncoding region was generally rich in GC. Several candidates for the initiation codon were found but, according to the scanning model, the 5th ATG of the cDNA clone (bases Nos.
368-370) was estimated as the initiation codon. The termination codon was located at nucleotides Nos. 1490-1492. The polyadenylation signal (AATAAA) was located at nucleotides Nos. 1703-1708. The calculated molecular weight of the TMP-2 gene product was 41,400 daltons.
As mentioned above, the transmembrane genes have a follistatin module and an EGF domain. These motifs were also found conserved in the novel human gene of the present invention.

The TMP-2 gene of the present invention presumably plays an important role in.cell proliferation or intercellular communication, since, on the amino acid level, said gene shows homology, across the EGF domain, to TGF-a (transforming growth factor-a; Derynck, R., et al., Cell, 38, 287-297 (1984)], beta-cellulin [Igarashi, K. and Folkman, J., Science, 259, 1604-1607 (1993)], heparin-binding EGF-like growth factor [Higashiyama, S., et al., Science, 251, 936-939 (1991)] and schwannoma-derived growth factor (Kimura, H., et al., Nature, 348, 257-260 (1990)].

(2) Northern blot analysis Northern blot analysis was carried out as des-cribed in Example 1 (2). Thus, the clone GEN-092E10 was amplified by PCR, the PCR product was purified and labeled with [32P]-dCTP (random-primed DNA labeling kit, Boehringer Mannheim), and the expression of TMP-2 mRNA in normal human tissues was examined using an MTN blot with the labeled product as a probe.

As a result, high levels of expression were detected in brain and prostate gland. Said TMP-2 gene mRNA was about 2 kb in size.

According to the present invention, the novel human TMP-2 gene is provided and the use of said gene makes it possible to detect the expression of said.gene in various tissues or produce the human TMP-2 protein by the technology of genetic engineering and, through these, it becomes possible to study brain tumor and prostatic cancer, which are closely associated with cell proliferation or intercellular communication, as mentioned above, to diagnose these diseases and to screen out and evaluate drugs for the treatment and prevention of such diseases.

Example 9 Human NPIK gene (1) Human NPIK gene cloning and DNA sequencing ' Following the procedures of Example 1 and Example 2, cDNA clones were arbitrarily selected from=a human fetal brain cDNA library and subjected to sequence analysis, and database searches were performed. As a result, two cDNA clones highly homologous to the gene coding for an amino acid sequence conserved in phosphatidylinositol 3 and 4 kinases [Kunz, J., et al., Cell, 73, 585-596 (1993)] were obtained. These were named GEN-428B12c1 and GEN-428B12c2 and the entire sequences of these were determined as in the foregoing examples.

As a result, the GEN-428B12c1 cDNA clone and the GEN-428B12c2 clone were found to have coding sequences differing by 12 amino acid residues at the 5' terminus, the GEN-428B12c1 cDNA clone being longer by 12 amino acid residues.

The GEN-428B12c1 cDNA sequence of the human NPIK gene contained an open reading frame of 2,487 nucleotides, as shown under SEQ ID NO:32, encoding an amino acid sequence comprising 829 amino acid residues, as shown under SEQ ID NO:31. The nucleotide sequence of the full-length cDNA clone comprised 3,324 nucleotides as shown under SEQ ID NO:33.

The estimated initiation codon was located, as ...._ ... . .,,. . . . .. ...,. __ ...

shown under SEQ ID NO:33, at nucleotides Nos. 115-117 corresponding to the second ATG triplet of the cDNA
clone. The termination codon was located at nucleotides Nos. 2602-2604 and the polyadenylation signal (AATAAA) at Nos. 3305-3310.

On the other hand, the GEN-428812c2 cDNA
sequence of the human NPIK gene contained an open reading frame of 2,451 nucleotides, as shown under SEQ ID N0:29.
The amino acid sequence encoded thereby comprised 817 amino acid residues, as shown under SEQ ID N0:28. The nucleotide sequence of the full-length cDNA clone comprised 3,602 nucleotides, as shown under SEQ ID N0:30.

The estimated initiation codon was located, as shown under SEQ ID N0:30, at nucleotides Nos. 429-431 corresponding to the 7th ATG triplet of the cDNA clone.
The termination codon was located at nucleotides Nos.
2880-2882 and the polyadenylation signal (AATAAA) at Nos.
3583-3588.

(2) Northern blot analysis Northern blot analysis was carried out as des-cribed in Example 1 (2). Thus, the entire sequence of human NPIK was amplified by PCR, the PCR product was purified and labeled with [32P]-dCTP (random-primed DNA
labeling kit, Boehringer Mannheim), and normal human tissues were examined for expression of the human NPIK

= mRNA using the MTN blot membrane with the labeled product as a probe. .

As a result, the expression of the human NPIK
gene was observed in 16 various human adult tissues examined and an about 3.8 kb transcript and an about 5 kb one could be detected.

Using primer A having the nucleotide sequence shown below in Table 8 and containing the initiation codon of the GEN-428B12c2 cDNA and primer B shown in table 8 and containing the termination codon, PCR was Tm performed with Human Fetal Brain Marathon-Ready cDNA
(Clontech) as a template, and the nucleotide sequence of the PCR product was determined.

Table 8 Primer Nucleotide sequence Primer A 51-ATGGGAGATACAGTAGTGGAGC-3' Primer B 5'-TCACATGATGCCGTTGGTGAG-3' As a result, it was found that the human NPIK
mRNA expressed included one lacking in nucleotides Nos.
1060-1104 of the GEN-428B12c1 cDNA sequence (SEQ ID

N0:33) (amino acids Nos. 316-330 of the amino acid sequence under SEQ ID N0:31) and one lacking in nucleotides Nos. 1897-1911 of the GEN-428B12cl cDNA
sequence (SEQ ID N0:33) (amino acids Nos. 595-599 of the amino acid sequence under SEQ ID N0:31).

_ .------------__ _._.,_:__ , ._... .. . . -.-:._.

It was further revealed that polymorphism existed in this gene (428B12cl.fasta), as shown below in Table 9, in the region of bases Nos. 1941-1966 of the GEN-428B12c1 cDNA sequence shown under SEQ ID NO:33, whereby a mutant protein was encoded which resulted from the mutation of IQDSCEITT (amino acid residues Nos. 610-618 in the amino acid sequence (SEQ ID N0:31) encoded by .GEN-428B12c1) into YKILVISA.

Table 9 TGGATCAAGCCAATACAAGATTCTTGTGAA
llillllllll IIIIlI1lllilllll ICCATTTGGGAACAGGAGCGAGTGCCCCTTTGGATCAAGCC-ATACAAGATTCTTGTG--ATIACGACTGATAGTGGCATC
III II IIIIIIIIIIIIII
ATTTCGGCTGATAGTGGCATGATTGAACCAGTGGTCAATGCTGTGTCCATCCATCAGGTG

(3) Chromosomal mapping of human NPIK gene by FISH
Chromosomal mapping of the human NPIK gene was carried out by FISH as described in Example 1 (3).

As a result, it was found that the locus of the human NPIK gene is in the chromosomal position 1q21.1-q21.3.

The human NPIK gene, a novel human gene, of the present invention included two cDNAs differing in the 5' region and capable of encoding 829 and 817 amino acid _ ..._.,...:_,.:.. . ,__._.,........_ residues, as mentioned above. In view of this and further in view of the findings that the mRNA corres-ponding to this gene includes two deletable sites and there occurs polymorphism in a specific region corres-ponding to amino acid residues Nos. 610-618 of the GEN-428B12c1 amino acid sequence (SEQ ID N0:31), whereby a mutant protein is encoded, it is conceivable that human NPIK includes species resulting from a certain number of combinations, namely human NPIK, deletion-containing human NPIK, human NPIK mutant and/or deletion-containing human NPIK mutant.

Recently, several proteins belonging to the family including the above-mentioned P13 and 4 kinases have protein kinase activity [Dhand, R., et al., EMBO J., 13, 522-533 (1994); Stack, J. H. and Emr, S. D., J. Biol.
Chem., 269, 31552-31562 (1994); Hartley, K. 0., et al., Cell, 82, 848-856 (1995)].

It was also revealed that a protein belonging to this family is involved in DNA repair [Hartley, K. 0., et al., Cell, 82, 849-856 (1995)] and is a causative gene of ataxia [Savitsky, K., et al., Science, 268, 1749-1753 (1995)].

It can be anticipated that the human NPIK gene-encoded protein highly homologous to the family of these PI kinases is a novel enzyme phosphorylating lipids or ..,., -. ._.. ., . .. :-- =-_-_=..,..----. ..... . .. .. .. .. _. .. . .
._.... .. . .

proteins.

According to this example, the novel human NPIK
gene is provided. The use of said gene makes it possible to detect the expression of said gene in various tissues and manufacture the human NPIK protein by the technology of genetic engineering and, through these, it becomes possible to study lipid- or protein-phosphrylating enzymes such as mentioned above, study DNA repairing, study or diagnose diseases in which these are involved, for example cancer, and screen out and evaluate drugs for the treatment or prevention thereof.

(4) Construction of an expression vector for fusion protein To subclone the coding region for a human NPIK
gene (GEN-428B12c2), first of all, two primers, Cl and C2, having the sequences shown below in Table 10 were formed based on the information on the DNA sequences obtained above in (1).

Table 10 Primer Nucleotide sequence Primer Cl 5'-CTCAGATCTATGGGAGATACAGTAGTGGAGC-3' Primer C2 5'-TCGAGATCTTCACATGATGCCGTTGGTGAG-3' Both of the primers Cl and C2 have a BglII

site, and primer C2 is an antisense primer.

Using these two primers, cDNA derived from human fetal brain mRNA was amplified by PCR to provide a product having a length of about 2500 bases. The amplified cDNA was precipitated from ethanol and inserted into pT7BlueT-Vector (product of Novagen) and subcloning was completed. The entire sequence was determined in the same manner as above in Examples. As a result, it was revealed that this gene had polymorphism shown above in Table 9.

The above cDNA was cleaved by BQlII and subjected to agarose gel electrophoresis. The cDNA was then excised from agarose gel and collected using GENECLEAN II KIT (product of Bio 101). The cDNA was inserted into pBlueBacHis2B-Vector (product of Invitrogen) at the BalII cleavage site and subcloning was completed.

The fusion vector thus obtained had a BglII
cleavage site and was an expression vector for a fusion protein of the contemplated gene product (about 91 kd) and 38 amino acids derived from pBlueBacHis2B-Vector and containing a polyhistidine region and an epitope recognizing Anti-XpressTM antibody (product of Invitrogen).

(5) Transfection into insect cell Sf-9 The human NPIK gene was expressed according to the Baculovirus expression system. Baculovirus is a cyclic double-stranded insect-pathogenic virus and can produce large amounts of inclusion bodies named polyhedrins in the cells of insects. Using Bac-N-B1ueTM
Transfection Kit utilizing this characteristic of Baculovirus and developed by Invitrogen, the Baculovirus expression was carried out.

Stated more specifically, 4 pg of pBlueBacHis2B
containing the region of the human NPIK gene and 1 pg of Bac-N-BlueTM DNA (product of Invitrogen) were co-transfected into Sf-9 cells in the presence of InsectinTM
liposomes (product of Invitrogen).

Prior to co-transfection, LacZ gene was incorporated into Bac-N-B1ueTM DNA, so that LacZ would be expressed only when homologous recombination took place between the Bac-N-BlueTM DNA and pBlueBacHis2B. Thus when the co-transfected Sf-9 cells were incubated on agar medium, the plaques of the virus expressing the contemplated gene were easily detected as blue plaques.

The blue plaques were excised from each agar and suspended in 400 ul of medium to disperse the virus thereon. The suspension was subjected to centrifugation to give a supernatant containing the virus. Sf-9 cells were infected with the virus again to increase the titre and to obtain a large amount of infective virus solution.

(6) Preparation of human NPIK

The expression of the contemplated human NPIK
gene was confirmed three days after infection with the virus as follows.

Sf-9 cells were collected and washed with PBS.
The cells were boiled with a SDS-PAGE loading buffer for 5 minutes and SDS-PAGE was performed. According to the TM
western blot technique using Anti-Xpress as an antibody, the contemplated protein was detected at the position of its presumed molecular weight. By contrast, in the case of control cells uninfected with the virus, no band corresponding to human NPIK was observed in the same test.

Stated more specifically, three days after the infection of 15 flasks (175-cm2, FALCON) of semi-confluent Sf-9 cells, the cells were harvested and washed with PBS, followed by resuspension in a buffer (20 mM
Tris/HC1 (pH 7.5), 1 mM EDTA and 1 mM DTT). The suspended cells were lysed by 4 time-sonications for 30 seconds at 4 C with 30 seconds intervals. The sonicated cells were subjected to centrifugation and the supernatant was collected. The protein in the supernatant was immunoprecipitated using an Anti-Xpress antibody and obtained as a slurry of protein A-Sepharose beads. The slurry was boiled with a SDS-PAGE loading buffer for 5 minutes. SDS-PAGE was performed for identification and quantification of NPIK. The slurry itself was subjected to the following assaying.

(7) Confirmation of P14 Kinase activity NPIK was expected to have the activity of incorporation phosphoric acid at the 4-position of the inositol ring of phosphatidylinositol (PI), namely, P14 Kinase activity.

P14 Kinase activity of NPIK was assayed according to the method of Takenawa, et al. (Yamakawa,-A.
and Takenawa, T., J. Biol. Chem., 263, 17555-17560 (1988)) as shown below.

First prepared was a mixture of 10 l of a NPIK
slurry (20 mM Tris/HCl (pH 7.5), 1 mM EDTA, 1 mM DTT and 50t protein A beads), 10 ul of a PI solution (prepared by drying 5 mg of a PI-containing commercial chloroform solution in a stream of nitrogen onto a glass tube wall, adding 1 ml of 20 mM Tris/HC1 (pH 7.5) buffer and forming micelles by sonication), 10 ul of an applied buffer (210 mM Tris/HC1 (pH 7.5), 5 mM EGTA and 100 mM MgCl2) and 10 l of distilled water. Thereto was added 10 l of an ATP
solution (5 l of 500 pM ATP, 4.9 ul of distilled water and 0.1 ul of y-32P ATP (6000 Ci/mmol, product of NEN
Co., Ltd.)). The reaction was started at 30 C and continued for 2, 5, 10 and 20 minutes. The time 10 minutes was set as incubation time because a straight---------------- -line increase was observed around 10 minutes in incorporation of phosphoric acid into PI in the assaying process described below.

After completion of the reaction, PI was fractionated by the solvent extraction method and finally re-suspended in chloroform. The suspension was developed by thin layer chromatography (TLC) and the radioactivity of the reaction product at the PI4P-position was assayed using an analyzer (trade name: Bio-Image; product of Fuji Photo Film Co., Ltd.).

Fig. 1 shows the results. Fig. 1 is an analytical diagram of the results of assaying the radioactivity based on TLC as mentioned above. The right lane (2) is the fraction of Sf-9 cell cytoplasm infected with the NPIK-containing virus, whereas the left lane (1) is the fraction of uninfected Sf-9 cell cytoplasm.

Also, predetermined amounts of Triton X-100 and adenosine were added to the above reaction system to check how such addition would affect the P14 Kinase activity. The P14 Kinase activity was assayed in the same manner as above.

Fig. 2 shows the results. The results confirmed that NPIK had a typical P14 Kinaze activity accelarated by Triton X-100 and inhibited by adenosine.

~,.:..,.s-------------- ------ --------Example 10 nel-related protein type 1 (NRP1) gene and nel-related protein type 2 (NRP2) gene (1) Cloning and DNA sequencing of NRP1 gene and NRP2 gene EGF-like repeats have been found in many membrane proteins and in proteins related to growth regulation and differentiation. This motif seems to be involved in protein-protein interactions.

Recently, a gene encoding nel, a novel peptide containing five EGF-like repeats, was cloned from a chick embryonic cDNA library [Matsuhashi, S., et al., Dev.
Dynamics, 203, 212-222 (1995)]. This product is considered to be a transmembrane molecule with its EGF-like repeats in the extracellular domain. A 4.5 kb transcript (nel mRNA) is expressed in various tissues at the embryonic stage and exclusively in brain and retina after hatching.

Following the procedure of Example 1 (1), cDNA
clones were randomly selected from a human fetal brain cDNA library and subjected to sequence analysis, followed by database searching. As a result, two cDNA clones with significantly high homology to the above-mentioned nel were found and named GEN-073E07 and GEN-093E05, respectively.

Since both clones were lacking in the 5' portion, 5' RACE was performed in the same manner as in Example 2 (2) to obtain the entire coding regions.

As for the primers for 5' RACE, primers having an arbitrary sequence obtained from the cDNA sequences of the above clones were synthesized while the anchor primer attached to a commercial kit was used as such.

5' RACE clones obtained from the PCR were sequenced and the sequences seemingly covering the entire coding regions of both genes were obtained. These genes were respectively named nel-related protein type 1 (NRP1) gene and nel-related protein type 2 (NRP2) gene.

The NRP1 gene contains an open reading frame of 2,430 nucleotides, as shown'under SEQ ID NO:35, the amino acid sequence deduced therefrom comprises 810 amino acid residues, as shown under SEQ ID N0:34, and the nucleotide sequence of the entire cDNA clone of said NRPI gene comprises 2,977 nucleotides, as shown under SEQ ID N0:36.

On the other hand, the NRP2 gene contains an open reading frame of 2,448 nucleotides, as shown under SEQ ID NO:38, the amino acid sequence deduced therefrom comprises 816 amino acid residues, as shown under SEQ ID
NO:37, and the nucleotide sequence of the entire cDNA
clone of said NRP2 gene comprises 3,198 nucleotides, as shown under SEQ ID NO:39.

...~:.-=__-_.._..,_______________. - .r.. . . . . .._ :" " ' .=%nrs':;t+r~r{,!'.-- -:. _.._. _.-_-==._._ _. .. . ..... _..___'__`-.._._.. ... ........ ... - -.._=-. _ _^_-'_' -__. ._ .....__ _ .._.......y._. . .. .. _ .. . ...__ _....-".-..-:.- __ _ .e... . _ . . . .

Furthermore, the coding regions were amplified by RT-PCR to exclude the possibility that either of the sequences obtained was a chimeric cDNA.

The deduced NRP1 and NRP2 gene products both showed highly hydrophobic N termini capable of func-tioning as signal peptides for membrane insertion. As compared with chick embryonic nel, they both appeared to have no hydrophobic transmembrane domain. Comparison among NRP1, NRP2 and nel with respect to the deduced peptide sequences revealed that NRP2 has 80$ homology on the amino acid level and is more closely related to nel than NRP1 having 504 homology. The cysteine residues in cysteine-rich domains and EGF-like repeats were found completely conserved.

The most remarkable difference between the NRPs and the chick protein was that the human homologs lack the putative transmembrane domain of nel. However, even in this lacking region, the nucleotide sequences of NRPs were very similar to that of nel. Furthermore, the two NRPs each possessed six EGF-like repeats, whereas nel has only five.

Other unique motifs of nel as reported by Matsuhashi et al. [Matsuhashi, S., et al., Dev. Dynamics, 203, 212-222 (1995)] were also found in the NRPs at equivalent positions. Since as mentioned above, it was shown that the two deduced NRP peptides are not transmembrane proteins, the NRPs might be secretory proteins or proteins anchored to membranes as a result of posttranslational modification.

The present inventors speculate that NRPs might function as ligands by stimulating other molecules such as EGF receptors. The present inventors further found that an extra EGF-like repeat could be encoded in nel upon frame shifting of the membrane domain region of nel.

When paralleled and compared with NRP2 and nel, the frame-shifted amino acid sequence showed similarities over the whole range of NRP2 and of nel, suggesting that NRP2 might be a human counterpart of nel. In contrast, NRP1 is considered to be not a human counterpart of nel but a homologous gene.

(2) Northern blot analysis Northern blot analysis was carried out as des-cribed in Example 1 (2). Thus, the entire sequences of both clones cDNAs were amplified by PCR, the PCR products were purified and labeled with [32P]-dCTP (random-primed DNA labeling kit, Boehringer Mannheim) and human normal tissues were examined for NRP mRNA expression using an MTN blot with the labeled products as two probes.

Sixteen adult tissues and four human fetal tissues were examined for the expression pattern of two NRPs.

As a result of the Northern blot analysis, it was found that a 3.5 kb transcript of NRP1 was weakly expressed in fetal and adult brain and kidney. A 3.6 kb transcript of NRP2 was strongly expressed in adult and fetal brain alone, with weak expression thereof in fetal kidney as well.

This suggests that NRPs might play a brain-specific role, for example as signal molecules for growth regulation. In addition, these genes might have a particular function in kidney.

(3) Chromosomal mapping of NRPl gene and NRP2 gene by FISH

Chromosomal mapping of the NRP1 gene and NRP2 gene was performed by FISH as described in Example 1 (3).
As a result, it was revealed that the chromosomal locus of the NRP1 gene is localized to llpl5.1-p15.2 and the chromosomal locus of the NRP2 gene to 12q13.11-q13.12.

According to the present invention, the novel human NRP1 gene and NRP2 gene are provided and the use of said genes makes it possible to detect the expression of said genes in various tissues and produce the human NRP1 and NRP2 proteins by the technology of genetic engineering. They can further be used in the study of --- ---------------- ---------the brain neurotransmission system, diagnosis of various diseases related to neurotransmission in the brain, and the screening and evaluation of drugs for the treatment and prevention of such diseases. Furthermore, the possibility is suggested that these EGF domain-containing NRPs act as growth factors in brain, hence they may be useful in the diagnosis and treatment of various kinds of intracerebral tumor and effective in nerve regeneration in cases of degenerative nervous diseases.

Example 11 GSPT1-related protein (GSPT1-TK) gene (1) GSPT1-TK gene cloning and DNA sequencing The human GSPT1 gene is one of the human homologous genes of the yeast GSTl gene that encodes the GTP-binding protein essential for the Gi to S phase transition in the cell cycle. The yeast GST1 gene, first identified as a protein capable of complementing a temperature-sensitive gstl (G1-to-S transition) mutant of Saccharomyces cerevisiae, was isolated from a yeast genomic library [Kikuchi, Y., Shimatake, H. and Kikuchi, A., EMBO J., 7, 1175-1182 (1988)] and encoded a protein with a target site of cAMP-dependent protein kinases and a GTPase domain.

The human GSPT1 gene was isolated from a KB
cell cDNA library by hybridization using the yeast GST1 gene as a probe [Hoshino, S., Miyazawa, H., Enomoto, T., Hanaoka, F., Kikuchi, Y., Kikuchi, A. and Ui, M., EMBO
J., 8, 3807-3814 (1989)]. The deduced protein of said GSPT1 gene, like yeast GST1, has a GTP-binding domain and a GTPase activity center, and plays an important role in cell proliferation.

Furthermore, a breakpoint for chromosome re-arrangement has been observed in the GSPT1 gene located in the chromosomal locus 16p13.3 in patients with acute nonlymphocytic leukemia (ANLL) [Ozawa, K., Murakami, Y., Eki, T., Yokoyama, K. Soeda, E., Hoshino, S. Ui, M. and Hanaoka, F., Somatic Cell and Molecular Genet., 18, 189-194 (1992)].

cDNA clones were randomly selected from a human fetal brain cDNA library and subjected to sequence analysis as described in Example 1 (1) and database searching was performed and, as a result, a clone having a 0.3 kb cDNA sequence highly homologous to the above-mentioned GSPT1 gene was found and named GEN-077A09. The GEN-077A09 clone seemed to be lacking in the 5' region, so that 5' RACE was carried out in the same manner as in Example 2 (2) to obtain the entire coding region.

The primers used for the 5' RACE were P1 and P2 primers respectively having the nucleotide sequences shown in Table 11 as designed based on the known cDNA

.... .... .......
,._.... . .
-,._.:__...._ ._.....

sequence of the above-mentioned cDNA, and the anchor primer used was the one attached to the commercial kit.
Thirtyfive cycles of PCR were performed under the following conditions: 94 C for 45 seconds, 58 C for 45 seconds and 72 C for 2 minutes. Finally, elongation reaction was carried out at 72 C for 7 minutes.
Table 11 Primer Nucleotide sequence P1 primer 5'-GATTTGTGCTCAATAATCACTATCTGAA-3' P2 primer 5'-GGTTACTAGGATCACAAAGTATGAATTCTGGAA-3' Several of the 5' RACE clones obtained from the above PCR were sequenced and the base sequence of that cDNA clone showing overlapping between the 5' RACE clones and the GEN-077A09 clone was determined to thereby reveal the sequence regarded as covering the entire coding region. This was named GSPT1-related protein "GSPT1-TK
gene".

The GSPT1-TK gene was found to contain an open reading frame of 1,497 nucleotides, as shown under SEQ ID
N0:41. The amino acid sequence deduced therefrom contained 499 amino acid residues, as shown under SEQ ID
N0:40.

The nucleotide sequence of the whole cDNA clone of the GSPT1-TK gene was found to comprise 2,057 nucleotides, as shown under SEQ ID N0:42, and the molecular weight was calculated at 55,740 daltons.
The first methionine code (ATG) in the open reading frame had no in-frame termination codon but this ATG was surrounded by a sequence similar to the Kozak consensus sequence for translational initiation.
Therefore, it was concluded that this ATG triplet occurring in positions 144-146 of the relevant sequence is the initiation codon.

Furthermore, a polyadenylation signal, AATAAA, was observed 13 nucleotides upstream from the polyadenylation site.

Human GSPT1-TK contains a glutamic acid rich region near the N terminus, and 18 of 20 glutamic acid residues occurring in this region of human GSPT1-TK are conserved and align perfectly with those of the human GSPT1 protein. Several regions (G1, G2, G3, G4 and G5) of GTP-binding proteins that are responsible for guanine nucleotide binding and hydrolysis were found conserved in the GSPT1-TK protein just as in the human GSPT1 protein.

Thus, the DNA sequence of human GSPT1-TK was found 89.4% identical, and the amino acid sequence deduced therefrom 92.4% identical, with the corresponding sequence of human GSPT1 which supposedly plays an important role in the G1 to S phase transition in the cell cycle. Said amino acid sequence showed 50.8%

identity with that of yeast GST1.
(2) Northern blot analysis Northern blot analysis was carried out as des-cribed in Example 1 (2). Thus, the GEN-077A09 cDNA clone was amplified by PCR, the PCR product was purified and labeled with [32P]-dCTP (random-primed DNA labeling kit, Boehringer Mannheim), and normal human tissues were examined for the expression of GSPT1-TK mRNA therein using an MTN blot with the labeled product as a probe.

As a result of the Northern blot analysis, a 2.7 kb major transcript was detected in various tissues.
The level of human GSPT1-TK expression seemed highest in brain and in testis.

(3) Chromosome mapping of GSPT1-TK gene by FISH

Chromosome mapping of the GSPT1-TK gene was performed by FISH as described in Example 1 (3).

As a result, it was found that the GSPT1-TK
gene is localized at the chromosomal locus 19p13.3. In this chromosomal localization site, reciprocal location has been observed very frequently in cases of acute lymphocytic leukemia (ALL) and acute myeloid leukemia (AML). In addition, it is reported that acute non-lymphocytic leukemia (ANLL) is associated with re-arrangements involving the human GSPT1 region [Ozawa, K., Murakami, Y., Eki, T., Yokoyama, K., Soeda, E., Hoshino, S., Ui, M. and Hanaoka, F., Somatic Cell and Molecular Genet., 18, 189-194 (1992)].

In view of the above, it is suggested that this gene is the best candidate gene associated with ALL and AML.

In accordance with the present invention, the novel human GSPT1-TK gene is provided and the use of said gene makes it possible to detect the expression of said gene in various tissues and produce the human GSPT1-TK

protein by the technology of genetic engineering. These can be used in the studies of cell proliferation, as mentioned above, and further make it possible to diagnose various diseases associated with the chromosomal locus of this gene, for example acute myelocytic leukemia. This is because translocation of this gene may result in decomposition of the GSPT1-TK gene and further some or other fused protein expressed upon said translocation may cause such diseases.

Furthermore, it is expected that diagnosis and treatment of said diseases can be made possible by producing antibodies to such fused protein, revealing the intracellular localization of said protein and examining its expression specific to said diseases. Therefore, it is also expected that the use of the gene of the present invention,makes it possible to screen out and evaluate drugs for the treatment and prevention of said diseases.

SEQUENCE LISTING
(1) GENERAL INFORMATION:

(i) APPLICANT: Tsutomu, FUJIWARA
Takeshi, WATANABE
Masato, HORIE
Toyomasa, KATAGIRI
(ii) TITLE OF INVENTION: HUMAN GENE
(iii) NUMBER OF SEQUENCES: 42 CORRESPONDENCE ADDRESS:
MARKS & CLERK
P.O.BOX 957 STATION B
OTTAWA, ONTARIO

(v) COMPUTER READABLE FORM:
(A) MEDIUM TYPE: Floppy disk (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS/MS-DOS
(D) SOFTWARE: PatentIn Release #1.0, Version #1.30 CURRENT APPLICATION DATA
APPLICATION NUMBER: 2458872 FILING DATE: 19-Mar-1997 CLASSIFICATION:

PRIOR APPLICATION DATA
APPLICATION NUMBER:
FILING DATE:
CLASSSIFICATION:

PATENT AGENT INFORMATION
NAME: MARKS & CLERK
REFERENCE NUMBER: 16487-9-DIV

(2) INFORMATION FOR SEQ ID NO:1:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 122 amino acids (B) TYPE: amino acid ... CA 02458872 2004-03-23 - - -(ii) MOLECULE TYPE: DNA(cDNA) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:

ATGGAGTI'GG GGAAGATGG CAGTGZCTAT AAGAOCATTT TOOIGACAAG CCAGGACAAG 60 GCTCCAAGrG TCAT~',AGZCG TGI'C7C;TTAAG AAAAACAATC GIGACPCI'GC AGPGOCPTCA 120 GAG'rATGAGC TGGTACAOCT GCTAOC',AGGG GAGOC'~A~f'~C TGACTATOOC AOOCTCOOCT 180 AATGTAT'PCT ACOCCATGGA TGC'aAGCTI'CA CAIOC',AT'I"I'OC TOC7lG~OC~OCA GOGGOCAAGG

ZCX.'iC.TAGTG C.TACACC70G aGI'CACCAGT GGOOOGTG7.'G CX,TC.AOGAAC
TOCPOOGA+C~P300 GAOGC'~GGAG GGOC~CTOf:'1T TO(X'.AGX"ATC AAGGOCACAG GGAOC'aAP,GAT TGCAC7GGGC'A

CTGriC 366 (2) INFORMATION FOR SEQ ID NO:3:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 842 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA(genomic) (iii) HYPOTHETICAL: NO

(iv) ANTI-SENSE: NO
(vii) IMMEDIATE SOURCE:
(A) LIBRARY: Human fetal brain cDNA library (B) CLONE: GEN-501D08 (ix) FEATURE:
(A) NAME/KEY: CDS
(B) LOCATION: 28..393 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:

CCCACGAGOC GTATCA4CCG AG'POC'AG ATG GAG TTG GGG GAA GAT GGC AGT 51 Met Glu Leu Gly Glu Asp Gly Ser Val Tyr Lys Ser Ile Lau Val Thr Ser Gln Asp Lys Ala Prro Ser Val ATC AGT UG`I' GTC CIT AAG AAA AAC AAT aGT GAC TCT GCA GTG GCT TCA 147 Ile Ser Arg Val Lau Lys Lys Asn Asn Arg Asp Ser Ala Val Ala Ser GAG TAT GAG CTG GTA CAG CTG CTA OC'A GGGG GAG OGA GAG CIG ACT ATC 195 Glu Tyr Glu L8u Val Gln Leu Leu Pro Gly Glu Arg Glu Leu Thr Ile aCA GOC TrJG GC.T AAT GTA TTC TAC QOC ATG GAT GGA GCT TCA CAC GAT 243 Pro Ala Ser A.la. Asn Val Phe Tyr Pro Met Asp Giy Ala Ser His Asp TTC CI'C CTG QOG CAG aGG OGA AOG TIJC TCT ACT GCT ACA aCT GOC GTC 291 Phe Leu Leu Asg Gln Arg Arg Arg Ser Ser Thr Ala Thr Pro Gly Val AOC AGT GGC CCG TCT GOC TCA GGA ACT OCT aCG AGr GAG GGA GGA GGG 339 Thr Ser Gly Pro Ser Ala Ser Gly Tbr Pro Pro Ser Giu Gly Gly Gly GGC. TOC TTT CCC AOG ATC AAG GfJC ACA GGG AGG AAG ATT GCA aGG GCA 387 Gly Ser Phe Pro Arg Ile Lys Ala Thr Gly Arg Lys Ile Ala Arg Ala CIG Tt^C TGAGGAGGAA OCOCI"PI'1'T TTTACAGAAGT CAT~'IGTTC ATACCAGATG 443 Leu Phe TGOGG'rAOCCA TaCIC`aAATGG TGGCAATTAT ATCACATTGA GACAGAAATT CAGkAAGGGA 503 GOCAGCCAiOC C'1GGGGCAGT GAAGTGOC'AC TGGITPAUCA GACAGCTGAG AAATCX',AOOC 563 CTGICGGAAC TGGI'GI'C,TPA TAAOC'.AA~siT OGATAUCIGT GTATAGGTIG CCACCTTCC'A 623 TGAGTGCAGC ACACAOGTAG TOCI'GGAAAA AOGCAZCAGP TPCZGF-T'IC,`I' TGGCC'ATATC 683 CTAACATGOA AOOGCC'.A11GC AAAGGCiT('A AOGCPCIY''AG CCCC',AGGGC:A GAGGOC'~ATG

GCAAAATGTA GGPCC`I'GGCA GGAGCTCT'IC TTCCCACTCP aGAGMITPCT ATCACPGTGA 803 CAAICACTAAG ATAATAAAOC AAAACACTAC CIC'7AATTCT 842 (2) INFORMATION FOR SEQ ID NO:4:

( i ) SEQUENCE QHP-RACTERISTICS:
(A) LENGPH : 193 amino acids ( B ) TYPE: amino acid ( D ) TOPOL4G'Y: linear (ii) MDLBCULE TYPE: protein ( xi. ) SEQUIINCE DESCRIPTION: SEQ ID PK): 4:

Met Glu Leu Glu Leu Tyr Gly Val Asp Asp Lys Phe Tyr Ser Lys Leu Asp Gln Glu Asp Ala Leu Leu Gly Ser Tyr Pro Val Asp Asp Gly Cys Arg Ile His Val Ile Asp His Ser Gly Ala Arg Leu Gly Glu Tyr Glu Asp Val Ser Arg Val Glu Lys Tyr Thr Ile Ser Gln Glu Ala Tyr Asp Gin Arg Gln Asp Thr Val Arrg Ser Phe Leu Lys Arg Ser Lys Leu Gly Arg Tyr Asn Giu Glu Glu Arg Ala Gln Gln Glu Ala Glu Ala Ala Gln Arg Leu Ala Glu Glu Lys Ala Gin Ala Ser Ser Ile Pro Vai Gly Ser Arg Cys Glu Val Arg Ala Ala Gly Gln Ser Pro Arg Arg Gly Thr Val Met Tyr Vai Gly Leu Thr Asp Phe Lys Pro Gly Tyr Trp Ile Gly Vai Arg Tyr Asp Glu Pro Ip-u Gly Lys Asn Asp Gly Ser Val Asn Giy Lys Arg Tyr Phe Glu Cys Gln Ala Lys Tyr Giy Ala Phe Val Lys Pro Ala Val Val Thr Val Gly Asp Phe Pro Glu Glu Asp Tyr Gly LSu Asp Glu Ile (2) INFORMATION FOR SEQ ID N0:5:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 579 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA(cDNA) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5:

ATGC'aAAiCI'GG AGCPGTATGG AGrPIGACGAC AAGTPCTACA GCAAGCPOGA TCAAGAGGAT 60 GOOLZ~OCICAG GCPaGTAOOC TGTAGATW GGC.'TOOOpC'A TC7C'AiOGPCAT TGACCACAG'r 120 GO~JG00f700C TTOQIG~PA ZG'A0GGAOOIG TOOCJOQOIC~G AiGAAGTAC~C GATCTCACAA 180 GAAGCCPAUG ACCAGAGGC'A AGACAOGGIC (70CIC'1TPOC TGAAGCGC',AG CAAOCTCGGC 240 CGGTAICAAOC' AGGAGGAGOG GGC'IPCAGCAG GAGGOOG.AOG CCGOOCAOOG CCiG000f"aAG 300 GAGAAGGOUC AOGOCAOCIC CATOOOOG'IG GOC'19OCOOC.'T GTGAQGTOOG GGOOOCGGC'aA 360 CAARti700C,'TC GOOGGGOCAC OGICATGPAT GTAOGt'CPCA CAGP-TPt'CAA GGC7POGCPAC 420 TGGA'PInGIG TUOC3CPATGA TGAGOC',AIC,ZG GGGAAAAATG ATGGCAGTGr GAATG3C'=AAA 480 aGC'PACT'I'OG AATGO('.AOOC CAAGTATG3C GOC'iTl'C~PCA AGOC,AGCAGT aGIC'~AIOGGIPG

f,GGGGF-CPI'CC OGGAGGAGC', CTACGGGPTG GAL7GGAGATA 579 (2) INFORMATION FOR SEQ ID NO:6:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 1015 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA(genomic) (iii) HYPOTHETICAL: NO

(iv) ANTI-SENSE: NO
(vii) IMMEDIATE SOURCE:
(A) LIBRARY: Human fetal brain cDNA library (B) CLONE: GEN-080G01 (ix) FEATURE:
(A) NAME/KEY: CDS

(B) LOCATION: 274..852 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6:

TGATZGG'7CA GGCACGC"aAOC AGGAGGOOGG CTGIATAGOOC AGCAGCAGCA GCGOOG70COG 60 QOGCt~G00C'~1 GOOOG'1C~lGA GOOOOC'1C1("aA QOOOGCPGCA GOCAT00GM GGCGOGOCAA 120 GATGGAGGTG AOGaGGG'I'GT CGGCACCAOG GTGA00 1TT TCATCAGCAG CTCOCICAGC 180 AOCT'l~OOOC'P COGAL''aAAGOG ATACAIG100GC AGOCPCAOCA TOOCt~GA[~IT CAAGTGTAAA

C'lGGAiGPTGC TGGTOGGC.AG aC)CTGC= Z'i0C ATG GAA CIG GAG CIPG TAT GGA 294 Met Glu Lau Glu Leu Tyr Gly G'1T GAC GAC AAG TTC TAC AOC AAG CTG GAT CAA GAG GAT GOG CTC GRG 342 Val Asp Asp Lys Phe Tyr Ser Lys Lau Asp Gin Glu Asp Ala Lau Leu GGC TCC TAC aCI' GTA GAT GAC GOC TOC QGC ATC CAC GZC ATT GAC CAC 390 Gly Ser Tyr Pro Val Asp Asp Gly Cys Arg Ile His Val Ile Asp His AGT GGC GCC CGC CiT GGT GAG TAT GAG GAC GTG TCC CGG GTG GAG AAG 438 Ser Gly Ala Arg Leu Gly Glu Tyr Glu Asp Val Ser Arg Val Glu Lys Tyr Thr Ile Ser Gln Glu Ala Tyr Asp Gin Arg Gln Asp Thr Val Arg Ser Phe Leu Lys Arg Ser Lys Leu Gly Arg Tyr Asn Glu Glu Glu Arg GCT CAG CAG GAG GOC GAG GOC GOC CAG CGC C'IG GOC GAG GAG AAG GOC 582, Ala Gin Gln Glu Ala Glu Ala Ala Gln Arg Leu Ala Glu Glu Lys Ala CAG GOC AOC TCC ATC COC GTG GOC AGC QOC TIaT GAG G'iG COG GOG GflG 630 Gln Ala Ser Ser Ile Pro Val Gly Ser Arg Cys Glu Val Arg Ala Ala Gly Gln Ser Pro Arg Ar+g Gly Thr Val. Met Tyr Val Gly Leu Thr Asp Phe Lys Pro Gly Tyr Trp Ile Gly Val Arg Tyr Asp Glu Pro ILeu Gly AAA AAT GAT GGC AGT GTG AAT GtflG AAA CGC TAC TTC GAA TGC CAG GOC 774 Lys Asn Asp Gly Ser Val Asn Gly Lys Arg Tyr Phe Glu Cys Gln Ala AAG TAT G{flC GCC TTT Gl'C AAG C7CA GCA GTC GTG ACG GIG GGG GAC TTC 822 Lys Tyr Gly Ala Phe Val Lys Pro Ala Val Val Thr Val Gly Asp Phe DOG GAG GAG GAC TAC GOG TTG GAC GAG ATA T('~"1lQCTAA GGAATPCCW 872 Pro Glu Glu Asp Tyr Gly Leu Asp Glu Ile OCACTGAM C70C(.'1~OC71C~P G1C~'TC~OOCAT OOOC'PT1R~C 932 TOCTTCAOCT aCTAG~CICAG

TO(."1C'aA000C ATTTTAAT'PP TATTCATTTT '1"1~OC1Ti'OOC ATTGATTTTP GA("aAC1CATG

(2) INFOBMTION FX)Z SEQ ID N0: 7:

( i ) SEXYJE24CE CHARACTERISTICS:
( A ) IEVGT'H: 128 aniro acids ( B ) TYPE : amino a.id ( D ) TOPOLOGY: linear (ii) MOLEQJLE TYPE: protein ( xi ) SEQUENCE DES(RIPTION: SP7Q ID N0: 7:

Met Thr Glu Ala Asp Val Asn Pro Lys Ala Tyr Pro Leu Ala Asp Ala His Leu Thr Lys Lys Leu Leu Asp Leu Val Gln Gln Ser Cys Asn Tyr Lys Gln Leu Arg Lys Gly Ala Asn Glu Ala Tthr Lys Thr Leu Asn Arg Gly Ile Ser Glu Phe Ile Val Met Ala Ala Asp Ala Glu Pro Leu Glu Ile Ile Leu His Leu Pro Leu Leu Cys Glu Asp Lys Asn Val Pro Tyr Val Phe Val Arg Ser Lys Gln Ala Leu Gly Arg Ala Cys Gly Val Ser Arg Pro Val Ile Ala Cys Ser Val Thr Ile Lys Glu Gly Ser Gin Leu Lys Gln Gln Ile Gln Ser Ile Gln Gln Ser Ile Glu Arg Leu Leu Val (2) INFORMATION FOR SEQ ID NO:8:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 384 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA(genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8:

ATGACTGAGG CTGATGIC'aAA TOCAAAGGOC TATOOOGR'Ir' OOCaAZGO0C.A OCICAC7CAAG 60 AAIX,'I'ACPGG ACCIC7GTTCA GCAGICATGT AACTATAAQC AOL'PInGC'AA AOGAGOCAAT 120 GAOG(7CAOCA AAACOCICAA CAGGGGCATC TCTGAGjTTCA TOQI'GATGGC TGCCAGACGOC 180 GAGCCAC:TOG AGATCATTCT GCAIOCI~OCX7G CTOCTGIv1G AAGACAAGAA TGPGOOCPAC 240 G1GTrT(:TGC GC'IC7CAAGCA GGOOC,ZC~~OOG AGl4GOCIGPG G(~GPCTOCAG GOCiCTCATC 300 GOC'I~CTC'AC('ATCAA A~'aAAGOC1POGG CAGiC'IGAAAC AGCAC'aATOCA ATOCAT'ICAG 360 (2) INFORMATION FOR SEQ ID N0:9:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 1493 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA(genomic) (iii) HYPOTHETICAL: NO

(iv) ANTI-SENSE: NO

(vii) IMMEDIATE SOURCE:
(A) LIBRARY: Human fetal brain cDNA library (B) CLONE: GEN-025F07 (ix) FEATURE:
(A) NAME/KEY: CDS
(B) LOCATION: 95..478 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9:

ATCOGTO'i~OC TTGOaQrOC.T GGGCAGCAGA COfOPCCAAW C7GACACGOG'P GG'TATO(.'TC(' 60 OOGI~GTOOOG CAAGAGAGTA CavrAcwA OOQP A7G AGT GAG GCT GAT GTG 112 Met Thr Glu Ala Asp Val AAT CCA AP-G GCC TAT CCC C3'T GOC GAT GOC CAC C'iC ACC A14G AAG CTA 160 Asn Pro Lys Ala Tyr Pro IQU Ala Asp Ala His Leu Thr Lys Lys Leu Lau Asp Leu Val Gln Gln Ser Cys Asn Tyr Lys Gln Leu Ar+g Lys Gly GOC AAT GAG GOC AOC AAA AUC CTC AAC AGG GGC ATC TCT GAG T'PC ATC 256 Ala Asn Glu Ala Thr Lys Thr Leu Asn Arg Gly Ile Ser Glu Prie Ile Val Met Ala Ala Asp Ala Glu Pro Leu Glu Ile Ile Leu His Leu Pro Leu Leu Cys Glu Asp Lys Asn Val Pro Tyr Val Phe Val Arg Ser Lys Gin Ala Leu Gly Azg Ala Cys Gly Val Ser Arg Pro Val Ile Ala Cys TCT GTC ACC ATC AAA GAA GGC TaG CAG CTG AAA CAG CAG ATC CAA TCC 448 Ser Val Thr Ile Lys Glu Gly Ser Gln Leu Lys Gln Gln Ile Gln Ser ATT CAG CAG TCC ATT GAA AGG CTC TTA GTC TAAACJC'IWG GCCPCIGCXA 498 Ile Gln Gln Ser Ile Glu Arg Leu Lau Val CG'I'GC'I'OCCT GOCAGCTTCC COOCTGAGGT 'PG'IGPA'ICAT ATTA'IC'IGIG TTAGCATGTA 558 GTATTTTOAG CTAC'IC,'ZCPA TPGITATAAA ATGTPuGTACT AAATCTGGIT 1. C1C~C',ATTTT 618 IUTGTTGM T'ITCPGiT TTACAOGM GCTATOOOOC TTOLTTTOGT OOCPOOCPCr 678 GOCATOCt*PC ATOCZ'PITAT OCIPOOCITi'P TOGAACAAGP GPI'CAGAGCA GAC'.AGAAGCA 738 GGGIGGIC'~GC AOOG'1'PGAAA GGC'AC'aAAAGA GOCAGGAiGAA AGCPGATGGA GOCAIDGACAG 798 AGAZCLGGTP OCApCTITCA GCICATAGCT T0.71WIVIG TGOGGC~GTGT GGPOCaAATTA 858 AACIAGCATTC ATTGTGZGIC IX,TG'i'GOCTC' GCACACAGAA TCATTCATAC GTGTICAAG'P 918 GATCAAOGGG TTPCAZTI"GC TG'PICXXOOC"aA TTAGGTATCA TT'iGGOGAGG AAGCATGTGT 978 TCTGT('aAOGT TGTTCX~OC,TA TGPOC'AA[3IG TOGI'lTACTA AZWAOOOC.T GCTGTIRuCT 1038 TITOGTAATG TGATG`ITC&T G2R~CI~OOOOC TAOOCACAAiC CATGOOCTIG AGGGTAOCAG 1098 GGCAGCAOC'.A TAOCAAAGAG AZG1C +C'IGCA GGACTCOGGA GOC'AOOCI'GG G'TGOGiC'~AIDC

CA.TGGGGCAG 7'1GAOGTOGG TCTIGAAAGA Gt'CGOGAGTG ACAPiGCZCAG AGAG(',ATGAA 1218 CIGAZGCPGf' CATGAAGGAT TGCAOGAAGA TCATGGAGAC CTGOGCPGGTA G.'I'G'PAACAG 1278 AIGATOGI+GG=P- G'IPOf',AAOGAA ACAOOCTGZC TC"IGGIGAAT GOGACP'ITCP
Tl'GGJ.'GGAICA 1338 CZTGGC'AOCA'GCI'CI'GAGAG C707rT0000T GPC~'IYJCTGOC ACCAZGTGOG TCAIGATGTAC 1398 TC7'CPGICAC ATGAOGGAGAU TGCPAGPI"CA TG'I'GI'TCTOC AZRCTI'GIC'~A GCATOCTAAT

AAATCPGI'TC CATTTZGAAA AAAAAAAAAA AAAAA . 1493 (2) INFOEMTION FUEt SDQ ID NO:10:

(1) SnQUIIVr'E CHARACTEPJWICS:
(A) LIIJGTfi: 711 amin4 acids ( B ) TYPE : amiryo acid ( D ) TOPOLOGY: linear ( ii ) MOLEC'1RE TYPE: protein ( xi ) SE7QUQICE DESCRIPTICN: SSQ ID N0:10:

Met Pro Ala Asp Val Asn Leu Ser Gln Lys Pro Gin Val. Leu Gly Pro Glu Lys Gln Asp Gly Ser Cys Glu Ala Ser Val Ser Phe Glu Asp Val 20 25 . 30 Thr Val Asp Phe Ser Arg Glu Glu Trp Gln Gln LSu Asp Pro Ala Gln Arg Cys Leu Tyr Arg Asp Val Met leu Glu Leu Tyr Ser His leu Phe Ala Val Gly Tyr His Ile Pro Asn Pro Glu Val Ile Phe Arg Met Leu Lys Glu Lys Glu Pro Axg Val Glu Glu Ala Glu Val Ser His Gln Arg Cys Gln Glu Arg Glu Phe Gly leu Glu Ile Pro Gln Lys Glu Ile Ser Lys Lys Ala Ser Phe Gln Lys Asp Met Val Gly Glu Phe Thr Arg Asp Gly Ser Trp Cys Ser Ile Leu Glu Glu Leu Arg Lau Asp Ala Asp. Arg Thr Lys Lys Asp Glu Gln Asn Gln Ile Gln Pro Met Ser His Ser Ala Phe Phe Asn Lys Lys Thr Leu Asn Thr Glu Ser Asn Cys Glu Tyr Lys Asp Pro Gly Lys Met Ile Arg Thr Arg Pro His Leu Ala Ser Ser Gin Lys Gin Pro Gln Lys Cys Cys leu Phe Thr Glu Ser Leu Lys Leu Asn L2u Glu Val Asn Gly Gln Asn Glu Ser Asn Asp Thr Glu Gin Leu Asp Asp Val Val Gly Ser Gly Gln Lau Phe Ser His Ser Ser Ser Asp Ala Cys Ser Lys Asn Ile His Thr Gly Glu Thr Pthe Cys Lys Gly Asn Gln Cys Arg Lys Val Cys Gly His Lys Gln Ser Lau Lys Gln His Gln Ile His Thr Gln Lys Lys Pro Asp Gly Cys Ser Glu Cys Gly Gly Ser Phe Thr Gln Lys Ser His Leu Phe Ala Gln Gln Arg Ile His Ser Val Gly Asn Lau His Glu Cys Gly Lys Cys Gly Lys Ala Phe Met Pro Gln Leu Lys Loeu Ser Val Tyr L$u Thr Asp His Thr Gly Asp Ile Pro Cys Ile Cys Lys Glu Cys Gly Lys Val Phe Ile Gln Arg Ser Glu Lau Leu Thr His Gln Lys Thr His Thr Arg Lys Lys Pro Tyr Lys Cys His Asp Cys Gly Lys Ala Phe Phe Gln Met Lsu Ser Leu Phe Arg His Gln Arg Thr His Ser Arg Glu Lys Lssu Tyr Glu Cys Ser Glu Cys Gly Lys Gly Phe Ser Gln Asn Ser Thr Leu Ile Ile His Gin Lys Ile His Thr Gly Glu Arg Gln Tyr Ala Cys Ser Glu Cys Gly Lys Ala Phe Thr Gin Lys Ser Thr Leu Ser Leu His Gln Arg Ile His Ser,Gly Gln Lys Ser Tyr Val Cys Ile Glu Cys Gly Gln Ala Phe Ile Gln Lys Ala His Leu Ile Val His Gln Arg Ser His Tlvc Gly Glu Lys Pro Tyr Gln Cys His Asn Cys Gly Lys Ser Phe Ile Ser Lys Ser Gln Lau Asp Ile His His Arg Ile His Thr Giy Glu Lys Pro Tyr Glu Cys Ser Asp Cys Gly Lys Thr Phe Thr Gln Lys Ser His Leu Asn Ile His Gln Lys Ile His Thr Giy Glu Arg His His Val Cys Ser Glu Cys Gly Lys Ala Phe Asn Gln Lys Ser Ile Leu Ser Met His Gln Arg Ile His Thr Gly Glu Lys Pro Tyr Lys Cys Ser Glu Cys Gly Lys Ala Phe Thr Ser Lys Ser Gln Phe Lys Glu His Gin Arg Ile His Thr Gly Glu Lys Pro ZYir Val Cys Thr Glu Cys Gly Lys Ala Phe Asn Gly Arg Ser Asn Phe His Lys His Gln Ile Thr His Thr Arg Glu Arg Pro Phe Val Cys Tyr Lys Cys Gly Lys Ala Phe 610 615 ' 620 Val Gin Lys Ser Glu Leu Ile Thr His Gin Arg Thr His Met Gly Glu Lys Pro TyrGlu Cys Leu Asp Cys Gly Lys Ser Phe Ser Lys Lys Pro Gin Leu Lys Val His Gln Arg Ile His Thr Gly Glu Arg Pro Tyr Val Cys Ser Glu Cys Gly Lys Ala Phe Asn Asn Arg Ser Asn Phe Asn Lys His Gln Tnr Tthr His Thr Arg Asp Lys Ser Tyr Lys Cys Ser Tyr Ser Val Lys Giy Phe T'hr Lys Gln (2)' INFORMATION FOR SEQ ID NO:11:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 2133 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA(genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11:

ATGOC.'ZbC1G ATGPGAATTT ATCO(',11GAAG CCPC,AOC'IYJC TGGGPOCAGA GAAGCAGGP-T 60 GGATCI"I'GOG AGGCA'ICAGP GTCA7TrGAG GAIOOIC'~AOCG TGGAC'PPCAG CAGGGAG("',~AG

TGGC'AGCAAC ZGGACCCTGC CC,A['~'aATGC CTGTAQOGGG ATGIGATGCT GGAGCZCTAT 180 AG(JCATCPCr TCGCAGTOOG GTA'1C'Af' ATT OOCp-ACCCAG AGGTCATGTT CAGAATCGC.'TA 240 AAAGAAAAGG AGOCCCGPGT GGAGGAGGCT GAAGTCPCAC ATCAGAC'G'IG TCAAGAAAGG 300 GAGTTI'OGOC T'iC'~AAATOOC ACAAAAQCaAG ATTTCrAAGA AAOCI'PCATT TCAAAAOGAT 360 ATaGTAOGIG AGT:rCACAAG AGATGGTTCA TC~~'QTTOCA TTTTAGAAGA ACI'GAOOCIG 420 GA7JaJIY'~iOC (OC',AL'AAAIGAA AGATGAGCAA AATC'AAATTC AAIOOC'ATC',AG
T'CACAG71i0CT 480 TT+CTTCAACA AOAAAACATT GAACACAI~'aAA AO('.AATZGPG AATATAAOGA OOC'POOGAAA 540 ATGAT'iCGCA C7C"~OOOf'A OCTi'C~CTTCT TCIACAC'~AAC AACCPG3GAA ATGlTOC,ZTA 600 TTTACAGAAA GPrTGAAOCT GAAC(.'TAGAA GTGAACOOPC AGAATGAAAO CAATGAC',ACA 660 GAAL:AGC.'TI'G ATGACOI'M TOOGT(,TGG'P CAGCTATTCA DOCATAOCTC TTCTGP~TOOC 720 TOC',A CAAd''aA ATATTCATAC AOGAGAGACA TTTTGCAAAG GTAACC'AQ1G TAGAAAAGI'C 780 ZCsT000C`ATA AAICAIGt'CALT ('AAQCAAC'AT CAAATTCATA C1'"CAGAAGAA AOCAGATOGA 840 Tt~t'ICTG~AAT OIC~OOOOC,Af CTTCA00('.AG AAGTCA('.AiOC T+C?I'1'IC~OOCA
ACAGAf'AATT 900 CATAGrGPAG GAAAL7CTOCA TGAATG'tGGC AAATGl'OGAA AAOOC.'TTCAT GOCACAAC'PA 960 AAACTCAGI'G TATA'I'C,"TGAIC AGATCATACA GGI'C'~ATATAC OCiC~TATATG CAAOGAATGT

OOC'~AAGGT(.'T TTATTCAGAG ATC'.AGFIATTG CTTAOOCAOC AGAAAACACA CAL'TAGAAAG 1080 AAGOOL`PATA AATG'OCATGA CI'G'i'dGAAAA OCPrIRTOC AlGATGTTATC TCTCTTCWA 1140 CATCAGAiGAA CICACAGPAG AC'aAAAAACTC TATOAA7GCA GTGAATGl'OG CAAA[OaCTPC 1200 TOOCAAAACT CAACO(71C'AT TATACAZCAG AAAATTCATA CIGGIGAGAG ACAG'PATOCA 1260 TGCAGrGAAT GPOOC',AAAOC CiTPAUOf'.AG AAiG'I'CAACAC TCAOCPPOCA C7CAGAGAATC 1320 CAICZCAAOOC AGAAIGTC7CTA T(~i'GTC~PATC GAATOOG= AIOGOCTWAT aCAGAA00CA 1380 GOGAAATCGT TCATI"IC7C'.AA GTCACAGCTT GATATACATC ATOGAATTCA TACAOOGif'aAG 1500 AAAUCTPATG AAT~'1AGiGA C'I'GPOGAAAA AOGTIC:AOOC AAAAQTC'ACA CCl'GAATATA 1560 CAQCA~C'~AAAA TTCATAICIGG AGAAAGACAC CATGTATOCA GTC,AATG170C' GAAAOOCITC 1620 AAOCAGAAG'7.' CAATAC't'CAG CATGCATCAG AGAATTCACA QOOC'~GAGAA GOCZTAiCAAA 1680 TGOCAG'iGAAT GTGGGAAAOC CTTC'ACTTGT AAGI'C,`TCAAT TY'.AAAGAOC'A TCA00('aAATT

C1suCACUGOGTG AGAAAOOCPA TGPGTOCACT GAATG'TGGC''A AOGOCITCAA OOOCAOGPCA 1800 AATTTOC'ATA AACATCAAAT AAICICACACT AGAGAGAGOC CTT'PTGn`IG TTA(.AAATGT 1860 GOGAACaOGTT TTGICJCAIGAA ATCAIGAGr'IG ATTAOCCATC AAAGAACTCA CA'IGGGAGAG 1920 AAAOOC,TATG AATaCC'=TTGA CTQPOGGAAA TOG'iRCAGrA AGAAAOCõACA'ACPCAAOGZG 1980 CAT('.AGOC'AA TTCACAfJGOG AC'õAAA(`aAC7CT TAZGTv1v1T G'IGAATGZW AAAGGUCT'II'C

AACAACAGGT CAAACITCIAA TAAACAUC'AA ACAAC,'TCATA OC=AG19GAC'.AA ATCTTACAAA 2100 TGCAG7ITATT CTGTIGAAAIOG CTTTACCAP-iG CAA 2133 (2) INFORMATION FOR SEQ ID N0:12:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 3754 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA(genomic) (iii) HYPOTHETICAL: NO

(iv) ANTI-SENSE: NO
(vii) IMMEDIATE SOURCE:
(A) LIBRARY: Human fetal brain cDNA library (B) CLONE: GEN-076C09 (ix) FEATURE:
(A) NAME/KEY: CDS
(B) LOCATION: 346..2478 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12:

GCTAAGOC.'TA TOPOIX.`ITAC TOGAOOC'IGA AGTGATiGG(` AATATTAO('.A CSIGt~C~*ITC 60 TGTAGGGTCA OGAAOOGOOG aCT00C.'TTTG GGGGAGTGAT GAOGOGC,'ZRC' TTGGO GI'GG 120 GGGIGOC~IGA TAAAOOGATT TC.'TOCGCiGA AGACGACGCT GI.'GAOGCI'TC TG('.AGAACOC 180 C3C,AGGI'CAGG OCAC'ATCAZT C',AG1GC'IGC.AIG GAZCTCrCTT CATAGOOC'1UG TACGACTCTC

CGCCGI'G1CC CTGGPIGGAA AATOCAAAIC'A CCTATOC'AGC T'IC'ZGGC'I'OC IGG("õAAAAGT

GGAGrTGPCA OCAAGAGA(',A aCGAGAGTAG AAGCCCAOAlG ZGC;AG ATG CCT GCT 354 Met Pro Ala GAT GTG AAT TTA TC:C C'AG RAG OC.'T CAG Gl'C CPG =OCA GAG AAG CAG 402 Asp Val Asn Leu Ser Gln Lys Pro Gln Val Leu Gly Pro Glu Lys Gin Asp Gly Ser Cys Glu Ala Ser Val Ser Phe Glu Asp Val Thr Val Asp TTC AOC 'AOG GAG GAG TGG CAG CAA CTG GAC aGT GOC CAG AGA TGC CPG 498 Phe Ser Arg Glu Glu Tip Gln Gln Leu Asp Pro Ala Gin Arg Cys Leu .Tyr Arg Asp Val Met Leu Glu Lau Tyr Ser His Leu Phe Ala Val Gly TAT CAC ATT (XJC AAC OCA GAG GTC ATC TTC AGA ATG CTA AAA GAA AAG 594.
Tyr His Ile Pro Asn Pro Glu Val Ile Phe Arg Met Leu Lys Glu Lys Glu Pro Arg Val Glu Glu Ala Glu Val Ser His Gin Arg GyS G3.n Glu AGG GAG TTT GGG C1T GAA ATC OCA CAA AA[", GAG ATT TL'T AAG AAA GCT 690 Arg Glu Phe Gly Leu Glu Ile Pro Gln Lys Glu Ile Ser Lys Lys Ala TGA TTT CAA AAG GAT ATG GTA GQT GAG Ti+C ACA AGA GAT GQP TGA TGG 738 Ser Phe Gln Lys.Asp Met Val Gly Glu Phe Thr Arg Asp Gly Ser Trp TCT TOC ATT TTA GAA GAA CTG AGG CTG GAT GCT GAC OGiC ACA AAG AAA 786 Cys Ser Ile Leu Glu Glu Lau Arg Leu Asp Ala Asp AxgThr Lys Lys GAT GAG CAA AAT CAA ATT CAA OOC ATG AGT CAC AGr GC.T TIC TTC AAC 834 Asp Glu Gln Asn Gln Ile G]n Pro Met Ser His Ser Ala Phe Phe Asn AAG AAA ACA TTG AAC ACA GAA AOC AAT TGT GAA TAT AAiG GAC OCT GGG 882 Lys Lys Thr Leu Asn Thr Glu Ser Asn Cys Glu Tyr Lys Asp Pro Gly AAA ATG ATT OOC AOG AGG OOC CAC CIT GGT TCT TCA CAG AAA CAA aCT 930 Lys blet Ile AxV Thr Arg Pro His Leu Ala Ser Ser GlnLys Gln Pro CAG AAA TGT TGC TTA TTP ACA GAA AGT TTG AAG C'I'G AAC GTA GAA GTG 978 Gln Lys Cys Cys Leu Phe Thr Glu Ser L8u Lys Leu Asn Leu Glu Val AAC GGT CAG AAT GAA AGC AAT GAC ACA GAA CAG CIT GAT GAC (31T GTT 1026 Asn Gly Gln Asn Glu Ser Asn Asp Thr Glu Gln Leu Asp Asp Val Val GGG TLT GGT CAG C,TA TTC AQC CAT AGC TCT TG`P GAT GOC TGC AQC AAG 1074 Gly Ser Gly Gln Lau Phe Ser His Ser Ser Ser Asp Ala Cys Ser Lys Asn Ile His Thr Gly Glu Ttr Phe Cys Lys Gly Asn Gln Cys Arg Lys GTC ZGP GGC CAT AAA CAG TCA CTC. AAG CAA CAT CAA ATr CAT ALT CAG 1170 Val Cys Gly His Lys Gln Ser Leu Lys Gln His Gln Ile His Thr Gin AAG AAA OCA GAT -GGA TgT TCr GAA T6'T GGG GOG AGC TTC ACC CAG AAG 1218 Lys Lys Pro Asp Gly Cys Ser Glu Cys Gly Gly Ser Phe Thr Gln Lys Z'CA CAC CiC TTT GOC CAA CAG AGA ATT CAT AGT GTA GGA AAG CIC CAT .1266 Ser His Leu Phe Ala Gln Gln Arg Ile His Ser Val Gly Asn Leu His GAA TGT GOC AAA TGT GGA AAA GOC TTC ATG OCA CAA C.'TA AAA C'TC AGT 1314 Glu Cys Gly Lys Cys Gly Lys Ala Phe Met Pro Gin Leu Lys Lsu Ser GTATATCTGArA GATCATAGAGGTGATATAQOCZGTATATOCAAGGAA`a 1362 Val Tyr Lau Thr Asp His Thr Gly Asp Ile Pro Cys Ile Cys Lys Glu 4C3r GGG AAG GTC TTP ATT CAG AGA TCA GAA TI'G GRT ACG CAC CAG AAA 1410 Cys Gly Lys Val Phe Ile Gln Arg Ser Glu LSu Leu Thr His Gln Lys Thr His Thr Arg Lys Lys Pro Tyr Lys Cys His Asp GYs Gly Lys Ala Phe Phe Gln Met Leu Ser Lau Phe Arg His Gln Arg Thr His Ser Arg GAA AAA C'PC TAT GAA TM AGT GAA ZGT GGC AAA GGC TTC TGC CAA AAC 1554 Glu Lys Leu Tyr Glu Cys Ser Glu Cys Gly Lys Gly Phe Ser Gin Asn TCA ACC C'I'C ATT ATA CAT CAG AAA ATT CAT ACT GGT GAG AGA CAG TAT 1602 Ser Thr Leu Ile Ile His Gin Lys Ile His Thr Gly Glu Arg Gln Tyr GCA TGC AAGr GAA ZCGT GOG AAA Gt7C TTT AOC CAG AAG TGA ACA G'TC AOC 1650 Ala Cys Ser Glu Cys Gly Lys Ala Phe Thr Gln Lys Ser Thr Leu Ser Leu His Gln Arg Ile His Ser Gly Gln Lys Ser Tyr Val Cys Ile Glu TGC GGG CAG GOC TTC ATC CAG AAr GCA CAC CIG ATT GTC CAT CAA AGA 1746 Cys Gly Gin Ala Phe Ile.Gin Lys Ala His Uu Ile Val His Gln Arg AGC CAC ACA GGA GAA AAA OCI' TAT CAG TOC CAC AAC TGT GGG AAA TOC .1794 Ser His Thr Gly Glu Lys Pro Tyr Gin Cys His Asn Cys Gly Lys Ser Phe Ile Ser Lys Ser Gin Leu Asp Ile His His Arg Ile His Thr Gly -Glu Lys Pro Tyr Glu Cys Ser Asp Cys Gly Lys Thr Phe Thr Gln Lys, TCA CAIC CPG AAT ATA CAC CAG AAA ATT CAT ACr GGA GAA AGA CAC CAT 1938 Ser His Leu Asn Ile His Gin Lys Ile His Thr Gly Glu Arg His His Val Cys Ser Giu Cys Gly Lys Ala Phe Asn Gln Lys Ser-Ile L8u Ser Met His Gln Arg Ile His Thr Gly Glu Lys Pro Tyr Lys Cys Ser Glu T'GT GOG AAA GOC TTC AICT TOT AAIG TL`T CAA TZC AAA GAG CAT CAG C7GA 2082 Cys Gly Lys Ala Phe Thr Ser Lys Ser Gln Phe Lys Glu His Gin Arg ATT CAC AOG GG'T GAG AAA CCC TAT GTG TaC ACT GAA TGT GOG AAG GOC 2130 Ile His Thr Giy Glu Lys Pro Tyr Val Cys Thr Glu Cys Gly Lys Ala TI'C AAC GGC AOG TCA MT TTC CAT AM CAT CAA ATA ACT CAC ACT AGA 2178 Phe Asn Gly Arg Ser Asn Phe His Lys His Gln Ile Thr His Thr Arg GAG AGG CCT TTT GTC ZG'T TAC AAA TGT GGG AAG GCT TTT GTC CAG AAA 2226 Glu Arg Pro Phe Val Cys Tyr Lys Cys Gly Lys Ala Phe Val Gln Lys TCA GAG TTG ATT ALJC CAT CAA AGA ejiCT CAC ATG GGA GAG AAA QOC TAT 2274 Ser Glu Lau Ile Thr His Gln Arg Thr His Met Gly Glu Lys Pro Tyr GAA TM GTT GAC TGT GGG AAA TCG Tl'C AGr AAG AAA OCA CAA C'IC AAG 2322 Glu Cys Leu Asp Cys Gly Lys Ser Ptie Ser Lys Lys Pro Gln Leu Lys (`a . CAT CAG CXaA ATT. CAC AOG GGA GAA AGA aCT TAT GTG TOT TCP GAA. 2370 Val His Gin Arg Ile His Thr Gly Glu Arg ProTyr Val Cys Ser Glu ZGr GGA AAG GOC TTC AAC AAC AGG TCA AAC TTC AAT AAA CAC CAA ACA 2418 Cys Gly Lys Ala Phe Asn Asn Arg Ser Asn Phe Asn Lys His Gln Thr Thr His Thr Arg Asp Lys Ser Tyr Lys Cys Ser Tyr Ser Val Lys Gly TTT AOC AAG CAA TGAATICX,,'TA GrGCATCADC ATATTCATAA ATGAAATATA 2518 Phe Thr Lys Gln CTC70CAGTTT CIRC'aAP,C'~,~AAG AGAACATGTP CPCAGAATCA GM"CPAATTA TA'tC~!'rATTG

AATTCATGCT TCAGAAAAAC TCTAGGGATG CALTOCATgI' GTGAACAICAT GATAAAAAAG 2638 ZCATGCCI'TTA TTITAGTGAG GGCAATTACA GAGAAAAGAG TAAOCA~'aAAA TOI'LTIC'IG 2698 AGTAC'POGCC TCATTAAGGA TTATAAATTT TCI'OOOCGOG AAGAAA<JOCT GAiCTAACGC'A 2758 TTGAGAAAAG CGTPTCTG'rA AAC,AATGGTA CAAGACAOGT TGITAC'PaGA TTAT'ITATAG 2818 TAAAATATGT GGGAAATTAT ATCAATGATA ACOCIGTITA T'PGIGGC'ATA TCAATATTi'T 2878 TAAAOi'GCCA ACACAGI'CAT GATAGGGACAA TATTITATG'P GI'GPGR'G'IGC GCCiTA'PGTA 2938 AAAATGuCTG GGATC:AGAAG CATTTTGGAT. TPCA(',ATACT TACAC'aATTIT GGAATATT'IG 3058 J*

CATTATATTP ATTGG1'TC'iAG CATOOC,TAAT CIGAAAATOC AAGATTAP-AT GCPOCAATTA 3118 Gf.;ATTTOC'IT TC`AGOGICAT GTTAGAGTPC AAAAAGTT'I'C AGATTIRCW TTTPGAIGATT 3178 AGGAATAO(7C AAOCiGTATG TA+OGPATATT TCPQPATCPA TGTATGTATA TATATGOCATA 3238 TOC14GACATA TOPATATGGT CiGGPCAOCA TATGTGPATG TATGOGPATG TATOTATGTA 3298 TGTATGOOC.T CAGTGCAGT','Y' GGGI'I'TC~G'P(' CAL"'aAAT'PCAC TGCATAQCAG
GAC,ATGTAAG 3358 CAGATGAGIT ATPPPPTAAG AGAATLTAAT G'TAATIGTIT TTATAAAAAT TATTOOCPAT 3418 TGAATATRTA TATAA'1GAGG TWTATC,AAC AATGATTAAC 'POCTITATTA TA+CATAC,AC,A 3478 TGAAT I= TPTIC~PAA ATCaf'.ATAAAT GAi(',ATTCTAT 'AATOt'ITALT GATCPI'PATA 3538 TTAOAGATTT . TACy1f;,ATTAOC TCAOGTZ~pOC QOOOC7TTOC ATChC7C'AOCA 3598 TL'TATAGTGA G(7CTC1C7C'AT AATTAOI'C~C7C AAO(ATTAGT C'POGTI~CATA T'ITPTACAOC

AOGAGICAAC AAACTGiGOC ATi'OOOCAAA TATOOOC,'TOC CAAGTGPI'TP TTTAAAATAA 3718 (2) I1vF0EN1ATI0N FOR SDQ ID N0:13:

(1) SEQ[1ENCE CTiARPiCPERISTICS:
(A) IENGTH: 389 aminu acids (B) TYPE: amino acid ( D ) TOPO.LOW: linear ( ii ) NDLEC7[1LE TYPE: probe,in ( x3. ) SBQtJIINCE DES(32IPTIaNi: SF]Q ID Ia0:13 :

Met Ala Asp Pro Arg Asp Lys Ala Lau Gin Asp Tyr Arg Lys Lys Leu Leu Glu His Lys Glu Ile Asp Gly Arg Leu Lys Glu Leu Arg Glu Gin Leu Lys Glu Leu Thr Lys Gin Tyr Glu Lys Ser Glu Asn Asp Leu Lys Ala Leu G1n.Ser Val Gly Gln Ile Val Gly Glu Val Leu Lys Gln LQu Thr Glu Glu Lys Phe Ile Val Lys Ala Thr Asn Gly Pro Arg Tyr Vaal Val Gly Cys RY+g Arg Gln Leu Asp Lys Ser Lys Leu Lys Pro Gly Thr Arg Val Ala Lau Asp Met Thr Thr Leu Thr Ile Met Arg Tyr Leu Pro Arg Glu Val Asp Pro Leu Val Tyr Asn Met Ser His Glu Asp Pro Gly Asn Val Ser Tyr Ser Glu Ile Gly Gly Leu Ser Giu G]n Ile Arg Glu Leu Arg Giu Val Zle Glu Leu Pro Lele Thr Asn Pro Glu Leu Phe Gln Arg Val Gly Ile Ile Pro Pro Lys Gly Cys Leu Leu Tyr Gly Pro Pro Gly Thr Gly Lys Thr Leu Leu Ala Arg Ala Val Ala Ser G]n Leu Asp Cys Asn Phe Leu Lys Val Val Ser Ser Ser Ile Val Asp Lys Tyr Ile Gly Glu Ser Ala Arg Leu Ile Arg Glu Met Phe Asn Tyr Ala Arg Asp His Gin Pro Cys Ile Ile Pbe Met Asp Glu Ile Asp Ala I.l.e Gly Gly Arg Arg Plhe Ser Glu Gly Thr Ser Ala Asp Arg Glu Ile Gln Arg Thr Leu Met Glu Leu Leu Asn Gin Met Asp Gly Phe Asp Thr Lau His Arg Val Lys Met Thr Met Ala Thr Asn Arg Pro Asp Thr Leu Asp Pro Ala Leu Leu Arg Pro Gly Arg Leu Asp Arg Lys Ile His Ile Asp Leu Pro Asn Glu Gin Ala Arg Leu Asp Ile Leu Lys Ile His Ala Gly Pro Ile Thr Lys His Gly Glu Ile Asp Tyr Glu Ala Ile Val Lys Leu Ser Asp Gly Phe Asn Gly Ala Asp Lau Arg Asn Val Cys Thr Glu Ala Gly Met Phe Ala Ile Arg Ala Asp His Asp Phe Val Val Gin Glu Asp Phe Met Lys Ala Val Arg Lys Val Ala Asp Ser Lys Lys L2u Glu Ser Lys Leu Asp Tyr Lys Pro Val 385 =

(2) INFORMATION FOR SEQ ID NO:14:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 1167 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA(genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID N0:14:

ATGOOGGAOC CTAGAGATAA GGflGC.TrCAG CAICPAUOOC',A AGAADTTGCT TGdo-ACAC'AAG 60 GAGATOGAOG GOOGTC.TrAA GGAGZTAAOG GAACAATTAA AAGAAGT'rAC CAAGCAGTAT 120 C',AAAAGIC,Z'G AAAATGATCT GAAGOOOLTA CAuGAGT(~'TTG GOCAC',ATaGT CaGGTGAAGTG

CTrAF-ACAQr TAA~.'rGAAC'A AAAATTCATT QITAAAGC.'TA CQhAZG1C'~QC AAGATATG'IT 240 GTuwTPGrC GTCGACAOCT TGHCAAAAGr AAGG'1'GAAOC CAGGAACAAG AGTrGG'ZTiG 300 GATATGACPA CACTAAC.TAT CATGAGATAT TrGOCGAGAG AGGIGGATaC ACZGGPiTAT 360 AACATGlCrC ATGAOGACOC TGGC'~ATM TCTPATTCiG AGATTOGAOG GCrATCAGAA 420 CAGAZbCGGG AATTAAGAGA GGIGATAGAA TTACC7rCITA CAAAOOCAGA GTTAT'ITCAG 480 WMAOC',~AA TAATACC'rCC AAAAGaCTGT Tr(~ITATATG GACCACCAGG TAOGGC'aAAAA 540 AlCAIC'tC.'rTOG CACGAGOOGT TGC'rAf30C14G CTOGACTGCA ATiTCITAAA OGPrGrATCT 600 AGTrCPATTG TAGACAAGrA CATrG(I'GAA AGrOGTCGZT TGATC.AGAGA AATGPTPAAT 660 TATGCTAGAIG ATCATCAAOC ATGCATCATT TTTAZGCaATG AAATAGATGC TATTGG7G(3T 720 OGPOf~GTTTT CTGAGWPAC TTCAOCIGAC AGAGAGATTC AGAGAACG'IT AATGGAGITA 780 CTGAP-ZC,AAA ZGGARCaGATT TGATACTCiG CATAGAGZTA AAATC'õAOCAT GOC,TACAAAC 840 AGACCAGATA CALTGGP-TOC ZGiCPlRCdCiG CG1OCA3GAA GATTAGATAG AAAAATACAT 900 ACAAAGC'AT'G GiC'aAAATAGA TTATCaAAOCA ATTGPGAAOC TTI'CGGATGG CTTTAAZbC'aA 1020 GCAGATCZC'aA GAAATG'1'Tl'G TALTC'AAOC'A GGTATGITOG CAATPOM'GC TGATCATGAT 1080 TPIGTAGrAC AGGAAGACiT CAZCAAAQC"A GTCAGAAAAG TGC~C'i'GATTC TAAGAAGCi'G 1140 GAGPC.'TAAAT TOGACTAICAA AQChG'hG 1167 (2) INFORMATION FOR SEQ ID N0:15:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 1566 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA

(iii) HYPOTHETICAL: NO
(iv) ANTI-SENSE: NO
(vii) IMMEDIATE SOURCE:
(A) LIBRARY: Human fetal brain cDNA library (B) CLONE: GEN-331G07 (ix) FEATURE:
(A) NAME/KEY: CDS
(B) LOCATION: 17..1183 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:15:

Met Ala Asp Pro Arg Asp Lys Ala Leu Gln Asp Tyr Arg Lys Lys Leu Leu Glu His Lys Glu Ile Asp Gly Arg Leu Lys GAG TTA AGG GM C.AA TTA AAA GAA G'IT AOC AP-G CAG TAT GAA AAG TCT 145 Glu Leu Arg Glu Gln Leu Lys Glu Leu Thr Lys Gln Tyr Glu Lys Ser GAA AAT GAT CTG AAG GflC C.TA CAG AGr GTT GGG CAG ATC G'PG GGT GAA 193 Glu Asn Asp Leu Lys Ala Leu Gin Ser Val Gly Gln Ile Val Gly Glu GTG CIT AAA CAG TTA ACT GAA GAA AAA TTC ATT GTP AAA GGT A[JC AAT 241 Val Leu Lys Gln Leu Thr Glu Glu Lys Phe Ile Val Lys Ala Thr Asn pGA CCA AGA TAT G'IT GTG GG1' WP OGP OGA CAG C1T GAC AAA AGr AArG 289 Gly Pro Arg Tyr Val Val Gly Cys Arg Arg Gln L8u Asp Lys Ser Lys QiG AAG af:A. GGA ACA AGA G1T GCI' TTG GAT ATG ACT ACA CTA AICT ATC 337 Leu Lys Pro Gly Thr Axg Val Ala Leu Asp Met Thr Thr L8u Zhr-Ile ATG AGA TAT TTG QOG AGA GAG GTG GAT CCA CPG GiT -TAT AAC ATG TLLT 385 Met Arg Tyr Leu Pro Arg Glu Val Asp Pro Leu Val Tyr Asn Met Ser His Glu Asp Pro Gly Asn Val Ser Tyr Ser Glu Ile Gly Gly Leu Ser GAA CAG ATC COG GAA TTA AGA GAG GTG ATA GP,A TTA aGT CiT ACA AAC 481 Glu Gin Ile Arg Giu Leu Arg Glu Val Ile Glu Leu Pro Leu Thr Asn CCA GAG TTA T'iT CAG OCT GTA GGA ATA ATA OCT CCA AAA GOC TGT TTG 529 Pro Glu L2u Phe Gin Arg Val Gly Ile Ile Pro Pro Lys Gly Cys Leu Leu Tyr Gly Pro Pro Gly Thr Gly Lys Thr Leu Leu Ala Arg Ala Val GCT AQC CAG CTG GAC TGC AAT T1C TTA AAG GPr GTA = AGT WT ATT 625 Ala Ser Gin Leu Asp Cys Asn Phe Lau Lys Val Val Ser Ser Ser Ile GPA GAC AAG TAC ATT GGr GAA AOr GCT OGT TTG ATC AGA GAA ATG TTT 673 Val Asp Lys Tyr Ile Gly Glu Ser Ala Arg Leu Ile Arg Glu Met Phe AAT TAT GG'T AGA GAT CAT CAA aCA TGC ATC ATT TIT ATG GAT GAA ATA 721 Asn Tyr Ala Arg Asp His Gln Pro Cys Ile Ile Phe Met Asp Glu Ile GAT GL'T ATT GGT GGP CGT OGG TTT TGT GAG GGT AC,T 'ICA GCT GAC AGA 769 Asp Ala Ile Gly Gly Arg Arg Phe Ser Glu Gly Thr Ser Ala Asp Arg Glu Ile Gln Arg Thr Lau Met Glu Leu Leu Asn.Gin Met Asp Gly Phe GAT AIC'!' CTG CAT AGA GTT AAA ATG AOC ATG OCT ACA AAC AGA a(:A GAT 865 Asp.Thr Leu His Arg Val Lys Met Thr Met Ala Thr Asn Arg Pro Asp ACA CTG GRT aC'1' GCT TTG C1G a(OT OCA GGA AGA TTA GAT AGA AAA ATA 913 Thr Leu Asp Pro Ala Leu Lau Arg Pro Gly Arg Leu Asp Arg Lys Ile His ile Asp Leu Pro Asn Glu Gin Ala Arg Leu Asp Ile Leu Lys Ile CAT GCA GGP OOC ATT ACA AAG CAT Gt31 GAA ATA GAT TAT GAA GCA ATT 1009 His Ala Gly Pro Ile Thr Lys His Giy Glu Ile Asp Tyr Glu Ala Ile GTG AAG C'I'T TaG GAT GOC TTT AAT GCA GCA GAT CIG AGA AAT GiT TGT 1057 Val Lys Lsu Ser Asp Giy Phe Asn Gly Ala Asp Lau Arg Asn Val Gys AGT GAA GCA GGT ATG TTC GCA ATT OGT GC.T GAT CAT GAT TTT GrA CTA 1105 Thr Glu Ala Gly Met Phe Ala Ile Arg Ala Asp His Asp Phe Val Val CAG GAA GAC TTC ATG AAA GCA GTC AGR AAA GIG GGT GAT Tt.'T AAG AAG 1153 Gln Glu Asp Phe Met Lys Ala Val Arg Lys Val Ala Asp Ser Lys Lys CTG GAG TG`P AAA TTG GAC TAC AAA OCT GIG TAATTPAL'ZG TAAGATTITP 1203 Leu Glu Ser Lys Leu Asp Tyr Lys Pro Val GAT(0GC'tGCA TGAtCAGATGT TOOC'iTATTG TAAAAATAAA GTTAAAGAAA ATAATGTATG 1263 TAT'IGOC'.AAT GATGICATTA AAAGPATATG AATAAAAATA TGGAGrAAICAT CATAAAAATT 1323 AGTAATI'.AA CTI'I'TAAGAT ACACAP-GAAA TTTGPATGIT TGTTAAAGPP GCATTTATTG 1383 CAGCAAGTTA CAAAGGOGAAA GTGTTGAAGC TPTPCATATT TGC'IbOGPGA GCATri'TG"TA 1443 AAATAT'I'f',AA ADt%'IT'iC ~A GATAGIGGTA TAAGAAAOC'A ZTTC'PTATGA CITATTTPC:'T

ATCATPIK7TT TTC7C',PCATO'T AAAAAGPIC'aA ATAAAATC'IG TTI'GAZTC,AG TTCl'oC,'TAAA

(2) INFnFiMATION FUEt SDQ ID NO:16 :

( i ) SDQUENC'E CHARACTERISTICS:
(A) IE3VMH: 223 2Qa3no acids (B) TYPE: 8mi,no acid ( D ) TOPOLOGY: litye3r ( ii ) M3IEC.UIE TYPE: protBin ( xi ) SBOI)IIN.'E DFSCRIPTION: SBQ ID 1V0:16 :

MBt Ser Asp Glu Glu Ala Arg Gin Ser Gly Gly Ser Ser Gin Ala Gly Val Val Thr Val Ser Asp Val Gln Glu L$u Met Arg Arg Lys Glu Glu Ile Giu Ala Gln Ile Lys Ala Asn Tyr Asp Val Leu Glu Ser G1n.Lys Gly Ile Gly Met Asn Glu Pro Leu Val Asp Cys Glu Gly Tyr Pro Arg Ser Asp Val Asp Leu Tyr Gln Val Arg Thw Ala Arg His Asn Ile Ile Cys Leu Gln Asn Asp His Lys Ala Val Met Lys Gln Val Glu Glu Ala Leu His Gln Leu His Ala Arg Asp Lys Glu Lys Gln Ala Arg Asp Met Ala Glu Ala His Lys Glu Ala Met Ser Arg Lys Leu Gly Gln Sear Glu Ser Gln Gly Pro Pro Arg Ala Phe Ala Lys Val Asn Ser Ile Ser Pro Gly Ser Pro Ala Ser Ile Ala Gly Leu Gin Val Asp Asp Glu Ile Val Glu Phe Gly Ser Val Asn Thr Gln Asn Phe Gln Ser Leu His Asn Ile Gly Ser Val Val Gln His Ser Glu Gly Lys Pro Leu Asn Val Thr Val Ile Arg Arg Gly Glu Lys His Gln Leu Arg Leu Val Pro Thr Arg Trp Ala Gly Lys Gly Leu Lau Gly Cys Asn Ile Ile,Prc Leu Gln Arg (2) INFORMATION FOR SEQ ID NO:17:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 669 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D). TOPOLOGY: linear (ii) MOLECULE TYPE: DNA(genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:17:

ATGTCCGACG AGGP-AG(X'~G GCA~C'aAl00GC'~ GGCTOC'POGC ~r CGTGAL`lGIC 60 AOC('~?lOGTM AGGAIOCTC'aAT GCGOOGCAAG GAGGAGATAG AAGOGCAGAT CAAGGOC',AAC 120 TATGACGPGC ZGC,hAAOOCA AAAAOGCATT GGGATGAACG A CCGCTGOT GGAICTCOlGAG 180 GGCTAO000C GGPCAGACGT GGACCiOPAC CAAG'i'OOOC',A CCGOCAOGCA CAACATCATA 240 TGOC'!'GCAiGA ATGATCACAA aOCAG'Z+C'~ATG APuGCAGGTGG AGGAi0GO0CP GCACCAOC.'TG

CAOGCTC'XGCG ACAAOC'~A (~('1LGGOOCGG GACATGGC,'TG AGOCOCACAA AGAGGYJC.ATG 360 A COGC',AAAC TGGGTCAGAG TGAC'~AGCCAG GGOCCPOCAC GGGCCrPCGC CAAAG'iC'aAAC 420 AQCAZ'CAOOC OL~G C'i'OOOC AGbCAGCATC GOGl3C~'TCPGC AAG'rOGATGA TGAGRTTGiG 480 GAC~ITOOGCP ClGIC'~AACAC CC'.ACAACTPC CAGTCACTOC ATAACATTGG CAtGPGrGGTG 540 CAGCACAGIG AGGCGGC'~CC CCTGAATCOPG ACAGI'GATCC GCAOGGGOGA AAAACACCAG 600 CTTAGACTPG Ti'OCAACACG CPGGGCAGGA AAAGGAL'PGC TGGGCI'GCAA CATTATTOCP 660 (2) INFORMATION FOR SEQ ID NO:18:
(1) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 1128 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: CDNA
(iii) HYPOTHETICAL: NO
(iv) ANTI-SENSE: NO

(vii) IMMEDIATE SOURCE:
.(A) LIBRARY: Human fetal brain cDNA library (B) CLONE: GEN-163D09 (ix) FEATURE:
(A) NAME/KEY: CDS
(B) LOCATION: 125..793 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:18:

ACIC~imCi+OG OOI*I'0 OG('~A OOOCPGl'OGT GTTTTGGOOC ATGGGC00C'aAG OGTAGiTACG 60 G71'CC'~CTOOG GQIC)GIOOC TAGOOOOOGA GCOGGGTL`rC TGGAG7.`OGOG GOOOOOOGIT 120 CAOG ATG TOC GAC GAG GAA GOG ApG CAG ROC GGA GOC TUC RC)G CAG GOC 169 Met Ser Asp Glu Glu Ala Arg G1n Ser Gly Gly Ser Ser Gin Ala GOC OW GTG ALT GTC AOC GAC G'M CAG GAG CTG ATG COG COC A14G GAG 217 Gly Val Val Thr Val Ser Asp Val Gln Glu Lau Met Arg Arg Lys Glu Glu Ile Glu Ala Gln Ile Lys Ala Asn Tyr Asp Val Leu Glu Ser Gln Lys Gly Ile Gly Met Asn Glu Pro Leu Val Asp Cys Glu Gly Tyr Pro COG TCA GAC GTG GAC CTG TAC CAA GTC aGC ACC GL7C AGO CAC AAC ATC 361 Arg Ser Asp Val Asp Leu Tyr Gln Val Arg Thr Ala Arg His Asn Ile Ile Cys Leu Gln Asn Asp His Lys Ala Val Met Lys Gln Val Glu Glu GOC CIG CAC CAG CTG CAC GCT t)GC GAC AAG GAG AAG CAG GOC CGG GAC 457 Ala Lsu His Gln Lau His Ala Arg Asp Lys Glu Lys Gln Ala Arg Asp ATG GCT GAG GOC CAC AAA GAG G{7C ATG AGC OGC AAA CIG GGT CAG AGT 505 Met Ala Glu Ala His Lys Glu Ala Met Ser Arg Lys Leu Gly Gln Ser Glu Ser Gln Gly Pro Pro Arg Ala Phe Ala Lys Val Asn Ser Ile Ser 0 C GGC TOC af.'A GOC AGC ATC GOG GOT CTG CAA GIG GAT GAT GAG ATT 601 Pro Gly Ser Pro Ala'Ser Ile Ala Gly Leu Gln Val Asp Asp Glu Ile Val Glu Phe Gly Ser Val Asn Thr Gln Asn Phe Gln Ser Leu His Asn Ile Gly Ser Val Val Gln His Ser Glu Gly Lys Pro Leu Asn Val Thr GTG ATC aGC AGG GGG GGAP, AAA CAC CAG CIT AGA C'iT GTT aCA ACA OSC 745 Val Ile Arg Arg Gly Glu Lys His Gln Leu Arg Leu Val Pro Thr Arg Trp Ala Gly Lys Gly Leu Lsu Gly Cys Asn Ile Ile Pro Leu Gin Arg TGATTC#iK70C TGGO['AAOAG TAACl410GAAA GCATCTTOOC TTGOOCIC'GCGA C'1'i'GwlC`PA

GGGATIT,OCA ACTTQIC."TTC TCPOOCIGAA GCATAAGGAT CTGGAAGAGG CT'iGTAAOGT 913 GAACTTCTGT GTOGPGGCAG TAC.'TGPOGOC CAOCAG'PCOPA ATC'i'OOCI'GG ATTAAGOCAT 973 TGRTAAAAAC TTAGGCPt'GG C7C7PC'ITiCAC AAATTAGGC7C AOGGOOC.'TAA ATAGC',AATTC

aCTOC'~-TTG GGGCAAG'I'GG GOaGAAOPTA TPCIGGCAOG TAAC'PGGTGTG ATTATTATTA 1093 TTA'PTTTPAA TAAAGAGTTT TACAGTGC'I'G ATATG 1128 (2) INFQFiMATION FOR SEQ ID N0:19 :

( i ) SEQUENCE CHARACTERMICS:
(A) LFNG'i'H : 506 acRi no acids (8) TYPE: amizb acid ( D ) TOPOLOGR: linear ( ii ) MOL CIILE TYPE: protein ( xi ) SEQi7IINCE DESCRIPTICN: SH]Q ID N0:19 :

Met Ala Glu Ala Asp Phe Lys Met Val Ser Glu Pro Val Ala His Gly Val Ala Glu Glu Glu Met Ala Ser Ser Thr Ser Asp Ser Gly Glu. Glu Ser Asp Ser Ser Ser Ser Ser Ser Ser Thr Ser Asp Ser Ser Ser Ser Ser Ser Thr Ser Gly Ser Ser Ser Gly Ser Gly Ser Ser Ser Ser Ser Ser Gly Ser Thr.Ser Ser Arg Ser Arg Leu Tyr Arg Lys Lys Arg Val Pro Glu Pro Ser Arg Arg Ala Arg Arg Ala Pro Leu Gly Thr Asn Phe Val Asp Arg LSU Pro Gln Ala Val Arg Asn Arg Val Gln Ala Lau Arg Asn Ile Gln Asp Glu Cys Asp Lys Val Asp Thr Leu Phe Leu Lys Ala.

Ile His Asp Leu Glu Arg Lys Tyr Ala Glu Leu Asn Lys Pro Lau Tyr Asp Arg Arg Phe Gin Ile Ile Asn Ala Glu Tyr Glu Pro Thr Glu Glu Glu Cys Glu Trp Asn Ser Glu Asp Glu Glu Phe Ser Ser Asp Glu Glu Val Gln Asp Asn Thr Pro Ser Glu Met Pro Pro Leu Glu Gly Glu Glu Glu Glu Asn Pro Lys Glu Asn Pro Glu Val Lys Ala Glu Glu Lys Glu Val Pro Lys Glu Ile Pro Glu Val Lys Asp Glu Glu Lys Glu Val Ala Lys Glu Ile Pro Glu Val Lys Ala Glu Glu Lys Ala Asp Ser Lys Asp Cys Met Glu Ala Thr Pro Glu Val Lys Glu Asp Pro Lys Glu Val Pro Gln Val Lys Ala Asp Asp Lys Glu Gln Pro Lys Ala Thr Glu Ala Lys Ala Arg Ala Ala Val Arg Glu Zhr His Lys Arg Val Pro Glu Glu.P,zg LQu Arg Asp Ser Val Asp Letz Lys Arg Ala Arg Lys Gly Lys Pro Lys Arg Glu Asp Pro Lys Gly Ile Pro Asp Tyr Trp Leu Ile Val Lau Lys Asn Val Asp Lys Lsu Gly Pro Met Ile Gln Lys Tyr Asp Glu Pro Ile Leu Lys Phe Leu Ser Asp Val Ser Leu Lys Phe Ser Lys Pro Gly Gln Pro Val Ser Tyr Thr Phe Glu Phe His Phe Leu Pro Asn Pro Tyr Phe Arg Asn Glu Val Leu Val Lys Thr Tyr Ile Ile Lys Ala Lys Pro Asp His Asn Asp PFro Phe Phe Ser Trp Gly Trp Glu Ile Glu Asp Cys Lys Giy Cys Lys Ile Asp Arg Arg Arg Gly Lys Asp Val Thr Val Thr Thr Thr Gln Ser Arg Thr Thr Ala Thr Gly Glu Ile Glu Ile Gin Pro Arg Val Val Pro Asn Ala Ser Phe Phe Asn Phe Phe Ser Pro Pro Glu Ile Pro Met Ile Gly Lys L8u Giu Pro Arg Glu Asp Ala Ile Leu Asp Glu Asp Phe Glu Ile Gly Gln Ile Leu His Asp Asn Val Ile Leu Lys Ser Ile Tyr Tyr Tyr Thr-Gly Glu Val Asn Gly Thr Tyr Tyr Gln Phe Gly Lys His Tyr Gly Asn Lys Lys Tyr Arg Lys (2) INFORMATION FOR SEQ ID NO:20:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 1518 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA(genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:20:

AT(30CAGIAAG CAGATITPAA AA7GU1'CTQG GAACCIGIC7G CX7C'A7npp(;P ZGOCGAAGAG 60 GAGARCiOCPA GCTOGALTAG ZGATd'C.ZGGG. GAAGAATCTG AIC'AGCAGTAG CTCTAGC'AGC 120 PGCACrAG3G ACAGC'1DC'.AC'' CAiOC',AIOCAOC ACTAGi'GOC'A GCAlOCAGCOG CAOCGGCAGC

AGCAOC'.AOCA GCAGCGGCAG CACTAOC'AOC CGC,AG000CT TOrATAC',A GAAG140GCTA 240 OCTGA(~OC'IT CCAGAAOOGC GODU0MOC CCGPiGOC,AA CAAATT'IC7GT GGATAGOCIG 300 CfCTCAGGCAG TTAGAAATCG TGZGCAAOOG CTPAGAAA~(`.A 4TCAA~('õATGA ATGt'GGAC,AAG

OPAGATACOC TGl'PCITAAA AGCAATI'CAT GAT(,'TTf'mAAA GkAAATATGC TGAACIrAAC 420 AAGCCt`CI'GV ATGA.TAGG0(" GT'IZ'CAAATC ATC'.AATGC',AG AATACGAGOC TACAC'aAAGAA

GAATGTt`=AAT GGAATP('1~1G& GGATGAGC"aAG TTCFuOCAGIG ATGAGGAiGGT GCAOC'aATAAC

A+GOC7CPAGZG AAATGCCt"OC CTTAGAOGQr GAOC'~AA('~AG AAAA00(.~TAA AGAAAAOCC'A 600 GAGGTCkAAG CTGAAGAiC,AA GGAAGI"IC)CT AAAC'aAAATTC CTGAGGl'('aAA GGATGAAGAA 660 AAiOGAAGTIG CTAAAC'1kAAT TC7CTC'rAiOGTA AAGGCTGA+-G AAAAAGCACaP- TTCPAAAGAC

TG'TATGGAOG CAAOCCCI'GA AGTAAAAGAA GATCCPAAAG AAG''TOCCCCA GGTAAApG('.A 780 GATGATAAAG AACAGOGTAA AOCAP-CAGAG GCTAAQOCAA GGOC.`PGCAGT AAIGA~"~At"'ACT 840 CATAAAAGAG TTOCPGAGC'~A AAGGCTIYJGG GACAG'TGTAG A'iCTTAAAAG A+OCI'AOGAAG 900 GGAAADCCTA AAAGAGAAGA COCTAAAGGC ATTOCrGACP AZTGOCTGAT TO`PITPAAAG 960 AAZCTTGACA AGCTOOOGOC TATG:ATir'.,AG AAGTATGATG AOOOCATTCT GAAiG'T`t'CPiG 1020 TOGGATGTTA GOCTGAAG'iT CrCAAAACL."T GGOf`~GOLTG TAF-GITACAC CZTPGAATTT 1080 CATTTTGTAC OCAAOOCATA CPTCA~''aAAAT GAGvR~GCR~C~G TGAAGAIC'ATA TATAATAAAG 1140 GCAAAAC'AG A'L^CAMTGA '!'OCC.'TTCPTI' ZCTIC~OOC'aAT GGGC'aAFiAT'i'GA

CGCIGCAAGA TAGAOOGGAG AACaAGGAAAA GATO1TAC1G TGACAACtAC CCAGAGT00C 1260 -ACAACIGGTA CIGGWAAAT.'iGAAATOC,A[' (7CAA["aAGROG TTOCPAATGC ATCATTCIZC 1320 AAC1't'C7[TTA GI~OG9!OCi~GA GAZ'i'OGrATG ATPOOGAAOC TGGAAOC.AOC' AGAAGF,TGCT

ATCCPGC'aA'!G AOGALR'TTGA AATPGGOCAG ATTITACA'I"G ATAATQiC'AT 0CIGAATCA 1440 ATCTATTACT ATALTGGAGA AG'iC'AATGGT AC(TACTATC AA7TI'OGCAA ACATTATGGA 1500 AAiCAAGAAAT ACAGAAAA 1518 (2) INFORMATION FOR SEQ ID NO:21:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 2636 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA(genomic) (iii) HYPOTHETICAL: NO

(lv) ANTI-SENSE: NO
(vii) IMMEDIATE SOURCE:
(A) LIBRARY: Human fetal brain cDNA library (B) CLONE: GEN-078D05 (ix) FEATURE:
(A) NAME/KEY: CDS
(B) LOCATION: 266..1783 (xi) SEQUENCE DESCRIPTION: SEQ ID N0:21:

GATTOGOC.`IG CGGPAICATCT aGGCACPCTA GC'POCAGOOG GGAGAGGOCT TGUOGCCAaC 60 aC'1'GPC7G'OOC AAGOCTOC'AC TGCOGCTGCC ACC't'CAOOOC CGG0CTC'PGC ATC7COCAGCT 120 OCAGC'1'OOOC ZC;tO00000C TGCZGCC7CATC GOOGCT'GCCA aCPCX7GC'.AQC (X70GOCCI'aC

GOOOCOOCCA CCCAApCATC CGTGAGICAT TTTCI'GOOCA TCPCIC~G'POG OOOOGPC'I'OC 240 CZGGPAIGAGP TTafAGGCiT GGAAG ATG GCA GAA GCA GAT TTP AAA ATG GTG 292 Met Ala Glu Ala Asp Phe Lys Met Val Ser Glu Pro Val Ala His Gly Val Ala Glu Glu Glu Met Ala Ser Ser Thr Ser Asp Ser Gly Glu Glu Ser Asp Ser Ser Ser Ser Ser Ser Ser ACT AGT GdAC AOC AOC AGC AGC AGC AOC ACT AGT GGC AGC AGC AG1C GOC 436 Thr Ser Asp Ser Ser Ser Ser Ser Ser Thr Ser Gly Ser Ser Ser Gly Sex' Gly Ser Ser Ser Ser Ser Ser Gly Ser Thr Ser Ser Arg Ser Arg TIPG TAT AGA AAG AAG AGG GrA OCT GAG OCT TCC AGA AGG GCG COG COG 532 L8u Tyr Arg Lys Lys Arg Val Pro Glu Pro Ser AYg Arg Ala Arg Arg Gt7C OOG TTG GGA ACA AAT TTC GTG GAT AGG CPG C7CT CAG GCA OIT AGA 580 Ala Pro Leu Gly Thr Asn Phe Val Asp Arg Leu Pro Gin Ala Val Arg AAT Q(T Gi'G CAA GCG CIT AGA AAC ATT CAA GAT GAA TGT GAC AAG GTA 628 Asn Arg Val Gin Ala Leu Arg Asn Ile Gln Asp Glu Cys Asp Lys Val GAT AiOC CIG TTC TTA AAA GCA ATT CAT GAT CIT GAA AGA AAA TAT GCT 676 Asp Thr Leu Phe Lau Lys Ala Ile His Asp L8u Glu Arg Lys Tyr Ala Giu Leu Asn Lys Pro Leu Tyr Asp Arg Arg Phe Gln Ile Ile Asn Ala GAA TAC GAG OC'1' ACA GAA GAA GAA TGI' GAA TGG AAT TCA GAG GAT GAG 772 Glu Tyr Glu Pro Thr Glu Glu Glu Cys Glu Trp Asn Ser Glu Asp Glu Glu Phe Ser Ser Asp Glu Glu Val Gln Asp Asn Thr Pro Ser Glu Met CCT OOC TTA GAG GGT GAG GAA GAA GAA AAC CCT AAA GAA AAC aCA GAG 868 Pro Pro Lp-u Glu Gly Glu Glu Glu Glu Asn Pro Lys Glu Asn Pro Glu GTG AAA GCT GAA GAG AAG GAA GTP aCT AAA GAA ATT OCT GAG GTG AAG 916 Val Lys Ala Glu Glu Lys Glu Val Pro Lys Glu Ile Pro Glu Val Lys GAT GAA GAA AAG GAA GTT GCT AAA GAA ATT aCT GAG GTA AAG GCT GAA 964 Asp Glu Glu Lys Glu Val Ala Lys Glu Ile Pro Glu Val Lys Ala Glu GAA AAA OCA GAT TZ:T AAA GAC TGT ATG GAG GCA ACC OCT GAA GTA AAA 1012 Glu Lys Ala Asp Ser Lys Asp Cys Met Glu Ala Thr Pro Glu Val Lys GAA GAT OCI' AAA GAA GTC OOC CAG GTA AAG GC'A GAT GAT AAA GAA CAG 1060 Glu Asp Pro Lys Glu Val Pro Gln Val Lys Ala Asp Asp Lys Glu Gln Pro Lys Ala Thr Glu Ala Lys Ala Arg Ala Ala Val Arg Glu Thr His AAA AGA GiT CCT GAG GAA AGG GTP OGG GAC AGT GTA GAT CiT AAA AGA 1156 Lys Arg Val Pro Glu Glu Arg Leu Arg Asp Ser Val Asp Lau Lys Arg GCT AIOG AAG GGA AAG aCT AAA AGA GAA GAC OCT AAA GGC ATT OCT GAC 1204 Ala Arg Lys Gly Lys Pro Lys Arg Glu Asp Pro Lys Gly Ile Pro Asp Tyr Trp Leu Ile Val Leu Lys Asn Val Asp Lys Leu Gly Pro Met Ile CAG AAIG TAT GAT GAG OOC ATT G"IG AAG TTC TTG TOG GAT GTT AGC CIG 1300 Gin Lys Tyr Asp Glu Pro Ile Leu Lys Phe Leu Ser Asp Val Ser Leu Lys Phe Ser Lys Pro Gly Gln Pro Val Ser Tyr Thr Phe Glu Phe His 350 355 = 360 Phe Leu Pro Asn Pro Tyr Phe Arg Asn Glu Val Leu Val Lys Thr Tyr ATA ATA AP-G GCA AAA C7CA GAT CAC MT GAT QOC TTG TTT Tt.T TGG GGA 1444 Ile Ile Lys Ala Lys Pro Asp His Asn Asp Pro Phe Phe Ser Trp Gly Trp Glu Ile Glu Asp Cys Lys Gly Cys Lys Ile Asp Arg Arg Arg Gly AAA GAT GTT A+CT GTG ACA ACT AOC CAG AGT GGL ACA ACT GCT ACT GGA 1540 Lys Asp Vai Thr Val Thr Zhr Thr Gln Ser Arg Thr Thr Ala Thr Gly GAA ATT GAA ATG CAG CxA AGA GIG GT'T OCT AAT GCA TCA TTC TTC AAC 1588 Glu Ile Glu Ile G1n-Pro Arg Val Val Pro Asn Ala Ser Phe Phe Asn TTC TTT AGT OCT GCT.GAG ATT C7CT ATG ATT GOG AAG CTG GAA aCA CJGA 1636-Phe Phe Ser Pro Pro Glu Ile Pro Met Ile Gly Lys Leu Glu Pro Arg Giu Asp Ala Ile Leu Asp Glu Asp Phe Glu Ile Gly Gln Ile Leu His GAT AAT GTC ATG C'IG AAA TCA ATC TAT TAC TAT ACT GGA GAA GTC AAT 1732 Asp Asn Val Ile Leu Lys Ser Ile Tyr Tyr Tyr Thr Gly Glu Val Asn Gly Thr Tyr Tyr Gln Rwe Gly Lys His Tyr Gly Asn Lys Lys Tyr Arg AAA. TAAiC~'PC.AATC TGAAAGATZT TTCAAGIATC TTAAAATCf C AA~'aAAGTC'aAA 1833 Lys GCAGATTCAT ACAOOC.`I'!GA AAAAAGPAAA AOOC'I'GAOLT GTAAGCTGAA CACITATTATT 1893 aGTTATAGIC AAG'1'TTT'1GT GGPTTCTPuG TAlGTCTATAT TTTAAAAATA GTCC.TAAAAA 1953 GTGTCTAAGT GOCRGTi'TAT TCTATGTAGG ('TGPT(`TAGT ATAATATTG'1' TC'.~1AAATATG 2013 TAAGC7."GTIG TCAATTATGT AAAGC'ATG<I'T AGTTTGGTTW TAICAC'AGTGP TGAZTTPPGT 2073 GATGTOCPTT GG'iCATGI"iT CTGTTAGACT GTAGCTG'1'GA AACTG7CAGA AT'i'GTTAAL'T 2133 GAAACAAATA TTTGCTIC'aAA AAAAAAAGTT CATGAAGTAC CAATCI,AAGT GTT'iTATTTT 2193 T'IT1C'ITPtT 'I'OC'.AGOOCAT AAGAC,TAAOG GTITAAATCr GCITGCA~.'TA GCI'GIGOClV

CAZTAGTTTG CTATAGAAAT OCAGTAGTTA TAIGTAAATAA AACAGiGTAT TTWAAGTI'P 2313 GACI'GCTZGA AAAAOhTTAG CATACA'I'C.TA A'ICRC'aAAAAG AIQCACATTPG ATTC;AAGTGA

GAaC'PI'QPGP ATGZY'ACATA TAGTOGOCTA TAAATTTAAT CATAATGATG TTAT'iGT7TA 2433 OCAICTGAGGT GTTAATATAA CATAGTkPIT TPGAAAFsAGP T7CT'ICAT{,`P TATATTGIGP 2493 AATTGTAAPC TAAAGATA+OC G'IvTPTTC7IT TGTATL`QTG'P TGTAOCTPOC CITTCACrGA 2553 AAATGATCAC TT~AT'ITGAT RCi'GITPITC ATG'PI'CTl'GP ATZGCAAQCT AAAATAAATA 2613 (2) INFIOWATION FOR SEQ ID N0: 22 :

( i ) sDQ[1BNCE CWUUCTERLSTICS:
(A) LENC#iH: 170 amino acids ( B ) TYPE: aatirm acid ( D ) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SnQ[IF.~VCE DESCRIPTION: SDQ ID N0: 22:

Met Thr Glu Leu Gln Ser Ala Leu Leu Leu Arg Arg Gin Leu Ala Glu Leu Asn Lys Asn Pro Val Glu Gly Phe Ser Ala Gly Leu Ile Asp Asp Asn Asp Leu Tyr Arg Trp Glu Val Leu Ile Ile Gly Pro Pro Asp Thr Lsu Tyr Glu Gly Gly Val Phe Lys Ala His L2u Thr Phe Pro Lys Asp Tyr Pro Leu Arg Pro Pro Lys Met Lys Phe Ile Thr Glu Ile Trp His Pro Asn Val Asp Lys Asn Gly Asp Val Cys I1e Ser Ile Leu His Glu Pro Gly Glu Asp Lys Tyr Gly Tyr Glu Lys Pro Glu Glu Arg Trp Leu Pro Ile His Thr Val Glu Thr Ile Met Ile Ser Val Ile Ser Met Leu Ala Asp Pro Asn Gly Asp Ser Pro Ala Asn Val Asp Ala Ala Lys Glu Trp Arg Glu Asp Arg Asn Gly Glu Phe Lys Arg Lys Val Ala Arg Cys Val Arg Lys Ser Gin Glu Thr Ala Phe Glu (2) INFORMATION FOR SEQ ID N0:23:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 510 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA(genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:23:

ATC'aACGGAOC TGCAGZ'00GC AC'POCTALTG CGAAGAC',AOC RCGCALdAPdLT CAACAAAAAT 60 CCAG7I'GGGAAG GCTiTI'G`IC~C AGGTZTAATA GATGACAATG ATCTCPACCG ATOGGAAGIC 120 CTTATTATTG GCOC'i'CCAGA TAC.ACTZTAT GAAGG1'GGTG TTl'TTAA<3GC TCATLRTACT 180 T'iC)CC.AAAAG ATTATCCOCP CCGACCTCCT AAAATGAAAT TCATTACAC'xA AATCTGGCAC 240 CCAAATGTTC ATAAAAATGG TGAT I'GTGC ATl'TCTATTC TTCAZOAGCC ZGGGCoAAGAT 300 AAGTATGUT'P ATGAAAAOOC AG'AGGAAOOC TOOC.TOOCPA TCG9CACTGP GGAAAOCATC 360 ATGATTAGIG TCAT=AT GCTGGCAGAC CCTAAZbC'~(' ACl'CAUCTGC TAATGT'1'GAT 420 GCPOOC'~AW AATGGAGGGA AGATAGAAAT GGAGAATTTA AAAGAAAAOr TGCOOO= 480 GTAAGAAAAA GC7GAAGAiGAiC TGCPTTIC'aAG 510 (2) INFORMATION FOR SEQ ID NO:24:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 617 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA(genomic) (iii) HYPOTHETICAL: NO

(iv) ANTI-SENSE: NO
(vii) IMMEDIATE SOURCE:
(A) LIBRARY: Human fetal brain cDNA library (B) CLONE: GEN-423A12 (is) FEATURE:
(A) NAME/KEY: CDS
(B) LOCATION: 19..528 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:24:

GGGOCCfOG(' CAGGC'AM ATG AC7G GAG CTG CAG 'hOG GCA CI+G CTA CiG CGA .51 Met Thr Glu Leu Gln Ser Ala Leu Lau Leu Arg AGA CAG CTG GCA GAA C3'C AAC AAA AAT OCA GTG GAA GOC TTT TC'T GCA 99 Arg Gin Lau Ala Glu Leu Asn Lys Asn Pro Val Glu Gly Phe Ser Ala Gly Leu Ile Asp Asp Asn Asp Leu Tyr Arg Trp Glu Val Leu Ile Ile GOC CCT CCA GAT ACA CTT TAT GAA GGT GGr GTT TTT AAG GCT CAT CTT 195 Gly Pro Pro Asp Thr Leu Tyr Glu Gly Gly Val Phe Lys Ala His Lau AGT TTC OCA AAA GAT TAT COC CTC aGA CGT aCT AAF- ATG AAA TRC ATT 243 Thr Phe Pro Lys Asp Tyr Pro Leu Arg Pro Pro Lys Met Lys Phe Ile Thr Glu Ile Trp His Pro Asn Val Asp Lys Asn Gly Asp Val Cys Ile Ser Ile Leu His Glu Pro Gly Glu Asp Lys Tyr Gly Tyr Glu Lys Pro Glu Glu Arg Trp L8u Pro Ile His Thr Val Glu Thr Ile Met Ile Ser Val Ile Ser Met Leu Ala Asp Pro Asn Gly Asp Ser Pro Ala Asn Val Asp Ala Ala Lys Glu Trp Arg Glu Asp Ai+g Asn Gly Glu Phe Lys Arg At,A GTT Gt7C GOC TGT GTA AGA AAA AOC CAA GAG AICT GCT TT'T GAG 528 Lys Val Ala Arg Cys Val Arg Lys Ser Gln Glu Thr Ala Phe Glu TGACATITAT TTAGCAGGTA GTAACITCAC TTAT'iTCAGG GICTOf:AATT GAGAAAICATG 588 OC~T ~CZC~C~+CPC TAC0('.NJ(X` 617 (2) IMM,TION FOR SDQ ID NC): 25:

( i ) SEQUIIVCE CHARACTERIMICS:
(A) IE[VG't'fi: 374 aneino acids ( H ) TYPE: aomino ac3.d (D) ToPOLOGY: linear ( ii ) NDIECXJLE TYPE: protein ( xi ) SEQUENCE DESQtIPTIaN: SDQ ID A10: 25 :

Met Val Leu Tip Glu Ser Pro Arg Gln Cys Ser Ser Trp Thr.LBu Cys Glu Gly Phe Cys Trp Leu Leu Leu Leu Pro Val Met Leu Lau Ile Val Ala Arg Pro Val Lys LSu Ala Ala Phe Pro Thr Ser L2u Ser Asp Cys Gln Thr Pro Thr Gly Trp Asn Cys Ser Gly Tyr Asp Asp Arg Glu Asn Asp Leu Phe Leu Cys Asp Thr Asn Thr Cys Lys Phe Asp Gly Glu Cys L8u Arg Ile Gly Asp Thr Val Thr Cys Val Cys Gln Phe Lys Cys Asn Asn Asp Tyr Val Pro Val Cys Gly Ser Asn Gly Glu Ser Tyr Gln Asn Glu GYs Tyr Leu Arg Gln Ala Ala Cys Lys Gln Gln Ser Glu Ile Leu Val Val Ser Glu Gly Ser Cys Ala Thr Asp Ala Gly Ser Gly Ser Gly Asp Gly Val His Glu Gly Ser Gly Glu Thr Ser Gln Lys Glu Thr Ser Thr Cys Asp Ile Cys Gin Phe Gly Ala Glu Cys Asp Glu Asp Ala Glu Asp Val Txp Cys Val Cys Asn Ile Asp Gys Ser Gin 'i'rr Asn Phe Asn Pro Leu Cys Ala Ser Asp Gly Lys Ser Tyr Asp' Asn Ala Cys Gin Ile Lys Glu Ala Ser Cys Gin Lys Gin Glu Lys.Ile Glu Val Met Ser Leu Gly Arg Cys Gln Asp Asn Thr Thr Thr Thr Thr Lys Ser Glu Asp Gly His Tyr Ala Arg Thr Asp Tyr Ala Glu Asn Ala Asn Lys Leu Glu Glu Ser Ala Arg Glu His His Ile Pro Cys Pro Glu His Tyr Asn Gly Phe Cys Met His Gly Lys Cys Glu His Ser Ile Asn Met Gin Glu Pro Ser Cys Arg Cys Asp Ala Gly Tyr Thr Gly Gln His Cys Glu Lys Lys Asp Tyr Ser Val Leu Tyr Val Val Pro Gly Pro Val Arg Phe Gln Tyr Val Iau Ile Ala Ala Val Ile Gly Thr Ile Gln Ile Ala Val Ile Cys Val Val Val Leu Cys Ile Thr Arg Lys Cys Pro Arg Ser Asn Arg Ile His Arg Gin Lys Gln Asn Thr Gly His Tyr Ser Ser Asp Asn Thr Thr Arg Ala Ser Thr Arg Leu Ile (2) INFORMATION FOR SEQ ID NO:26:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 1122 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA(genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:26:

ATGiC~I~CI~G'P 11OOO7 OCGOCRMM AO('.AOG'T+OG'A CACTTI'OfX'A OOOCt'1T1C~C 60 T+OOCt'OGRti~C TOCiCd00UGT CAZ=ACZC ATOOTAGt'70C GOI~(~OIG~~A GCTOOGTOCP 120 TTOOCPAOCP aCZTAAGIGA CTOOC,AkAOG QO(`.+~UOOOC'T Gx',AAT1CaC.'I~C TGG'iTAZG'AT

GACAGAGAAA ATGATCPCiT OC1C1C~iC`aAC AOCAAC,AOCP G!'AAATPiC',A ZTGOGGGAATOP 240 TTAAGAATTG GAGGiACAC7iUr GAL`Z't~00C~1PC ZC7J[~:A~C"A AQ'iGCAACAA TGAL'TATGRG

GCIC7CAATOG GGA~('aAOCTAC CAGkATGAGT GTPACCPOOG ACAGGGZCrCA 360 TGCAAAICAGC AGAGTGWAT ACTT.GTGC"1G TCAC'~AAiOGAT CAZGTOC7C".AC AGATGC'AGGA 420 TC;AIOGATCTG GAC'~AZGC''P OCATGAAOOC Tt:TGGAGAAA CTAGTCAAAA GGAGACATfJC 480 ACCTGhGA.TA TTZCrOCAGGPP TGGl'GCAGAA TGIC''~lOGAAG ATGOOGAGGA TC~1'CTOGIGT 540 =

GIGTOPAATA TT~GAC[GPTC 7~(`.AAA(7CAAC TTC',AATOCCC TC'iCXOGx.I'TC TGATOOGAAA

ZCTPATGATA AZnC'AZnOf'.A AATCAAAICiAA GCATCGI'Ol'C AGAAACAGGA GAAAATl'GAA 660 QPCATOTCIT TGOQiXX'aATG TCAAGATAAC ACAACTACAA CTAGTAAGTC TGAAC,ATGG(" 720 CATTAZGCAA GAACA[',ATTA ZGC'AGAGAAT aCCTTAAC'AAAT TAGAAGAAAG TGCCAGAGAA 780 CACCACATAIC CTl'G1b00C'aA iACATPACAAT GC~CI'TCIC~ICA TOCATGGGAA
G1GiC',AG1f',AT 840 ZCTATCAATA TGCA6iGi40CC ATCPiGCAGG TGZGAZC~C.`Z~G GITATACTGG ACAAClACTV'T 900 GAAAAAAAGG ACTACAQPOT ZC.TATAOGZT G7"I'OOOGiO1C CTOr1CGATT ZCAGTAZG'PC 960 TTAATOOC',AG CTQI'GATTOG AACAAT'ICAG ATTGCTGI'CA TCTGl'OTOGT GGi'OC'iC'MOC

ATCACAAi+OGA AATGOOCCAG AAGCAACAGA ATPCACAIGAIC A-GAAOCAAAA TAIC,AGGOCAC 1080 TP,iCAGPTCAG ACAATACAAC AAGAGCGTCC ACGAI GTTAA TC 1122 (2) INFORMATION FOR SEQ ID NO:27:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 1721 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA(genomic) (iii) HYPOTHETICAL: NO.

(iv) ANTI-SENSE: NO

( vii ) IMMEDIATE SOURCE:
(A) LIBRARY: Human fetal brain cDNA library (B) CLONE: GEN-092E10 (ix) FEATURE:
(A) NAME/KEY: CDS
(B) LOCATION: 368..1489 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:27:

~OG O~ QOCI~OCAOOC TGOCPOCi'CG GGCTOCI9C'I'C QI'CPGOOOT 60 GGACi'OOCGr CTCCTCCi'GT OCTO GGCTP COCAGAG= OCTOCITATG GCAGCAOCZT 120 COOGOGTCIC Q000G(',Ai(~CT TCIC'.AGOGGA OGAOOCIti`IC GCPOOGGGOC TC',AiGOCAG'TC

CCI'GC'aATGTT GC!'GAAACIC TCGAGp-TCAT GOCdOGGGI'iT GGCPOCPGCT TOOOOOC70GG 240 GTOOCAC'1GC CA~]CGOOOOC GOCPCi'GCIG UOGOOGIC)0(~ CGOC'aATGCPC AGTAGOOOGC 300 00G0C31kTaCT GPOr'IKACIM GAAGCOGTTT GC1GCPGCAG AGPIUCPdCGA 360 ACTA+GIC ATG GTG CTG TGG GAG TOC QOG aGG CAG TaC AGC AOC TOG ACA 409 Met Val Ieu Trp Glu Ser Pro Arg Gln Cys Ser Ser Trp Thr Lsu Cys Glu Gly Phe Cys Trp Leu Leu Lau Lau Pro Val Met Lau Leu Ile Val Ala Arg Pro Val Lys Leu Ala Ala Phe Pro Thr Ser Leu Ser Asp Cys Gin Thr Prro Thr Gly Trp Asn Cys Ser Gly Tyr Asp Asp Arg GAA AAT GAT CPC TTC CIC TGT GAC A,OC AAC AOC TGT AAA TTT GAT GGG 601 Glu Asn Asp Lau Phe Lsu Cys Asp Thr Asn Tthr Cys Lys Phe Asp Gly GAA TGT TTA AGA ATT GGA GAC AGT GTG ACT TGC Gi'C TGT CAG TRC AP-G 649 Glu Cys Lsu Arg Ile Gly Asp Thr Val Thr Cys Val Cys Gln Phe Lys 80 = 85 90 TGC AAC AAT GAC TAT QIg aCT GTG TOT GGC TOC AAT GGG GAG AGC TAC 697 Cys Asn Asn Asp Tyr Val Pro Val Cys Gly Ser Asn Gly Glu Ser Tyr CAG AAT GAG TGI' TAC = C!G OGA CAG GCT GCA TGC AAA CAG CAG AGT GAG 745 Gln Asn Glu Cys Tyr Leu Arg Gln Ala Ala. Cys Lys Gin Gln Ser Glu ATA CLT G'M G't'G TCA GAA GGA TM TGT GOC ACA GAT GCA GGA TCA GGA 793 Ile Leu V.al Val Ser Giu Gly Ser Cys Ala Thr Asp Ala Gly Ser Gly Tt,'T GGA. GAT GGA GTC CAT GAA GGC TL:T GGA GAA ACT AGT CAA AAG GAG 841 Ser Gly Asp Gly Val His Glu Gly Ser Gly Glu Ztr Ser Gin Lys Glu ACA TOC AOC TGT GAT ATT = CAG TTT GGT GCA GAA TGT GAC GAA GAT 889.
Thr Ser Thr Cys Asp Ile Cys Gln Phe Gly Ala Glu Cys Asp Glu Asp GOC GAG GAT GTC TGG TGr G1'G TGT AAT ATT GAC TOT RCT CAA AOC AAC 937 Ala Glu Asp Val Trp Cys Val Cys Asn Ile Asp Cys Ser Gin Thr Asn Phe Asn Pro Leu Cys Ala Ser Asp Gly Lys Ser Tyr Asp Asn Ala Cys Gln Ile Lys Glu Ala Ser Cys Gln Lys Gln Glu Lys Ile Glu Val Met TCT TTG GGT GGA TGT CAA GF-T AAC ACA AiCT ACA ALT ACT APuG TCT GAA 1081 Ser Leu Gly Arg Cys Gin Asp Asn Thr Thr Thr Tthr Thr Lys Ser Glu 225 . 230 235 GAT GGG CAT TAT GCA AGA ACA GAT TAT GCA GAG AAT Gt:T AAG AAA TTA 1129 Asp Gly His Tyr Ala Axg Thr Asp Tyr Ala Glu Asn Ala Asn Lys Leu Glu Glu Ser Ala Arg Glu His His Ile Pro Cys Pro Glu His Tyr Asn Gly Phe Cys Met His Gly Lys Cys Glu His Ser Ile Asn Met Gln Glu Pro Ser Cys Arg Cys Asp Ala Gly Tyr Thr Gly Gln His Cys Glu Lys AAIGGACTACAO,'TGRTGTATACG'1TGTTOCCG(GPOCTGTAOGATTTCAG 1321 Lys Asp Tyr Ser Val Lau Tyr Val Val. Pro Gly Pro Val Arg Phe Gln TAT GTC TTA ATC G1C;A GCT GIG ATT GGA ACA ATT CAG ATT GCT GTC ATC 1369 Tyr Val. Leu Ile Ala Ala Val Ile Gly Thr Ile Gln Ile Ala Val ile Tt7r GTG GTG GTC CTC TGC ATC ACA AGG AAA TGCC COC AGA AOC AAC AGA 1417 Cys Val Val Val L8u Cys Ile Thr Arg Lys Cys Pro Arg Ser Asn Arg Ile His Arg Gln Lys Gin Asn Thr Gly His Tyr Ser Ser Asp Asn Thr ACA AGA GOG TaC AIOG AOG TPA ATC TAA AGGGAGCATG TTTCACAGM 1512 Thr Arg Ala Ser Thr Arg Leu Ile GCICaGACl'AC CGAGAG7CI"i'G GGACTACAC'AA TACIAG'PATTA TAGACAAAAG AATAA~'aAIGAA

GAG'ATG'TACA CATGTIGOCP T(~('ATITQIG GTAATCTACA OCAAZCAAAA CATMACPAC 1632 ,AiOCTATATZT GATTAZGPAT GGATATATZT GAAATAQTAT ACATTGiti`iT GATGPT'IRTP 1692 (2) INFORNATION FOR SnQ ID ND:28:

(1) SEQUENCE t3RARAC'PEZISTICS :
(A) LENGtH: 817 aiaino acids ( B ) TYPE: amino acid ( D ) TOPOIAG'Y: linear ( ii ) NlOLECxTLE TYPE: protein ( xi. ) SDQUIIViGE DFSCRIPTION: SHQ ID NO: 28:

Met Gly Asp Thr Val Val Glu Pro Ala Pro Leu Lys Pro Thr Ser Glu Pro Thr Ser Gly Pro Pro Gly Asn Asn Gly Gly Ser Leu Leu Ser Val Ile Thr Glu Gly Val. Gily Glu Leu Ser Val Ile Asp Pro Glu Val. Ala G]n Lys.Ala Cys Gln Glu Val Leu Glu Lys Val Lys Leu Lieu His Gly Gly Val Ala Val Ser Ser Arg Gly Thr Pro Leu Glu Leu Val Asi Gly Asp Gly Va1 Asp Ser Glu Ile Arg Cys Leu Asp Asp Pro Pro Ala Gln Ile Arg Glu Glu Glu Asp Glu Met Gly Ala Ala Val Ala Ser Gly Thr Ala Lys Gly Ala Arg Arg Arg Arg Gln Asn Asn Ser Ala Lys Gln Ser Txp Leu Lau Arg leu Phe Glu Ser Lys Loau Phe Asp Ile Ser Met Ala Ile Ser Tyr Leu Zyr Asn Ser Lys Glu Pro Gly Val Gln Ala Tyr -Ile Gly Asn Arg Leu Phe Cys Phe Arg Asn Giu Asp Val Asp Phe Tyr Leu Pro Gin Leu Leu Asn Met Tyr Ile His Met Asp Glu Asp Val Gly Asp Ala Ile Lys Pro T-yr Ile Val His Arg Cys Arg Gln Ser Ile Asn Phe Ser Leu Gln Cys Ala Leu L8u Leu Gly Ala Tyr Ser Ser Asp Met His Ile Ser Thr Gin Arg His Ser Arg Gly Thr Lys Leu Arg Lys Leu Ile Leu Ser Asp Glu Leu Lys Pro Ala His Arg Lys Arg Glu Leu Pro Ser Leu Ser Pm Ala Pro Asp Thr Gly Leu Ser Pro Ser Lys Arg Thr His Gln Arg Ser Lys Ser Asp Ala Thr Ala Ser Ile Ser Leu Ser Ser Asn Leu Lys Arg Thr Ala Ser Asn Pro Lys Val Glu Asn Glu Asp Glu Glu Leu Ser Ser Ser Ttvc Glu Ser Ile Asp Asn Ser Phe Ser Ser Pro Val Arg Leu Ala Pro Glu Arg Giu Phe Ile Lys Ser Lau Met Ala Ile Gly Lys Arg Leu Ala.Thr Leu Pro Thr Lys Glu G]n Lys'Thr Gin Arg Leu Ile Ser Glu Leu Ser Leu L$u Asn His Lys LSu Pro Ala Arg Val Trp LSu Pro Thr Ala Gly Phe Asp His His Val Val Arg Val Pro His Thr Gin Ala Val Val Leu Asn Ser Lys Asp Lys Ala Pro Tyr Leu Ile Tyr Val Glu Val Leu Glu Cys Glu Asn Phe Asp Thr Thr Ser Val Pro Ala Arg Ile Pro Glu Asn Arg Ile Arg Ser Thr Arg Ser Val Glu Asn Leu Pro Glu Cys Gly Ile Thr His Glu Gln Arg Ala Gly Ser Phe Ser Thr Val Pro Asn Tyr Asp Asn Asp Asp Glu Ala Trp Ser Val Asp Asp Ile Gly Glu Leu Gln Val Glu Leu Pro Glu Val His Thr As.n Ser Cys Asp Asn Ile Ser Gln Phe Ser Val Asp Ser Ile Thr Ser Gln Glu Ser Lys Glu Pro Val Phe Ile Ala Ala Gly Asp Ile Arg Arg Arg Leu Ser Glu Gin Leu Ala His Thr Pro Thr Ala Phe Lys Arg Asp Pro Glu Asp Pro Ser Ala Val Ala Leu Lys Glu Prcm Trp Gin Glu Lys Val Arg Arg Ile Arg Glu Gly Ser Pro Tyr Gly His Leu Pro Asn Trp Arg Leu Leu Ser Val Ile Val Lys Cys Gly Asp Asp Leu Arg GIn Glu Leu Leu Ala Phe Gin Val Leu Lys Gln Leu Gln Ser Ile Trp Glu Gin Glu Arg Val Pro Leu Trp Ile Lys Pro Ile Gln Asp Ser Cys Glu Ile Thr Thr Asp Ser Gly Met Ile Glu Pro Val Val Asi Ala Val Ser Ile His Gln Val Lys Lys Gin Ser Gln Leu Ser LSu Leu Asp Tyr Phe Lau Gln Glu His Gly Ser Tyr Thr Thr Glu Ala Phe Leu Ser Ala Gln Arg Asn Phe Val Gln Ser Cys Ala Gly Tyr Cys Leu Val Cys Tyr Leu Leu Gin Val Lys Asp Arg His Asn Gly Asn.Ile Lau Leu Asp Ala Glu Gly His Ile Ile His Ile Asp Phe Gly Phe Ile Leu Ser Ser Ser Pro Arg Asn Leu Gly Phe Glu Ttir Ser.Ala Phe Lys Leu Thr Thr Glu Phe Val Asp Val Met Gly Gly Leu Asp Gly Asp Met Phe Asn Tyr Tyr Lys Met Leu Met Leu Gin Gly Leu Ile Ala Ala Arg Lys His Met Asp Lys Val Val Gin Ile Val Glu Ile Met Gln Gln Gly Ser Gln Leu Pro Cys Phe His Giy Ser Ser Thr Ile Arg Asn Leu Lys Glu Arg Phe His Met Ser Met Thr Glu Glu Gln Leu Gln Leu L2u Val Glu Gln Met Val Asp Gly'Ser Met Arg Ser ~

Ile Thr Thr Lys Leu Tyr Asp Gly Phe Gln Tyr LQu Thr Asn Gly Ile Met (2) INFORMATION FOR SEQ ID NO:29:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 2451 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA(genomic) (xi) SEQUENCE'DESCRIPTION: SEQ ID NO:29:

AZGDf',,,AGATA CAGTAOrGC'aA GCCTGOC0(7C TPGAAGOCAA CPPCTC'aA00C CACTTCI'GOC 60 CCACCAGGGA ATAAZUOGOG GTUCGRC~C'rA AGPG'ir'ATCA. CGC"~GGGGGT aGGGGAACTA 120 TCAG'IC'aATTG AICCCTGAGGT GGOCC'AGAAG GOCIGOCAGG AOGI'GrTGGA GAAAGTCAAG 180 CTZTIGCATG GAGGOGTGGC AGTCrCrAGC AGAGGCAIOCC CACiGUAIT GGZC'.AATGGG 240 GATOGTGTGG ACAG-IGAGAT CC7Gr'IGCCrA GATGATCCAC C'I'GCCCAGAT CAGGGAGC'~FUG 300 GAA!('~ATGAiGA TOGGGOOOOC TG'rGOC7C'YCA GGCAC,l1O0CA AAGGAGt'AAG AAGAlUGGOGG

CAGAACAACr CAGC.TAAACA GICTrCG~COC.TG CTGAGGCTGT 420 ATC.'rOCATGG CJCARTTCATA CCIGTATAAC TaC'AAGCAGC C.IC'GAGTACA AOC7CTACATT 480 GGCAACCGGC TCT'I'CTCM ZbGCAAOG?1G GACGPQGACT Tr7rATCPC~fJC OCAGITGCTT 540 AACATG'rACA TCCACATGGA TGAGGAOGPG GGI'GATGCCA TTAAGOO~,.TA CATAGTCCAC 600 CG'r'P00MCC AGAGC'ATTAA C'I'TTTCCCTC CAGTGI'GCCC TGTZGCTrGG GGCCrATiCT 660 TCAGACATGC ACATr'I'C7C`,AC TCAAOGACAC TCCCGrGGGA CCAAGC,TACG GAAGC,'TC',ATC

C'1C.'TCAGATG AGCTAAAGOC AGCTCAC'.AGG AAGAGOGAOC TGOOCTOCPT GAGOCCGGCC 780 CC.'TGATACAG GGCIGTCI'CC C'POCAAAAGG ACZC'ACCAGC GC.ZCTAAG'IC AGATGCCACT 840 G(7CAGC'ATAA GTCTCAGCAG C'AACCTGAAA CGAACAGCCA pCAAOnCrAA AGTGGAGAAT 900 GAGGATGAGG A+CGCTG=rCCTC Cl4GCACOGAG AGTATTGATA ATTCATI'CAC TTOCCCTGTT 960 C7C'~ACTGGC,'TC CTGAGAGAGA ATTCATCAAG TCxCZGATGG CGAT00GC'.AA GIXGGC'TGOOC

AOGCTOOOCA OC'AAAGAGCA GAAAAICACAG AGGCTGF-TCT CAGAGCTG'rC C7CI'GCTCAAC 1080 CATAAGCTCC C.TGOCXX"'aAGT CTGGGTGOCC AC.TIX7rGGCT TTGAi0CA0CA OGrOGrQO(~`r GPAOOOCAICA CAICAGGCTGT TGrC:C'ICAAC TC)CAAGGAlC'.A AGGCr00CrA OCrGATTTAT 1200 GTGf",AAGrCC TIGAATGTGA AAAIC'IRT(`lIC AOCAOCAGZG TCJOC.TGO(70G GAZ"OOOOGAG

AAC70GAP,TTC GGAGTACGAG Gr000PACAA AACTTGOOCG AATGrGGTAT TAOOC'.ATGAG 1320 CAGOGAQCTG GC'AOCIrCAG CACTGr000C AACTA4G~AC'A AOC'1TGA7GA GGOC'IC~GTCG 1380 GTGGATGACA TAGGCJGAGCr GCAAG'rGGAG C'r000('aAA[" TGCATAIX'.AA CAGGPGTGFUC 1440 AAICATCr= AGTZCTCWr GGAiCAGC''ATC A+OCAG(7C',AGC' AGAOC'.AAOGA GOC'IC~I'GR'rC

ATTGCAOC'AG CiGGAC'ATOCIG ~7~OOOOCTr TCGCGAAC,AG'C 'rGGCTC'ATAC OOOGACAGOC

TTCAAACGAIG AOOCA~'~AAGA TCGRTC.TGC'A GTTGCTCrCA AAGAGOOCrG GCõAQGAGAAA 1620 GTACGGOGGA TCAGAGAGGG CTOOOOCTAC GGOCATC'IC7C OC.AATIG(.aOG GC1Y+~OCrGrCA 1680 GrCATZGTCA AIGPGI`GGGGA TGAOC`IRO~G CAFIIC'zP,IOCPTC TGOOG'ZTIC'A GGPGPTGeAAG

CAACrGCAQr CCATT'PGGGA. AC,AGGAGOf3A GrO000C'PIT GGATC.AAOOC AATACAP-GAT 1800 TCTTGIGAAA TTAOGAICTGA TAGTGGCATG ATTGAAOCAG TGGTC'AAT C TGRGTCC'ATC 1860 CATC'.AOC=rGA AIGAAAC.AGrC ACArGC'I'CTOC TTGCTC+GATT AL'TTOCTACA GGAGCAOGaC

AGTTACAC7CA CPGAGGiC'.ATT C1C:TCAGrOCA CAGCGCAATT TI"GTGCAAAG TTG~`GC'IGGG

TAGTGiC,'TTGG TCTGC.`rAOCT GCTaCAAGTC AAGGACACdAC ACAATGGGAA TATOG'iTTTG 2040 GACGCAGAAG GOCACP-TCAT OCACATO(3AC TTTQGCTrCA TOCTCiCX'.AG CrCA,0000GA 2100 AATC:TCGGCr TTGAGACGrC AGOCT'rrAAG cTC3AloCAC.AG AGTTrGI'GGA TGc1GATGGGC 2160 aGOC'rGGPiTG GOGACATGZT CAACrAGTAT AAGATGCrGA TGCTGC'AAOG GCZGATTGOC 2220 aC'ICM~ ACATGGAMA GG'rOG'rOCAIG ATOG'1GGAGA TCATaCAGC'A AQGITCTCAG 2280 CTTaCTTGCT TC7CATGIX,`TC CAGCAOC'ATT OGAAAOCPCA AFuGAGAGGTr OCACATGAGC 2340 ATGF,CrGADG AGCAGCIGCA GG'ZGCrGGrG GAGC'AGP-ZGG TGGATOOCAG TATGO(YG'rCT 2400 ATCAQC.ACCA AACTCTATGA c7GGCTI'OCAG TAOCTCAOCA ACGa('.ATCAT G 2451 (2) INFORMATION FOR SEQ ID NO:30:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 3602 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA(genomic) (iii) HYPOTHETICAL: NO

(iv) ANTI-SENSE: NO
(vii) IMMEDIATE SOURCE:
(A) LIBRARY: Human fetal brain cDNA library (B) CLONE: GEN-428B12c2 (ix) FEATURE:
(A) NAME/KEY: CDS
(B) LOCATION: 429..2879 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:30:

GGTGGCTCAC GCCPGPAATC CCAGCAC.`ITT CaGGAGGoACAA GCAGATOfJC TTCAOOOCAG 60 GAGGTAGAGG CTGCAG'TGAG CPGI'~,~ATGGP GC(',ACTGC'.AC TCCAGCC'IM GCAATGAAGC 120 AAGA=AT CTC%kkkkkkJk AAATITTPAA AAAAGGCAAA GATGGGCX.TG GGGCACCAAA 180 TAZTCCI4GAG GAAAGGGAAC G'PGlGTACTC CTTGAGGTOG GGAACATGAC (7CACT'PGAGG 240 TGC',AGAAAGA AGAC.'TTGTAT GGGGC'I'GGTG CAGCCTCOGC GGOOGCTGIC AOGC'~AAOCGC 300 AQGOOGCCAA TGGAACCOGG GAGCGG'i'CGC ZGCTO(.~TGAG GOGGCAGTGP CGGC',AG'rCCA 360 AOCOC7GACIG CCCGCAOCCC C'POOOCGGGIG TCOOOCAGAG CTIGC'aAAGCP CGkAGTCTGG 420 Ci'GM3GCC ATG GGA GAT ACA GTA GTG GAG CCT OC CCC TTG AAG CCA ACT 470 Met Gly Asp Thr Val Val Glu Pro Ala Pro Leu Lys Pro Thr TCT GAG aCC ACT TCT GOC CCA CCA GGG AAT AAT GGG GGG TOC CTG CTA 518 Ser Glu Pro Thr Ser Gly Pro Pro Gly Asn Asn Gly Gly Ser Leu Leu Ser Val Ile Thr Glu Gly Val Gly Glu Leu Ser Val Ile Asp Pro Glu GTG GOC CAG AAG GC1C TGC CAG GAG GTG TTG GAG AAA GTC AAG CI'T TTG 614 Val Ala Gln Lys Ala Cys Gln Glu Val LSu Glu Lys Val Lys L8u Leu CAT GGA GOC GTG GCA GTC TGT AGC AGA GGC AOC CCA CTG GAG T'IG G'TC 662 His Gly Gly Val Ala Val Ser Ser Arg Gly Thr Pro Leu Glu L2u Val AAT GOG GAT GGT GTG GAC AGT GAG ATC CGr TGC G'TA GAT GAT aC'A CCT 710 Asn Gly Asp Gly Val Asp Ser Glu Ile Arg Cys Leu Asp Asp Pro Pro Ala Gln Ile Arg Glu Glu Glu Asp Glu Met Gly Ala Ala Val Ala Ser GOC ACA GOC AAA GGA GCA AGA AGA CJGG COG CAG AAC AAC TCA GC,'T AAA 806 Gly Thr Ala Lys Gly Ala Arg Arg Arg Arg Gln Asn Asn Ser Ala Lys CAG TCT TaG CTG CTG AOG C.TG TTT GAG TCA AAA CZG TTT GAC ATC TOC 854 Gln Ser Trp Leu Leu Arg Leu Phe Glu Ser Lys Leu Phe Asp Ile Ser ATG GCC ATT TCA TAC CTG TAT AAC TCC AAG GAG CCT GGA.GTA CAA GOC 902 Met Ala I1e Ser Tyr Leu Tyr Asn Ser Lys Glu Pro Gly Val Gin Ala TAC ATT GGC A24C CX1G CIC TTC TGC TZT CGC AA+C GAG GAC GI'G GAC TTC 950 Tyr Ile Gly Asn Arg Leu Phe Cys Phe Arg Asn Glu Asp Val Asp Phe TAT CTG OC;C CAG TTG C1T AAC ATG TAC ATC CAC ATG GAT GAG GAC GTG 998 Tyr Leu Pro Gln Lsu Leu Asn Met Tyr Ile His Met Asp Glu Asp Val Gly Asp Ala Ile Lys Pro Tyr Ile Val His Arg Cys Arg Gln Ser Ile AAC TTT TCC CTC CAG TGT GOC CTG TTG CTT GflG GOC TAT TLT TCA GAC 1094 Asn Phe Ser Leu Gln Cys Ala Leu Leu Leu Gly Ala Tyr Ser Ser Asp ATG CAC ATT TOC ACT CAA CGA CAC TCC aG=I' GGG ACC AAG CTA aGG AAG 1142 Met His Ile Ser Thr Gln Arg His Ser Arg Gly Thr Lys Lsu Arg Lys CPG ATC CIC TCA GAT GAG CTA AAG CCA GCT CAC AGG AAG AGG GAG CiG 1190 Leu Ile Leu Ser Asp Glu Leu Lys Pro Ala His Arg Lys Arg Glu Lsu Pro Ser Lau Ser Pro Ala Pro Asp Thr Gly Leu Ser Pro Ser Lys Arg ACT CAC CAG OGC TGZ' AAG TCA GAT GOC ACT GrJC AOC ATA AGT CTC AOC 1286 Thr His Gln Arg Ser Lys Ser Asp Ala Thr Ala Ser Ile Ser Leu Ser AGC AAC CI'G AAA OGA ACA GGC AGC AAC OC't' AAA GTG GAG AAT -GAG GAT 1334 Ser Asn Leu Lys Arg Thr Ala Ser Asn Pro Lys Val Glu Asn Glu Asp GAG GAG CrC TCC TrJC,AGC ACC GAG AGT ATT GAT AAT TCA TTC AGT TaC 1382 Glu Glu Leu Ser Ser Ser Thr Glu Ser Ile Asp Asn Ser Phe Ser Ser (7CT GTT OGA C'IG GCT CCT GAG AGA GAA TTC ATC AAG TOC CPG ATG GOG 1430 Pro Val Arg Leu Ala Pro Glu Arg Glu Phe Ile Lys Ser Leu Met Ala ATG GOC AAG CJGG C1G GOC AfJG GTC QOC ACC AAA GAG CAG AAA ACA CAG 1478 Ile Gly Lys Arg Leu Ala Thr Leu Pro Thr Lys Glu Gln Lys Thr Gln AGG C'i'G ATC TCA GAG C'I'C TCC CIG CTC AAC CAT AAG C'IC CCT GC7C CGA 1526 Arg Lsu Ile Ser Glu Leu Ser Lau Leu Asn His Lys Leu Pro Ala Arg GTC TOG C'I'G Ot7C ACT GCT GGC T'IT GAC CAC CAC GTG GTC C)GT GTA OOC 1574 Val Tzp Leu Pro Thr Ala Gly Phe Asp His His Val Val Arg Val Pro CAC ACA CAG GCT G'I'T GTC CTC AAC TOC AAG GAC AAG GCT UOC TAC CtG 1622 His Thr Gln Ala Val Val Leu Asn Ser Lys Asp Lys Ala Pro Tyr Leu ATT TAT GIG GAA G'TC CTT GAA TGT GAA AAC TTT GAC ACC ACC AGT GTC 1670 Ile Tyr Va]. Glu Val Leu Glu Cys Glu Asn Phe Asp Thr Thr Ser Val Pro Ala Arg Ile Pro Glu Asn Arg Ile Arg Ser Thr Arg Ser Val Glu AAIC TTG C:OC GAA TGT GGT ATT AGC CAT GAG CAG CGA GCT GflC AGC TTC 1766 Asn Leu Pro Glu Cys Gly Ile Thr His Glu Gln Arg Ala Gly Ser Phe Ser Thr Val Pro Asn Tyr Asp Asn Asp Asp Glu Ala Trp Ser Val Asp GAC ATA GGC GAG CTG CAA GTG GAG C'I'C COC GAA GIG CAT AOC AAC AGC 1862 Asp Ile Gly Glu Leu Gin Val Glu Leu Pro Glu Val His Thr Asn Ser TGP GAC AAC ATC TCC t'AG TTC TGT GTG GAC AGC ATC AOC AGC CAG GAG 1910 Cys Asp Asn Ile Ser Gln Phe Ser Val Asp Ser Ile Thr Ser Gin Glu -AOC AAG GAG OCT G'I'G Tl'C ATT OCA GCA GGG GAC ATC OGC (]OG COC CIT 1958 Ser Lys Glu Pro Val Phe Ile Ala Ala Gly Asp Ile Arg Arg Arg Leu TOG GAA CAG CTG GCT CAT ACC OOG ACA GOC TIC AAA OGA GAC aCA GAA 2006 Ser Glu Gin Leu Ala His Thr Pro Thr Ala Phe Lys Arg Asp Pro Glu GAT (X.T TC.T GCA GTT GCT CIC AAA GAG OOC TOG CAG GAG AAA GTA C7GG 2054 Asp Pro Ser Ala Val Ala Leu Lys Glu Pro Trp Gin Glu Lys Val Arg Arg Ile Arg Glu Gly Ser Pro Tyr Gly His Leu Pro Asn Trp Arg Leu C'IG 'I'CA GTC ATT GTC AAG TGT GGG GAT GAC CTT OOG CAA GAG CIT CPG 2150 Leu Ser Val Ile Val Lys Cys Gly Asp Asp Leu Arg Gln Glu Leu LSu Ala Phe Gin Val Leu Lys Gln Leu Gin Ser Ile Trp Glu Gin Glu Arg Val Pro Leu Tip Ile Lys Pro Ile Gln Asp Ser Cys Glu Ile Thr Thr GAT AGP GOC ATG AZT GAA aCA GTG GTC AAT GCT GIG TOC ATC CAT C'AG 2294 Asp Ser Gly Met Ile Glu Pro Val Val Asn Ala Val Ser I1e His Gln GTG AAG RAA CAG TCA CAG CTC TC7C TTG CTC GAT TAC 'ITC CTA CAG GAG 2342 Val Lys Lys Gln Ser Gln Leu Ser Leu Leu Asp Tyr Phe Leu Gln Glu CAC GGC AGT TAC AOC ACT GAG GCA TTC CTC PM GCA CAG OOC AAT m 2390 His Gly Ser Tyr Thr Thr Glu Ala Phe Lau Ser Ala Gln Arg Asn Phe GTG CAA AGT TGP GC,'T GGG TAC TGC TTG GTC TGC TAC CTG CTG CAA GTC 2438 Val Gln Ser Cys Ala Gly Tyr Cys Leu Val Cys Tyr Leu Leu Gln Val Lys Asp Arg His Asn Gly Asn Ile Leu Leu Asp Ala Glu Gly His Ile ATC CAC ATG GAC TTT GOC TTC ATC CrC TOC AGC TCA OOC aGA AAT CTG 2534 Ile His Ile Asp Phe Gly Phe Ile Leu Ser Ser Ser Pro Arg Asn Leu GGC TiT GAG AOG TGF- GOC TTT AAG CTG ACC ACA GAG TTT GTG GAT GTG 2582 Gly Phe Glu Thr Ser Ala Phe Lys Leu Thr Thr Glu Phe Val Asp Val Met Gly Gly Leu Asp Gly Asp Met Phe Asn Tyr Tyr Lys Met Leu Met C'i'G CAA GGG CTG ATT GCC GL'T CJGG AAA CAC ATG GAC AAG GTG GTG CAG 2678 Leu Gln Gly Leu Ile Ala Ala Arg Lys His Met Asp Lys Val Val Gln ATC GTG GAG ATC ATG CAG CAA GGT TCT CAG CTT aCT TOC TTC CAT GGC 2726 Ile Val Glu Ile Met Gin Gln Gly Ser Gln Leu Pro Cys Phe His Gly TOC AGC ACC ATT CGA, AAIC CTC AAA GAG AGG TTC CAC ATG AGC ATG ACT 2774 Ser Ser Thr Ile Arg Asn Leu Lys Glu Arg Phe His Met Ser Met Thr Glu Glu Gln Leu Gln Leu Leu Val Glu G1n Met Val Asp Gly Ser Met COGG TCT ATG ACC ACC AAA CI'C TAT GAC GGC TTC CAG TAC CTC ACC AAC 2870 Arg Ser Ile Thr Thr Lys Leu Tyr Asp Gly Phe Gln Tyr Leu Thr Asn GGC ATC ATG TGA CA(JGCTOCri'C AGOQCAGGAG 'PGGTGGGGGGG TaGAGGGCAC 2922 Gly Ile Met *

(7CTOOC,'TAIGA uAGOCC,`PTGT CTGAGAAACC aC'AAAOCAGG AAACOOCA<7C TAOOCAP-CCA

TOC.ACOCAAG GGAAAZGGAA CG('.AAGAAAC AOGAAGGATC AZGIXMAAC TGOGAGAGCT 3042 TaCTGlUOGGG TGGC'aAC",~AGC1C AGCTGi'OGGG TCCAGACI=I'G ZTGGC~C'ITC
CC'IGCOCC.'TC 3102 CTGG!'C'IGI'G TCAGTAZTAC CACC.A~f`aA 'IG AC'TCCAGGAC TCACTGCCCT OCAGAAAACA

GAD(7rGACAA ATGtr-%AGGGA CAC'1'GGOGCC TTTCITG`I'CC TTGTAGGGGP CZCTCAGAOG 3222 T'iC'ITTaCAC AGGCCATCCT CTTATTC7W'T TC.Z'GGGGOOC AGGAAGTGGG GAAGAGTAGG 3282 TTC'I'C1G(OPAC TTAGGACT'iG ATCCTG'IWT TGCCACTGGC CATGCI'GCTG CCCAGCTCPA 3342 OOCC'iC70C'.AL'' Gf'~40CTACOC C'i"CCC.AOGGA COGACCOC't'G GCCCAAGCTC OOLTAGCIGG

OGOGCGC:ZGC G'POOOOUCIG CACTi'GCTC'~+, GG'l.'ZC700C'AT CATGGGCAAG GCAAGGGAAT

Tl7CCACAGCC CTCCAGTGTA CTGAOdGPAC TGGOG'I'AGCC ATO!'GGAATT CCCTACO~.~TG 3522 ACI'OC`iTCCC CAAAC70CAGG GAAAAGAGC.T C'trAAT'ITPP TAZTPITAAT ZTTTGITI3582 AATAAAGIC7C TTAG'TPAGCC 3602 (2) INFORMATION FOR SEQ ID NO:31:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 829 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:31:

Met Arg Phe Leu Glu Ala Arg Ser Leu Ala Val Ala Met Gly Asp Thr Val Val Glu Pro Ala Pro Leu Lys Pro Thr Ser Glu Pro Thr Ser Gly Pro Pro Gly Asn Asn Gly Gly Ser Leu Leu Ser Val. Ile Thr Glu Gly Val Gly Glu Leu Ser Val Ile Asp Pro Glu Val Ala Gin Lys Ala Cys Gln Glu Val Leu Glu Lys Val Lys Leu Leu His Gly Gly Val Ala Val Ser Ser Arg Gly Thr Pro Lau Glu Leu Val Asn Gly Asp Gly Val Asp Ser Glu Ile Arg Cys Leu Asp Asp Pro Pro Ala Gin Ile Arg Glu Glu Glu Asp Glu Met Gly Ala Ala Val Ala Ser Gly Thr Ala Lys Gly Ala Arg Arg Arg Arg Gin.Asn Asn Ser Ala Lys Gin Ser Trp Leu Leu Arg Leu PYye Glu Ser Lys Leu Phe Asp Ile Ser Met Ala Ile Ser Tyr Leu Tyr Asn Ser Lys Glu Pro Gly Val Gln Ala Tyr Ile Gly Asn Arg Leu Phe Cys Phe Arg Asn Glu Asp Val Asp Phe Tyr Leu Pro Gln Isu Leu Asn Met Tyr Ile His Met Asp Glu Asp Vai Gly Asp Ala Ile Lys Pro Tyr Ile Val His Arg Cys Arg Gin Ser Ile Asn Phe Ser Leu Gln Cys '210 215 220 Ala Leu Leu Leu Gly Ala Tyr Ser Ser Asp Met His Ile Ser Thr Gln Arg His Ser Arg Gly Thr Lys Leu Arg Lys Leu Ile Leu Ser Asp Glu Leu Lys Pro Ala His Arg Lys Arg Giu Leu Pro Ser Leu Ser Pro Ala Pro Asp Thr Gly Leu Ser Pro Ser Lys Arg Thr His Gln Arg Ser Lys Ser Asp Ala Thr Ala Ser Ile Ser Leu Ser Ser Asn Leu Lys Arg Thr Ala Ser Asn Pro Lys Val Glu Asn Glu Asp Glu Glu Lau Ser Ser Ser Thr Glu Ser Ile Asp Asn Ser Phe Ser Ser Pro Val Arg Leu Ala Pro Glu Arg Glu Phe Ile Lys Ser Leu Met Ala Ile Gly Lys Arg Leu Ala Thr Leu Pro Thr Lys Glu Gln Lys Thr Gin Arg Leu Ile Ser Glu Leu Ser Leu Leu Asn His Lys Leu Pro Ala Arg Val Trp Leu Pro Thr Ala Gly Phe Asp His His Val Val Arg Val Pro His Thr Gln Ala Val Val Leu Asn Ser Lys Asp Lys Ala Pro Tyr Leu Ile Tyr Val Glu Val Leu Glu Cys Glu Asn Phe Asp Thr Thr Ser Val Pro Ala Arg Ile Pro Glu Asn Arg Ile Arg Ser Thr Arg Ser Val Glu Asn Lsu Pro Glu Cys Gly Ile Thr His Glu Gin Arg Ala Gly Ser Phe Ser Thr Val Pro Asn Tyr Asp Asn Asp Asp Glu Ala Trp Ser Val Asp Asp Ile Gly Glu Leu Gln Val Glu Leu Pro Glu Val His Thr Asn Ser Cys Asp Asn Ile.Ser Gin Phe Ser Val Asp Ser Ile Thr Ser Gin Glu Ser Lys Glu Pro Val Phe Ile Ala Ala Gly Asp Ile Arg Arg Arg Leu Ser Glu Gin Leu Ala His Thr Pro Thr Ala Phe Lys Arg Asp Pro Glu Asp Pro Ser Ala Val Ala Leu Lys Glu Pro Trp Gln Giu Lys Val Arg Arg Ile Arg Glu Gly Ser Pro Tyr Gly His Leu Pro Asn Trp Arg Lsu Leu Ser Val Ile Val Lys Cys Gly Asp Asp Lau Arg Gln Glu Leu Leu Ala Phe Gln Val Leu Lys Gln Leu Gln Ser Ile Trp Glu Gln Glu Arg Val Pro LQu Trp Ile Lys Pro Ile Gln Asp Ser Cys Glu Ile Thr Thr Asp Ser Gly Met Ile Glu Pro Val Val Asn Ala Val Ser Ile His Gln Val Lys Lys Gln Ser Gln Leu Ser Leu Leu Asp Tyr Phe Leu Gln Glu His Gly Ser Tyr Thr Thr Glu Ala Phe L8u Ser Ala Gln Arg Asn Phe Val Gin Ser Cys Ala Gly Tyr Cys Leu Val Cys Tyr Leu Leu Gln Val Lys Asp Arg His Asn Gly Asn I1e L2u Leu Asp Ala Giu Gly His Ile Ile His Ile Asp Phe Gly Phe Ile Leu Ser Ser Ser Pro Arg Asn Leu Gly Phe Glu Thr Ser Ala Phe Lys Leu Thr Thr Glu Phe Val Asp Val Met Gly Gly Leu Asp Gly Asp Met Phe Asn Tyr Tyr Lys Met Leu Met Leu Gln Gly Leu Ile Ala Ala Arg Lys His Met Asp Lys Val Val Gln Ile=Val Glu Ile Met Gin Gln Gly Ser Gin Leu Pro Cys Phe His Gly Ser Ser Thr Ile Arg Asn Leu Lys Glu Arg Phe His Met Ser Met Thr Glu Glu Gln L-au Gln Leu Leu Val Glu Gln Met Val Asp Gly Ser Met Arg Ser Ile Thr Thr Lys Leu Tyr Asp Gly Phe Gln Tyr Lau Thr Asn Gly Ile Met (2) INFORMATION FOR SEQ ID N0:32:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 2487 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA(genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID N0:32:

AT('aAC'ATZCT TG(''aAAIOC'PCG AAG"I'CTOOC.T GTOGCCATGG GAGATACAGT AGZC~"aAOCCT

GCCX.X"'..CTi'GA AGCCAACTI'C TGAGCCCAC.T TCTGGOCCAC CAGGGAATAA Ta00GGGPCC 120 CTOC,'TAAGTG TCATCACGGA CXXXXPCGGG GAACTATCAG TGATTGACOC ZGAGGT GCC 180 CAGAAGGCCT OCCAGGAGf3P GPt'0('aAGAAA G'PCAACaCTTT TGCATGGAGG CJ(3TOGCAGrC 240 TCTAGCAGAG GCAIOCCCACT GC'~UGPIGGI'C AAZCGGC~ATG GTGPOGACAG TCAGATCOGP 300 TGCGTAGATG ATOC'.AOCTgC CCAiGATC,AGC' GAGGAGGAAG ATGAC'~TOGG aGCCGCTG'1G 360 OCCiCAQOCA CAGCCAAAGG AOC.AAGAAGA aGGCGOCAIGA ACAACTCAGC TAAAICAGIY.'T 420 TOOCTOCTGA OGCTGIRTGA GICAAAACTG TTTGACATCT CCATOGIX,AT TTCATAfJCTG 480 TATAACl'OCA AOGAOCC'I'GG AGTACAAQCC TACATTOQCA AOOOOCt'IT CTUCITTCOC 540 AACGAOGACG TGGA(.'TTCTA TCTaCCCCAG TTQCZTAACA TGTACATaCA CA2OGATOAG 600 GAOGTOGGIG ATOOCATTAA GCCC.TAlCATA G"POCACOGTT GCCGOC.AGAG CATTAACiTT 660 TOOC'!'CCA~'T GTOOOC.Z'GTP OCTI'C~OC~GCC TATTCTIC'.AG ACATGCA[',AT TTCCACrCAA

t7GAC.AC'IY70C C''TOGGAICCAA GC.`PACO('aAAG CTGATCCIY,`P CAGATGAOC.T
AAAIGCC.AGC'P 780 CACAGGAAOA aGC=AOCTGCC CTCCTTGAGC CCGGCCCC'iG ATAC'AGGGC.T G7.'G"PCO(."i'CC

AAAAGCAL:1'C AOCAaCGCTC TAHGTI'AC'~AT GCCACZGCCA GCATAAGI'CT CAQCAOCAAC 900 CTtaAAACGAA CAODCAGCAA CCCTAAAG'TG GAGAATGAGG ATGADC'~,AGCT CTOCI'OCAGC 960 ACCC'~AIGAGTA TTGATAATTC ATTCAG'PI'OC CCTGTTOGAC T GCPOCT('aiA GAC'~AGAATTC

ATt;AAO'TCOC TGATOGOC'~P,T CGOCAAGC'GG CTGOCC'ACGC TOCOf'.ACCAA = AGP-GCAGAAA

ACACAGAGGC TGATCZCAGA CZCTOOCPG GTCAACCATA AGC.'TOCCTGC CCGAG't'CIGG 1140 GTOCCCAC'tG CTTOGCTTTGA CCACCACGTG Gi'CCGTGTAC CCCACACACA C~GCPGTI'(:'TC 1200 CI'C'AACTCf'.A AG'GACAAOGC TCCCTACCTG ATTTATGIGG AAG'TOCTIGA ATGTGAAAAC 1260 TTTCA~C'.ACX'A CCACTGTCCC ZGOCCGf'~TC CCCGAGAAQC GAATTCGGAG TACGAGGTCC 1320 GTACAAAAGT 'IGOOCGAAZG TGGPATTACC CATGACCAGC GAQCIGOC,AG GTPC14iGCACr 1380 GI' CC('.AACT AZGAuCAACGA TGATC'~i00CC TGGTCGGTGG A'I'GACATAGG CGAGCTOCAA 1440 ~

GZGGAGCTOC CxGAAG'IGCA TACCAAC,AGC TGTGACAACA TC'I'CCCAGTT CTC'IG'I'CGAC 1500 AGCATCACCA GC(',AGGAGAG CAAOGHGCCT GTGTTCATTG CAGC'AGGGGA CAZ'COQCCGG 1560 COOCTTPCGG AACAOC'I'GOC TCATACCCCG ACAGCCPICA AAOGAGACCC AGAAGATCCT 1620 TCIGCAGI'TG CTC1C'.AAAGA GCCCZGGCAG GAGAAAGrAC G CGGATCAG AGAGGGC'IY7C 1680 C(7CTACGGC7C ATC7IC.700CAA TIC~GOOGC,'TC CTC'TCAlGPCA TTGTCAAGIG TOGGGATGAC

CTTOOGCAAG AGCI'TCTGOC G`ITICAGGPG TTGAAGCAAC TGCAG'i'CCAT TIGGGAACAG 1800 GAOCGAQY'GC CC(TIRGGAT CAAG('.C.AATA CAAGATTCTT GPCAAATTAC GAC'iGATAGT 1860 GGCATGATTG AAOCAiGI'GGT CAATGCIG'IG TCCATCCATC AGGTGAAGAA ACAGTCACAG 1920 CTCZC7CT.[GC TCGAZTACTT aC;TAC,AGGAG C'.lAOGGCAGl'T AC'.ACCArCI'GA
GGC'.ATTCC'IC 1980 AGTGCACAGC GCAATTTPGr GCAAAGT'IGT GC'tGGGTACT (~T'i'GGIC`IG CTACC,'ZGC'1G 2040 CAAiG'iCAAQG ACAGACACA,A TOOGAATATC CTTTIGGAiOG CAGAAOGOCA CATCAT'CCAC 2100 ATCGACTPiG GCIRCATCCT CTOCAGCI'CA CCCCGAAATC ZGO CPTTGA, GACGIC'AGCC 2160 TTTAAGCMA CCACAGAGTT TGIUC'1TG7G A'IGGGOGGCC TGGA'i'OOOCaA CATGPIC'=AAC 2220 TACTATAAGA TGGZGATGCT GCAAQGOGRG ATIGOOOC:'iC GGAAACACAT GGACAAGGIG 2280 GTGCAGATCG T GAGATCAT GCAOCAAGGT TGTC'AOCITC CTTGCI'POC.'A TGGC't'CC.AGC 2340 ACCATI'CC'~AA ACCPCAAAGA GAGGTTCCAC ATGAGCATGA CTGAGGADCA GCTOC'AOG`IG 2400 C'TGG'I'GGAIDC AGATG(3TGf`aA ZGOC,AGTATG CGGPCTATCA CC',ACCAAALT C.TATGACGGC

TTCCAG'PAOC TC:AOf'.AAOGG CATCATG 2487 (2) INFORMATION FOR SEQ ID N0:33:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 3324 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA(genomic) (iii) HYPOTHETICAL: NO

(iv) ANTI-SENSE: NO

(vii) IMMEDIATE SOURCE:
(A) LIBRARY: Human fetal brain cDNA library (B) CLONE: GEN-428B12c1 (ix) FEATURE:
(A) NAME/KEY: CDS
(B) LOCATION: 115..2601 (xi) SEQUENCE DESCRIPTION: SEQ ID N0:33:

COGC'aAATTC)C GGGAAGOCXOG GAIOCAAG'TTT TGAAGAAGTC CXTAZCAGAT TACACPI`GGT 60 TGALTACTOC GGAGCAG(X'A CTAAGAGGGA TGAHC AGGGC 1GCGI'GC'~ TTGA ATG 117 Met AGA TTC TTG GP,A GL.`r CGA AGT CTG Gf.'T GTG GOC ATG GGA GAT ACA GTA 165 Arg Phe Leu Glu Ala ArggSer L2u Ala Val Ala Met Gly Asp Thr Val GTG GAG OCT GflC COC TTG AAG CCA ACT TCT GAG DOC ACT TLT GGC OCA 213 Val Glu Pro Ala Pro Leu Lys Pro Thr Ser Glu Pro Thr Ser Gly Pro CCA GGG AAT AAT GGG GflG TCC CTG CTA AC,'P GPC ATC ACG GAG GOG GTC 261 Pro Gly Asn Asn Gly Gly Ser Leu Leu Ser Val Ile Thr Glu Gly Val Gly Glu Leu Ser Val Ile Asp Pro Glu Val Ala Gln Lys Ala Cys Gln Glu Val Lau Glu Lys Val Lys Leu Leu His Giy Gly Val Ala Val Ser AGC AGA GflC ACC Cr'A CTG GAG TTG GTC AAT GGG GAT GGT GTG GAC AGT 405 Ser Arg Gly Thr Pro Leu Glu Leu Val Asn Gly Asp Gly Val Asp Ser GAG AZC CGT TGC C'TA GAT GAT CCA CCT GOC CAG ATC AGG GAG GAG GAA 453 Glu Ile Arg Cys Leu Asp Asp Pro Pro Ala Gln Ile Arg Glu Glu Glu Asp Glu Met Gly Ala Ala Val Ala Ser Gly Thr Ala Lys Gly Ala Arg AGA aGG CGG CAG AAC AAC TCA GCT AAA CAG TCT TG+G CTG CTG AGG CIG 549 Arg Arg Arg Gln Asn Asn Ser Ala Lys G1n Ser Trp Leu Lau Arg Lau Phe Glu Ser Lys Leu Phe Asp Ile Ser Met Ala Ile Ser Tyr Leu Tyr AAC TCC AAG GAG OCT GGA GTA CAA GOC TAC ATT GGC AArC CGG CTC TTC 645 Asn Ser Lys Glu Pro G1y Val Gln Ala Tyr I].e Gly Asn Arg Leu Phe Cys Phe Arg Asn Glu Asp Val Asp Phe Tyr Leu Pro Gln Iau Leu Asn Met Tyr Ile His Met Asp Glu Asp Val Gly Asp Ala Ile Lys Pro Tyr ATA GTG CAC aGT TGC OGC CAG AGiC ART AAC TTT TCC CTC CAG TGr GOC 789 Ile Val His Arg Cys Arg Gln Ser I1e Asn Phe Ser Leu Gin Cys Ala CPG TTG CIT GGG GflC TAT TCT TCA GAC ATG CAC AZTT TCC ACP CAA CGA 837 Lgu Leu Leu Gly Ala Tyr Ser Ser Asp Met His Ile Ser Thr Gin Arg CAC TCC CGT GflG AOC AAG CTA aGG AAG CPG ATG CIC TCA GAT GAG G'TA 885 His Ser Arg Gly Thr Lys Leu Arg Lys Leu Ile Leu Ser Asp Giu Lau AAG C7CA GCT CAC AGG AAG AGG GAG CTG OOC TCC TTG AGC OOG GOC CJC'P 933 Lys Pro Ala His Arg Lys Arg Glu Leu Pro Ser Leu Ser Pro Ala Pro GAT ACA GGG CTG TL'P OOC TCC AAA AGG AGT CAC CAG C7C7C TCT AAC TCA 981 Asp Thr Gly Leu Ser Pro Ser Lys Arg Thr His Gln Arg Ser Lys Ser GAT GOC ACT GflC AOC ATA AGr CTC AGC AOC AAC CTG AAA aGA ACA GOC 1029 Asp Ala Thr Ala Ser Ile Ser Leu Ser Ser Asn Leu Lys Arg Thr Ala Ser Asn Pro Lys Val Glu Asn Glu Asp Glu Glu Leu Ser Ser Ser Thr GAG AG'P ATT GAT AAT TCA TTC AIGT TCC OCT GTT CGA CTG GCT CCT GAG 1125 Glu Ser Ile Asp Asn Ser Phe Ser Ser Pro Val Arg Leu Ala Pro Glu AGA GAA TTC ATC AAG TCC C'I'G ATG GCG ATC GGC AAG CGG CTG GCC ACG 1173 Arg Glu Phe Ile Lys Ser Leu Met Ala Ile Gly Lys Arg Leu Ala Thr CTC QOC ACC AAA GAG CAG AAA ACA CAG AGG CIG ATC ZCA GAG C'I'C TCC 1221 Leu Pro Thr Lys Glu Gln Lys Thr Gln Arg Leu Ile Ser Glu Leu Ser CTG CTC AAC CAT AAG CTC OCT GOC CGA GTC TGG C'IG CCC AG'T GCT GGC 1269 Leu Leu Asn His Lys Leu Pro Ala Arg Val Trp Leu Pro Thr Ala Gly TTT GAC CAC CAC GTG GTC CGT GTA COC CAC ACA CAG GL'T GIT GTC CTC 1317 Phe Asp His His Val Val Arg Val Pro His Thr Gln Ala Val Val Leu AAC '1'C7C AAAG GAC AAG GO'!' OC7C TAC CTG AZT TAT GTG GAA GTC CTT GAA 1365 Asn Ser Lys Asp Lys Ala Pro Tyr Leu Ile Tyr Val Glu Val Leu Glu Cys Glu Asn Phe Asp Thr Thr Ser Val Pro Ala Arg Ile Pro Glu Asn Arg Ile Arg Ser Thr Arg Ser Val Glu Asn Leu Pro Glu Cys Gly Ile ACC CAT GAG CAG CGA GCT GGO AGO TTC AGC ACT GTG OOC AA+C TAT GAC 1509 Thr His Glu Gln Arg Ala Gly Ser Phe Ser Thr Val Pro Asn Tyr Asp Asn Asp Asp Glu Ala Trp Ser Val Asp Asp Ile Gly Glu Leu Gln Val GAG CIC QOC GAA GTG CAT ACC AAC AGC TGT GAC AAC ATC TOC CAG TI'C 1605 Glu Leu Pro Glu Vai His Thr Asn Ser Cys Asp Asn Ile Ser Gln Phe TCT GTG GAC AGC ATC ACC AGC CAG GAG AGC AAG GAG OC.'T GTG 'I'I'C ATT 1653 Ser Val Asp Ser Ile Thr Ser Gln Glu Ser Lys Glu Pro Val Phe Ile Ala Ala Giy Asp Ile Arg Arg Arg Leu Ser Glu Gln Leu Ala His Thr OOG ACA GUC TTC AAA CGA GAC C7CA GAA GAT C7CT TC,'T GCA GTT GCT CIC 1749 Pro Thr Ala Phe Lys Arg Asp Pro Glu Asp Pro Ser Ala Val Ala Leu AAA GAG QOC TGG CAG GAG AAA GTA CGG aGG ATC AGA GAG GGC TOC CCC 1797 Lys Glu Pro Trp Gln Glu Lys Val Arg Arg Ile Arg Glu Gly Ser Pro TAC GGC CAT C'PC OOC AAT TGG aGG CTC C'1'G ZCA GTC ATT GTC AAG TGT 1845 Tyr Gly His Leu Pro Asn Trp Arg Leu Leu Ser Val Ile Val Lys Cys GGG GAT GAC CZT COG CAA GAG C.'TT GTG Gt7C TTT CAG GTG TTG AAG CAA 1893 Giy Asp Asp Leu Arg Gln Glu Lsu Leu Ala Phe Gln Val Leu Lys Gln Ct'G CAG TOC ATT TOG GAA CAG GAG CGA GTG DOC CIT TGG ATC AAG OCA 1941 LBu Gln Ser Ile Trp Glu Gln Glu Arg Val Pro Leu Trp Ile Lys Pro Ile Gln Asp Ser Cys Glu Ile Thr Thr Asp Ser Gly Met Ile Glu Pro G=PG GTC AAT GCT GTG TCC ATC CAT CAG GTG AAG AAA CAG ZCA CAG C'I'C 2037 Val Val Asn Ala Val Ser Ile His Gln Val Lys Lys Gln Ser Gln Lau Ser Leu Leu Asp Tyr Phe Leu Gln Glu His Gly Ser Tyr Thr Thr Glu GCA TTC C'IPC AGT GCA CAG COC AAT TZT GTG CAA AGT ZGT GCT GGG TAC 2133 Ala Phe Leu Ser Ala Gln Arg Asn Phe Val Gln Ser Cys Ala Gly Tyr TGC TTG GTC TGC TP,C CTG CIG CAA GTC AAG GAC AGA CAC AAT GGG AAT 2181 Cys Leu Val Cys Tyr Leu Leu Gln Val Lys Asp Arg His Asn Gly Asn ATC CIT T'I'G GAC GC',A GAA GGC CAC ATC ATC CAC ATC GAC TTT GGC TTC 2229 ' Ile Leu Leu Asp Ala Glu Gly His Ile Ile His Ile Asp Phe Gly Phe ATC CTC TOC AGC TCA COC CGA AAT CTG GflC TTT GAG ACG TCA GOC TTT 2277 Ile Leu Ser Ser Ser Pro Arg Asn Leu Gly Phe Glu Thr Ser Ala Phe Lys Leu Thr n-ir Glu Phe Val Asp Val Met Gly Gly Leu Asp Gly Asp ATG T'i'C AAC TAC TAT AAG ATG CTG ATG CTG CAA GGG CTG ATT GCC GCT 2373 Met Phe Asn Tyr Tyr Lys Met LSu Met Leu Gln G1y.Leu Ile Ala Ala Arg Lys His Met Asp Lys Val Val Gin Ile Val Glu Ile Met Gln Gln GGT TCT CAG CIT CCT TGC TTC CAT GGC TCC AGC A(:C ATT CGA AAC GTC 2469 Gly Ser Gln Leu Pro Cys Phe His Gly Ser Ser Thr Ile Arg Asn Leu AAA GAG AGG TIC CAC ATG AGC ATG ACT GAG GAG CAG CI'G CAG CTG CPG 2517 Lys Glu Arg Phe His Met Ser Met Thr Glu Glu Gln Leu Gln Leu Leu GTG GAG CAG ATG CTIG GAT GGC AGT ATG COG TG`T ATC ACC ACC AAA CTC 2565 Val Glu Gln Met Val Asp Gly Ser Met Arg Ser Ile Ztr Thr Lys L8u TAT GAC GGC TTC CAG TAC CTC ACC AA+C GGC ATC ATG TGA CACGC'lYX.'TC 2614 Tyr Asp Gly Phe GlnTyr Leu Thr Asn Gly Ile Met *

AGCCCAGGAG TGGTG~GOOOG TCCAGOOC'AC CX.*tC70GTAGA GGGOOC1'TGT CZGAGAAA[JC 2674 CCAAAQCAGG AAA+COOCA0C TACCC.APuCCA TOCAOCCAAG GGAAATOGfi-A GGCAA['aAAAIC 2734 ACGAAGGATC AZGTGGTAAC TGOGAG,AGCT TOCIC'AOGf G TGGGAiGAGCC AGCTQI'OOGG 2794 TCCAGACT'1'G TTGGGGCITC CCTGCXC(,'TC CIGGPCTG'I'G TCAGTATTAC CACCAGACTG 2854 ACZCCAGGAiC TCAf.'TGCfx'F CCAGAAAACA GAIOGTGACAA ATGTGAOOC',~A CACTOOGGCC 2914 TTPCTTCTOC TTGTAGQOf't' CTC:'1'CAGAIOG TTCTTPOCAC ApGOC'ATaCT CTTATPCCGT 2974 ZC'IC~OC~f,iCOC AGGAAG!'OGG GAA('+,dGPAGG TPC'!'COG'PAC TTAGGACTTG ATOCZG'IWT

TGCCAC=IGGC CAZGC'IGCPG COCAGC'II'CTA COCCTCOCAG GGACCTAOOC CTCIXCAGf'GA 3094 CCGACOCC'I'G GCCC'.AAGC'I'C COCTTC'CI'GG CGGGCOC,'Z'GC G'7.'GOGCCCi'G
CACTTGCTC'xA 3154 GGT'POCOC'AT CA'IC'OGCAAG GCAAGGGAAT TCCCAC,AGOC CTC7CAG'I"GPA CRGAi00GTAC

TGOOCTAGOC ATGTGGAATT CCCPACCC'1G AC'POCITCCC CAAACCC'=AGC' GAAA~'aAGGT 3274 C'I''.AATPZTP TATZTITAAT TZTTGI'TPGA, AATAAAGIC7C TTAGITAGCC 3324 (2) INFORMATION FOR SEQ ID N0:34:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 810 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:34:

Met Pro Met Asp Leu Ile Leu Val Val Trp Phe Cys Val Cys Thr Ala Arg Thr Val Val Gly Phe Gly Met Asp Pro Asp Leu Gln Met Asp Ile Val Thr Glu Leu Asp leu Val Asn Thr Thr leu Gly Val Ala Gln Val Ser Gly Met His Asn Ala Ser Lys Ala Phe leu Phe Gln Asp I].e Glu Arg Glu Ile His Ala Ala Pro His Val Ser Glu Lys Leu Ile Gln leu Phe Gin Asn Lys Ser Glu Phe Thr Ile Leu Ala Thr Val Gln Gln Lys Pro Ser Thr Ser Gly Val Ile Leu Ser Ile Arg Glu Leu Glu His Ser Tyr Phe Glu Leu Glu Ser Ser Gly Leu Arg Asp Glu Ile Arg Tyr His Tyr Ile His Asn Gly Lys Pro Arg Thr Glu Ala Leu Pro Tyr Arg Met Ala Asp Gly Gln Trp His Lys Val Ala Leu Ser Val Ser Ala Ser His Leu Leu Leu His Val Asp Cys Asn Arg Ile Tyr Glu Arg Val Ile Asp Pro Pro Asp Thr Asn Leu Pro Pro Gly Ile Asn Leu Trp Leu Gly Gln Arg Asn Gln Lys His Gly Leu Phe Lys Gly Ile Ile Gln Asp Gly Lys Ile Ile Phe Met Pro Asn Gly Tyr Ile Thr Gln Cys Pro Asn Lgu Asn His Thr Cys Pro Thr Cys Ser Asp Phe Leu Ser Leu Val Gln Gly Ile Met Asp Leu Gin Glu Leu Leu Ala Lys Met Thr Ala Lys Leu Asn Tyr Ala Glu Thr Arg Leu Ser Gin Leu Glu Asn Cys His Cys Glu Lys Thr Cys Gln Val Ser Gly Leu Leu Tyr Arg Asp Gln Asp Ser Trp Val Asp Gly Asp His Cys Arg Asn Cys Thr Cys Lys Ser Gly Ala Val Glu Cys Arg Arg Met Ser Cys Pro Pro Leu Asn Cys Ser Pro Asp Ser Leu Pro Val His Ile Ala Gly Gin Cys Cys Lys Val Cys Arg Pro Lys Cys Ile Tyr Gly Gly Lys Val Leu Ala Glu Gly Gln Arg Ile Leu Thr Lys Ser Cys Arg Glu Cys Arg Gly Gly Val Leu Val Lys Ile Thr Glu Met Cys Pro Pro Leu Asn Cys Ser Glu Lys Asp His Ile Leu Pro Glu Asn Gln Cys Cys Arg Val Cys Arg Gly His Asn Phe Cys Ala Glu Gly Pro Lys Cys Gly Glu Asn Ser Glu Cys Lys Asn Trp Asn Thr Lys Ala Thr Cys Glu Cys Lys Ser Gly Tyr Ile Ser Val Gln Gly Asp Ser Ala Tyr Cys Glu Asp Ile Asp Glu Cys Ala Ala Lys Met His Tyr Cys His Ala Asn Ttir Val Cys Val. Asn Leu Pro Gly LSu Tyr Arg Cys Asp Cys Val Pro Gly Tyr Ile Arg Val Asp Asp Phe Ser Cys Thr Glu His Asp Glu Cys Gly Ser Gly Gln His Asn Cys Asp Glu Asn Ala Ile Cys Thr Asn Thr Val Gln Gly His Ser Cys Thr Cys Lys Pro Gly Tyr Val Gly Asn Gly Thr Ile Cys Arg Ala Phe Cys Glu Glu Gly Cys Arg Tyr Gly Gly Thr Cys Val Ala Pro Asn Lys Cys Val Cys Pro Ser Gly Phe Thr Gly Ser His Cys Glu Lys Asp Ile Asp Glu Cys Ser Glu Gly Ile Ile Glu GYs His Asn H;L.s Ser Arg Cys Val Asn Leu Pro Gly Trp Tyr His Cys Glu Cys Arg Ser Gly Phe His Asp Asp Gly Thr Tyr Ser Leu Ser Gly Glu Seac Cys Ile Asp Ile Asp Glu Cys Ala Leu Arg Thr His Thr Cys Trp Asn Asp Ser Ala Cys Ile Asn Leu Ala Gly Gly Phe Asp Cys Leu Cys Pro Ser Gly Pro Ser Cys Ser Gly Asp Cys Pro His Glu Gly Gly Leu Lys His Asn Gly Gin Val Trp Thr Lau Lys Giu Asp Arg Cys Ser Val Cys Ser Cys Lys Asp Gly Lys Ile Phe Cys Arg Arg Thr Ala Cys Asp Cys Gin Asn Pro Ser Ala Asp Leu Phe Cys Cys Pro Glu Cys Asp Thr Arg Val Thr Ser Gln Cys Leu Asp Gln Asn Gly His Lys Leu Tyr Arg Ser Gly Asp Asn Trp Thr His Ser Cys Gin Gin Cys Arg Cys Leu Glu Gly Glu Val Asp Cys Trp Pro Leu Thr Cys Pro Asn Leu Ser Cys Glu Tyr Thr Ala Ile Leu Glu Gly Glu Cys Cys Pro Arg Cys Val Ser Asp Pro Cys Leu Ala Asp Asn Ile Thr Tyr Asp Ile Arg Lys Thr Cys Leu Asp Ser Tyr Gly Val Ser Arg Leu Ser Gly Ser Val Trp Thr Met Ala Gly Ser Pro Cys Thr Thr Cys Lys Cys Lys Asn Gly Arg Val Cys Cys Ser Val Asp Phe Glu Cys Leu Gln Asn Asn (2) INFORMATION FOR SEQ ID N0:35:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 2430 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA(genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:35:

ATGCCXGATGG ATTTGATTZT AGI'I'Gi'Gi'GG GCAC'i'GCCAC GACAGiGGi'G 60 GGL`ITTGGGA TGGACCCT('aA CCTTC'AGATG GATATCGI'CA CCGAGC,'TTGA CCTTGTGAAC 120 ACCACCCT'IG GAIG'I'I'GC'i'CA GGTGIC;TGGA AZGCACAATG CCAGCAAAGC ATTZTPATTT 180 CAAGACATAG AAAGAGAGAT CCATGCAGCT CCI"CATGZGA GTGAGAAATT AATTC',AGC'IG 240 T'I'OCAGAACA AGAGI'GAATT CACCATPI'ZG GCCAC'i'GTAC AGC.AGAAOOC ATCCAC'ITCA 300 GGAG'Tf'~ATAC TGI'OCATTCG AGAACTOGAG CACAGCTATT TI'C'aAAC."iC'GGGA GAGCAGTGGC

CTGAGGGATG AGAT'POGGTA TCACTACATA CACAATGGC'~,A AGCCAAGGAC AGAGGCAC'IT 420 CCZTACCOCA TGGCAGATGG ACAAZGGCAC AAGGrPGCAC TGZCAGI'TAG CGCC'IY,TCAT 480 CTCCI'GC'I'CC ATGPCGACTG TAACAGGATT TATGAGO('TG TGATAGACCC TCCAGATACC 540 AAlOC.`TTCOOC CAGGAATCAA TPPATG+GC,'TT GGOCAGOGCA ACGAAAAGCA TGG(,'TTATTC 600 AAAGGGATCA TCCAAGATGG GAAGAZCATC TTTAZGOOC'~A ATGGATATAT AACACAGTGT 660 CC',AAATC'I'AA ATCACACTZG CCCAACC.'TGC AG=PC'~A'ITI'CP TAAGCC'POGr GCAAGC'aAATA 720 ATG{"~ATTTAC AAGAGCPPTT GGCCAAGATG ACPGCAAAAC TAAATTAZGC AGAGACAAGA 780 CTTAGPCAAT TGGAAAACTG TCATTGIPC',AG AAGACrl= AAGTGAGTGG ACTGCPCTAT 840 CGAGATCAAG ACPCITGGGT AGATGGIC3AC CATTOCAiOGA AC'I'OCACTTG CAP-AAGTOGT 900 GCW'TGGAAT GCOGAAGGAT GTOCJ[GZC7CC CCTC'iCAATT GCTCCCCAGA CI'CCCTCO('.A 960 GTACACATTG C'!.'GGOCAGIG CTGTAAOGI'C TGOCC'~~OCAA AATGTATCTA TGGAGGAAAA 1020 GTT'CP'IGC.AG AAQGOC'.AGCG GATITTAACC AAGAGC'I= GGC'aAAZGCCG AGGTGGACTT 1080 TTA+GTAAAAA TTACAC'aAAAT GZ~iC7CTCCP ZTC`aAACTG(,'T CAGAAAAG(''P- TCAICATTCTT

CCTGAGAATC AGI'GC.''1'GCOG TQiCTG'PAGA GQI'CATAAL'T ZTTGTOCA~'*A AGGACCPAAA

TGTGGI''aAAA ACTCAGAGTG CAAAAACTGG AATACAAAAG CTACTIC7I'GA GTGCAAGAGr 1260 GG'i'TACATCr CPGIC7CAGGG P,GACi'CPGCC TACrGT('~AiAG ATATTGATGA G"I'G'1GCAGCT

AAGAZGCATT AGTCa'tC'ATGC CAATACIGIG TG7G'1CAAOC TTOCPGOGTT ATATCGCi'GP 1380 GACTGTG7.CC CAOf'~ATACAT TCGIrGPGGAT GACt"I'GTCTP GTACAC'~AACA OGAT('aAATGI' G f',AGCGCC AGCACAAC1G TGATGAGAAT GtJCATCIGC'A CCAALA= CC.AGCGACAC 1500 AGC,"I'GC'AIOCT GCAAAOpGGG CTACG-rGGGG AACGGGAOCA TCiGCAGAGC TTTCTGTGAA 1560 GA GGC7,,GCA GATACGf"!'GG AACGZCTGIG GCZC70CAACA AATGT(~'ZK,'1'G TOC'.ATCTOGA

TTCA+CAGC'AA GCf'.ACI'GOC''~A GAAAIGA.TATT GATGAATG'PP CAGAGCGAAT CATTGAG=

C'ACAACC'ATT CCCGCPGO(~`T TAACX.TGCCA GGGTGQPAOC ACTGrGAGrG CA~',AAGOGCT 1740 T'POC`,ATGAIC7G ATGGGALCPA TZCAcR.'G']CC GGGC'AG'rOCT GTATTGAcAT TGATGAATGT

GOCT`PAAGAA CI't`.AiCACCIG TTGC'aAAOGP,T TCTGCCTG{'A TC AA<7CrGGC AGGGGGTPZT

, GOCCCP(,`TGG GCO(.,~I'OCPGC TCIGC;PGACT GPCCTCATGA AGGGGGGCI'G 1920 AAGiCACAATG CCC'AGGIGPG GACCTI'GAAA GAAGACAGGT GTTCTGTCTG CTOCTOCAAG 1980 GATGOC.AAGA TATi'CZGOCG ACGGACAiQCT TGTGATTGOC AGAATCC.AAG TGCTGACC'PA 2040 TTC~~C CAGAAZG'IC'~A CAOCAGAC"IC ACAAGP('.AAT GT1TAGoACCA AAATGGPCAC 2100 AADCTC'!'ATC GAAGi'GGAGA CAATTGGACC CATAGCIGI'C AIGCACTGI'CG GPGTCPGGAA 2160 GGAGAGGI'AG AT'IGCTGGCC ACTCAGTI'GC OCAACI''C'~A GC'1'GTGAGPA TACAGCTATC 2220 TTAGAAGGGG AATGTTGI'UC CCGCI'GTGTC AG'I`GACCCCT GCCTAGCI'C,A TAACA'ICACC 2280 TATGACATCA GAAAAAC'I'I'G CCTGGACAGC TATGGTGITT C'ACGGL'PPAG TGGC4CAG'iG 2340 TGGACGATGG CTGCATC'IC7C CTGCAC'.,AACC TG'TAAATGCA AGAATGGGAAG AGICZ'GTTGT 2400 TCTGTGGATT TTt'aAG']['GTC'r TC'AAAATAAT 2430 (2) INFORMATION FOR SEQ ID N0:36:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 2977 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA(genomic) (iii) HYPOTHETICAL: NO

(iv) ANTI-SENSE: NO
(vii) IMMEDIATE SOURCE:
(A) LIBRARY: Human fetal brain cDNA library (B) CLONE: GEN-073E07 (ix) FEATURE:
(A) NAME/KEY: CDS
(B) LOCATION: 103..2532 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:36:

TAGCAAGTTP GGCGGC'!'OCA AGCCAGGCGC GCC'!'CAGGAT CCAGGCTCAT TTGC'I'TOCAC 60 CTAGCTII'CGG TGCCCCCTGC TAGGCGGGGA CCC.'lC7GAGAG CG ATG CCG ATG GAT 114 Met Pro Met Asp T'IG ATT TTA GTT GTG TGG TTC TGT GTG TGC ACT GOC AGG ACA GTG GTG 162 Leu Ile Leu Val Val Trp Phe Cys Val Cys Thr Ala Arg Thr Val Val Gly Pte Gly Met Asp Pro Asp Leu Gln Met Asp Ile Val Thr Glu Leu GAC CTT GTG AAC ACC ACC C'IT GGA GT'T GCT CAG GTG TCT GGA ATG CAC 258 Asp Leu Val Asn Thr Thr Leu Gly Val Ala Gln Val Ser Gly Met His Asn Ala Ser Lys Ala Phe Leu Phe Gln Asp Ile Glu Arg Glu Ile His GCA GC,'T OCT CAT GTG AGT GAG AAA TTA ATT CAG C'IG TTC CAG AAC AAG 354 Ala Ala Pro His Val Ser Glu Lys Leu Ile Gln Leu Phe Gln Asn Lys AGT GAA TTC ACC ATT TTG G{jC ACT GTA CAG CAG AAG UCA TOC ACT TCA 402 Ser Glu Phe Thr Ile Leu Ala Thr Val Gin Gin Lys Pro Ser Thr Ser Gly Vai Ile Lau Ser Ile Arg Glu Leu Glu His Ser Tyr Phe Glu Leu Glu Ser Ser Gly Leu Arg Asp Glu Ile Arg Tyr His Tyr Ile His Asn GOG AAG OCA AGG ACA GAG GCA CIT (7CT TAC aGC ATG GCA GAT GGA CAA 546 Gly Lys*Pro Arg Thr Glu Ala Leu Pro Tyr Arg Met Ala Asp Gly Gln TGG CAC AAG GTT GCA C't'G TCA GTT AGC GOC TOT CAT CTC CrG CTC CAT 594 Trp His Lys Val Ala Leu Ser Val Ser Ala Ser His Leu Leu Leu His GI'C GAC TGT AAC AaG ATP TAT GAG OGT GTG ATA GAC CGT CCA GAT AOC 642 Val Asp Cys Asn Arg Ile Tyr Glu Arg Val Ile Asp Pro Pro Asp Zhr Asn Lsu Pro Pro Gly Ile Asn Leu Trp L8u Gly Gln Arg Asn Gln Lys His Gly Leu Phe Lys Gly Ile Ile Gln Asp Gly Lys Ile Ile Phe Met Pro Asn Gly Tyr Ile Thr Gln Gys Pro Asn Leu Asn His Thr Cys Pro ACC TGO AGT GAT TTC TTA AGC C'I`G GTG CAA GGA ATA ATG GAT TTA CAA 834 Thr Cys Ser Asp Phe Leu Ser Leu Val Gin Gly Ile Met Asp Leu Gin CA 02458872 2004-03-23 --^

Glu Leu Leu Ala Lys Met Thr Ala Lys Leu Asn Tyr Ala Glu Thr Arg C,''iT AGP CAA T'iG GAA AAC TGT CAT TGT GAG AAG ACT TGT CAA GTG AGT 930 Leu Ser Gln Lsu Glu Asn Cys His Cys Glu Lys Thr Cys Gln Val Ser Gly Leu LSu Tyr Arg Asp Gln Asp Ser 'i'zp Val Asp Gly Asp His qis AGG AlAG = P,CT TCaC AAA AGT GGT GOC GTG GAA RGC OGA AGG ATG TCC 1026 Arg Asn Cys Thr Cys Lys Ser Gly Ala Val Glu Cys Arg Arg Met Ser TGT CCC aCT CTC AAT TOC TOC OCA GAC TOC CTC OCA GTA CAC ATT GCT 1074 Cys Pro Pro Leu Asn Cys Ser Pro Asp Ser L8u Pro Val His Ile Ala GflC CAG TOC TGT AAG GTC TGC OGA CCA AAA TGT ATC TAT GGA GGA AAA 1122 Gly Gin Cys Cys Lys Val Cys Arg Pro Lys Cys Ile Tyr Gly Gly Lys Val Leu Ala Glu Gly Gln Arg Ile Lsu Thr Lys Ser Cys Arg Glu Cys CXaA GGT GGA GTT TPA GTA AAA ATT ACA GAA ATG TGT aCT aCT TTG AAC 1218 Arg Gly Gly Val Leu Val Lys Ile Thr Glu Met Cys Pro Pro Leu Asn Cys Ser Glu Lys Asp His Ile Leu Pro Glu Asn Gln Cys Cys Arg Val TG'T AGA GGT CAT AAC TTT TGT GCA GAA GGA aCT AAA TGT GGT GAA AAC 1314 Cys Arg Gly His Asn Phe Cys Ala Glu Gly Pro Lys GYs Gly Glu Asn TCA GAG TGC AAA AAC T{zG AAT ACA AAA GC.T ACT ZGP GAG TGC AAG AG'T 1362 Ser Glu Cys Lys Asn Trp Asn Thr Lys Ala Thr Cys Glu Cys Lys Ser GGT TAC ATC TCT GTC CAG GGA GAC 'ICT GflC TAC TGT GAA GAT ATT GAT 1410 Gly Tyr Ile Ser Val Gln Gly Asp Ser Ala Tyr Cys Glu Asp Ile Asp GAG TGT GCA GCT AAG ATG CAT TAC TGT CAT GOC AAT ACT G'TG TGT GTC 1458 Glu Cys Ala Ala Lys Met His Tyr Cys His Ala Asn Thr Val Cys Val AAC CTT CCT GGG TTA TAT CGC TGT GAC TGT GTC CCA GGA TAC AZT aG'I' 1506 Asn Leu Pro Gly Leu Tyr Arg Cys Asp Cys Val Pro Gly Tyr Ile Arg Val Asp Asp Phe Ser Cys Thr Glu His Asp Glu Cys Gly Ser Gly Gln CAC AAC TGT GAT GAG AAT GOC ATC TGC ACC AAC lAGT GTC CAG GGA CAC 1602 His Asn Cys Asp Glu Asn Ala Ile Cys Thr Asn Thr Val Gln Gly His AGC TGC ACC ZM AAA a0G GGC TAC GTG GGG AAC GGG ACC ATC TGC AGA 1650 Ser Cys Thr Cys Lys Pro Gly Tyr Val Gly Asn Gly Thr Ile Cys Arg GCT TZ'C TGT GAA GAG GOC TOC AGA TAC GGT GGA ACG TGT GTG GCT QOC 1698 Ala Phe Cys Glu Glu Gly Cys Arg Tyr Gly Gly Thr Cys Val Ala Pro AAC AAA TGT GTC TGT CX'A TC,T GGA TTC ACA GGA AGC CAC TGC GAG AAA 1746 Asn Lys Cys Val Cys Pro Ser Gly Phe Thr Gly Ser His Cys Glu Lys Asp Ile Asp Glu Cys Ser Glu Gly Ile Ile Glu Cys His Asn His Ser GGC TGC GTT AAC CIG aCA GGG TGG TAC CAC TGr GAG TGC AGA AGC GGT 1842 Arg Cys Val Asn Leu Pro Gly Trp Tyr His Cys Glu Cys Arg Ser Gly TPC CAT GAC GAT GtflG ACC TAT TCA CTG TOC GGG GAG TOC TGT ATT GAC 1890 Phe His Asp Asp Gly Thi- Tyr Ser Leu Ser Gly Glu Ser Cys Ile Asp Ile Asp Glu Cys Ala Leu Arg Thr His Thr G`ys Tip Asn Asp Ser Ala TGC ATC AAC CTG GOA GGG GGT TTT GAC TGT C'I'C TGC CCC TC,T GGG CCC 1986 Cys Ile Asn Leu Ala Gly Gly Phe Asp Cys Lau Cys Pro Ser Gly Pro TC7C TGC TCT GGT GAC TGT CCI' CAT GAA GOG GOG CI'G AAG CAC AAT GGC 2034 Ser Cys Ser Gly Asp Cys Pro His Glu Gly Gly Leu Lys His Asn Gly CAG GTG TGG A.OC TTG AAA GJ4A GAC AGG TGT TCT GTC TGC Tt7C TGC AAG 2082 Gln Val Trp Thr Leu Lys Glu Asp Arg Cys Ser Val Cys Ser Cys Lys GAT GGC AAG ATA TTC TGC OGA taGG ACA GCT TGT GAT TaC CAG AAT aCA 2130 Asp Gly Lys Ile Phe Cys Arg Arg Thr Ala Cys Asp Cys Gln Asn Pro AGT CaCT GAC CTA TTC TGT TGC CCA GAA TGT GAC ACC AGA GTC ACA AQr 2178 Ser Ala Asp Leu Phe Cys Cys Pro Glu Cys Asp Thr Arg Val Thr Ser CAA TGT TTA GAC CAA AAT GGT CAC AAG CiG TAT t7GA AGT GGA GAC AAT 2226 Gin Cys Leu Asp Gln Asn Gly His Lys Leu Tyr Arg Ser Gly Asp Asn TGC ACC CAT AGC TGT CAG CAG TGT CGG TGP CI'G GAA GGA GAG GTA GAT 2274 Tip Thr His Ser Cys Gin Gin Cys Arg Cys Leu Glu Gly Glu Val Asp TOC TGG CCA CTC ACT TGC aCC AAC TTG AOC TGT GAG TAT ACA GGT ATG 2322 Cys Trp Pro Ieu Thr Cys Pro Asn. Leu Ser Cys Glu Tyr Thr Ala Ile TTA GAA GGG GAA TGT ZGT CCC CGC TGT GTC AGT GAC CCC TaC CTA GCT 2370 Leu Glu Gly Giu Cys Cys Pro Arg Cys Val Ser Asp Pro Cys Leu Ala Asp Asn Ile Thr Tyr Asp Ile Arg Lys Thr Cys Leu Asp Ser Tyr Gly GTT TCA OGG CTT AGT GGC TCA GTG TGG AaG ATG GGT GGA TGT CCC TGC 2466 Val Ser Arg Leu Ser Gly Ser Val Trp Thr Met Ala Gly Ser Pro Cys ACA ACc TG'P AAA TGC AAG AAT GGA AGA GTC TGT TGT TC'I' GTG GAT TTT 2514 Thr Thr Cys Lys Cys Lys Asn Gly Arg Val Cys Cys Ser Val Asp Phe GAG TGT CTT CAA AAT AAT ZGAA~'~TAT'PT ACAGTOGAlCT CAACXGCAGAA 2562 Glu Cys Leu Gin Asn Asn GAAZGGACC,A AATGACCP-TG CAACGPGATT AAOGATAGGA ATOOGPAGTT ZGGITFITTT 2622 GTTi'GI'T"!.*PG TTTI'I`ITAAC CACAGATAAT TGCCAAAGTT 'ICCACCTGAG GA+OOGTGI'TT

aGGAGG'I'TGC CT'1'TTGC'~A+OC TACCA,CPTTG C,'TC'ATTCP'IG CTAACCTAGr CTAGGPGAiCC

TAC;AGTOCCG TGC'ATTTAAG TCAATOGTI'G TTAAAAGAAG ZTTOOGG'TGP TGTAAATCAT 2802 GTT'r'(ACTTA TC'AIGATCATT TGCAAP-TACA TTTAAATGAT CTCATOGTAA ATOGTI'GATG 2862 TAT'I'Z*I't'TGG GTTTATTTIG TGrAG'TAACC ATAATAGAGA GAGACTCAGC TC{.`1TITATT 2922 TATT'I'TG'TTG ATTTATGGAT CAAATTCTAA AATAAAQPIG CCTGr'rG'IGA CT~PT 2977 (2) INFORMATION FOR SEQ ID NO:37:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 816 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:37:

Met Glu Ser Arg Val Leu Leu Arg Thr Phe Cys Leu Ile Phe Gly Leu Gly Ala Val Trp Gly Leu Gly Va1 Asp Pro Ser Leu Gin Ile Asp Val Leu Thr Glu Leu Glu Leu Gly Glu Ser Thr Thr Gly Val Arg Gln Val Pro Gly Leu His Asn Gly Thr Lys Ala Phe Lgu Phe Gln Asp Thr Pro Arg Ser ile Lys Ala Ser Thr Ala Thr Ala Glu Gln Phe Phe Gln Lys Leu Arg Asn Lys His Glu Phe Thr Ile Leu Val Thr Lau Lys Gln Thr His Leu Asn Ser Gly Val Ile Leu Ser Ile His His Leu Asp His Arg Tyr Leu Glu Leu Glu Ser Ser Gly His Arg Asn Glu Val Arg Leu His Tyr Arg Ser Gly Ser His Arg Pro His Thr Glu Val Phe Pro Tyr Ile Lsu Ala Asp Asp Lys Trp His Lys Leu Ser Lsu Ala Ile Ser Ala Ser His Leu Ile Leu His I1e Asp Cys Asn Lys Ile Tyr Glu Arg Val Val Glu Lys Pro Ser Thr Asp Leu Pro Lau Gly Thr Thr Phe Trp Leu Gly Gln Arg Asn Asn Ala His Gly Tyr Phe Lys Gly Ile Met Gln Asp Val Gln Leu Leu Val Met Pro Gln Giy Phe Ile Ala Gln Cys Pro Asp Leu Asn Arg Z'hr Cys Pro Thr Cys Asn Asp Phe His Gly Leu Val Gln Lys Ile Met Glu Leu Gin Asp Ile Leu Ala Lys Thr Ser Ala Lys Leu Ser Axg Ala Glu Gln Arg Met Asn Arg Leu Asp Gln Cys Tyr Cys Glu Arg Thr Cys Thr Met Lys Gly Thr Thr Tyr Arg Glu Phe Glu Ser Trp Ile Asp Gly Cys Lys Asn Cys Thr Cys L8u Asn Gly Thr Ile Gin Cys Glu Thr Leu Ile Cys Pro Asn Pro Asp Cys Pro Lsu Lys Ser Ala Leu Ala Tyr Val Asp Gly Lys Cys Cys Lys Glu Cys Lys Ser Ile Cys Gin Phe Gin Gly Arg Thr Tyr Phe Glu Gly Glu Arg Asn Z7w Va1 Tyr Ser Ser Ser Gly Val Cys Val Leu Tyr Glu Cys Lys Asp Gin Thr Met Lys Leu Val Glu Ser Ser Gly Cys Pro Ala Leu Asp Cys Pro Glu Ser His Gln Ile Thr Leu Ser His Ser Cys Cys Lys Val Cys Lys Gly Tyr Asp Phe Cys Ser Glu Arg His Asn Cys Met Glu Asn Ser Ile Cys Arg Asn Leu Asn Asp Arg Ala Val Cys Ser Cys Arg Asp Gly Phe Arg Ala Leu Arg Glu Asp Asn Ala Tyr Cys Glu Asp Ile Asp Glu Cys Ala Glu Gly Arg His Tyr Cys Arg Glu Asn Thr Met Cys Val Asn Thr Pro Gly Ser Phe Met Cys Ile Cys Lys Thr Gly Tyr Ile Arg Ile Asp Asp Tyr Ser Cys Thr Glu His Asp Glu Cys Ile Thr Asn Gln His Asn Cys Asp Glu Asn Ala Leu Cys Phe Asn Thr Val Gly Gly His Asn Cys Val Cys Lys Pro Gly Tyr Thr Gly Asn Gly Thr Thr Cys Lys Ala Phe Cys Lys Asp Gly Cys A.rg Asn Gly Gly Ala Cys Ile Ala Ala Asn Val Cys Ala Cys Pro Gln Gly Phe Thr Gly Pro Ser Cys Glu Thr Asp Ile Asp Glu Cys Ser Asp Gly Phe Val Gin Cys Asp Ser Arg Ala Asn Cys Ile Asn Leu Pro Gly Trp Tyr His Cys Glu Cys Arg Asp Gly Tyr His Asp Asn Gly Met Phe Ser Pro Ser Gly Glu Ser Cys Glu Asp Ile Asp Glu Cys Gly Thr Gly Arg His Ser Cys Ala Asn Asp Thr Ile Cys Phe Asn Leu Asp Gly Gly Tyr Asp Cys Arg Cys Pro His Gly Lys Asn Cys Thr Gly Asp Cys Ile His Asp Gly Lys Val Lys His Asn Gly Gln Ile Trp Val Leu Glu Asn Asp Arg Cys Ser Val. Cys Ser Cys Gin Asn Gly Phe Val Met Cys Arg Arg Met Val Cys Asp Cys Glu Asn Pro Thr Val Asp Leu Phe Cys Cys Pro Glu Cys Asp Pro Arg Leu Ser Ser Gln Cys Leu His Gin Asn Gly Glu Thr Leu Tyr Asn Ser Gly Asp Thr Trp Val Gln Asn Cys Gln Gin Cys Arg Cys Leu: Gln Gly Glu Val Asp Cys Trp Pro Leu Pro Cys Pro Asp Val Glu Cys Glu Phe Ser Ile Lieu Pro Glu Asn Glu Cys Cys Pro Arg Cys Val Tthr Asp Pro Cys Gln Ala Asp Thr Ile Arg Asn Asp Ile Thr Lys Thr Cys Leu Asp Glu Met Asn Val Val Arg Phe Thr Gly Ser Ser Trp Ile Lys His Gly Tthr Giu Cys Thr Lau Cys Gln Cys Lys Asn Gly His Ile Cys Cys Ser Val Asp Pro Gln Cys Lau Gln Glu Leu (2) INFORMATION FOR SEQ ID N0:38:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 2448 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA(genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:38:

ATGGAG'IC;TC GGGTC.'TTACT GAGAACATTC !'TGATCT TCGGPC,'I'CX~G AGCAG'I=IRGG 60 GGGCTTGGTG TGGACOCTTC CCTACAGATT GACGTC'TTAA CAGAG2TAGA ACT'I'GGGGAG 120 TOCAOGACCG GAG`1`GOGICA GG'ITOCX."GOGG Ct'OC'ATAATG Gt'10GAAAGC CtPI'C'iCTT'P

C.AAGATAC'I'C CCAGAAGC;AT AAAAGC'AZTOC ACl'OCTACAG CTGAAC',AU'TT TTTTCAGAAG

CnGAGAAATA AACATGAATT TACTATT'ITG GTGAQOC'TAA AACAIGAOOCA CTTAAATTCA 300 GGAGITAZTC TCPC'AATTCA CCACTIGC'aAT CACAQGTAOC TGGAAC'iGGA AAGPAG'i'OC',C 360 CATCGGAATG AAGfrAGACP GCATTAOCGC TC,AGGCAGIC ACOCGCCCPCA CACAGAAGIG 420 'ITL'CJCZTACA TT'PPOOCTGA ZGACAAGPGG CACAAGCTCT CClTAGCCAT CAGPOC'I'PCC 480 CATTTGATTT TACACATTGA CTOCAATAAA ATTTAZGAAA GGGPAGTAGA AAAOOCCI'CC 540 ACAGACT'= CTCPAGG(',AC AACATTTPGG CTAGGP-CA~'~A GAAATAATGC GCATGGATAT 600 TTTAAGGGTA TAATOCAAGA TGTIX',AATTA CiTGPCATGC CCCAGGGATT TATTGCPCAG 660 TGOCCAGATC TTAATCOCAC CIG'i'CCAACT TGCAAZGoACP TCCATGGAGT TGl'GCAGAAA 720 ATCATGGAGC TACAGGATAT TTTAOCCAAA AlCATCAGCCA AGCTG't'C'I'CG AGCTGAACAG 780 C7GAATGAATA GATi'GGATCA GZC~CPATT~I' GAAAGGGAC1T GCACCATGAA GGGAACX'.AICC 840 TAC0C'~AGAAT TTG~QI'CCPG GATAGAOGOC TOtAAGAACT GCAC'ATGOCY GAAZGGAACC 900 ATCX;AQI'('I'G 14P-AL`I'CYAAT C'I'GCCGAAAT aCTt'aACIGCC CACZTAAG'i'C
GGCI'CTTGCG 960 TATGPGGATG GCAAATG'CIG TAAG~'~AATGC AAATCGATAT GCG1ATTi'CA AGGACGAACC 1020 TACTZ'PGAAG GAGAAACAAA TACAGTCTAT TCCZCTTL`IG C'~AGTATGI'GP TCTCPATGAG 1080 TGCAAGGACC AGACCATGAA A(,'T1GT'IGAG AQP1"C,AGOC,`T CZ'OC.AGCTIT GGATIGPOCA

GAG'rCTCATC AGATAAOGZT GTCfCACAGC ZGPI'GC'AAAG TI'TGTAAAQG TTATGACTTT 1200 ZYT=).'CPC',AAA GOC'ATAACPG CATGGAGAAT TCCAZCZGCA GAAAZCT'C'~A TGACAGGGCT 1260 GTTPGrAGCT GPOGAGATGG TTTTAGGGGT CITCGAGAGG ATAATGCCPA CTG!'C'aAAGAC 1320 ATZ7GATGAGr GZGC'i'GAAGG GCGCCATTAC TG'ICJGICAAA ATACAATGTG TGPCAACACC 1380 CCGGGi'I'CTT TTATGI'CCAT CI'OC'AAP,ACT GGATACATCA GAATTGATGA TTATTCATGT 1440 ACAGA,ACATG A'1C'~AGZGTAT CAGAAATCAG CACAAG'TGTG ATGAAAATGC TTTATOCPI'C 1500 AAC'AC't"G'!TG GADGACACAA CTGIGTrTTGC AAGCCGGGCT ATACAGGGAA TIXGAACX"aACA 1560 TGCAP-AGC'.AT TTTGCAAP,GA TCGCTGTAGG AATGGAGGAG CCTG'PATTaC CGCTAATG'IG 1620 TG'I'GCC'i'Of'.C CACAAGGCTT CACTGGACCC AOC'I'GPGAAA CGGACATTGA TGAATOGTCT 1680 GATGGP'i"I"PG TTC'AATGt'GA CAGIC7GTGC.'T AATTGCATTA ACCPGGC'iG1G ATGG'TACCAC

TGTGAGTGCA GAGATGGCTA CCATGACAAT GGGATGITIT CACCAAGi'GG AGAATCGI'GT 1800 GAAGATATTG ATGAGTGPGG GACOOGGAGG CACAGCI'GZG CCAATGATAC CATT'IGGTI'C 1860 AATPTGGATG GOOC'aATATGA TTGTCC;ATGT dC:'I'CATGGAA AGAATTGCAIC AGCGGACTGC 1920 ATC7CAZCATG GAAAP,GPTAA CCAC',AATGGP CAGA-TT'1'GGG TGTIGC'~AP,AA TGACAGGTGC

TCTGZGTCI;T CATGTCAGAA TGGAT'I'CGiT ATGPGPOGAC GGATGGTCTG TGAC7IGZC'aAG 2040 AATCCCACAG TTGAZCTTTr TTG~,'i'GCC7(.~' GAAZGTGACC CAAGGCTTAG TAGPCAGTGC 2100 C't'CC'.ATCAAA ATGGGGAAAC TI'TGTATAP-C AGrGG7GACA CCTGGGPtXA GAATTGICAA 2160 CAGTGOCGCP GCPPGCAAGG GGAAGT'iGAT TGTMGCCCC TGOCTIC~C7CC AGATGTGGAG 2220 'PG'IGAATTCA GCATI'CTOOC AGAGAATGAIG TGC.'TGOff)OGC GCTGIC~PC'.AiC
Af'õAiC1CCTIGC 2280 CAGGC.'TGiACA CCA't'CCGCAA ZGACAT(',ACC AAGACI'POOC TGGACGAAAT GAATG'POG'IT

OGC.'TTC',AOOG WPOCrCPIG GATCAAACAT GGCACPGAGr GTACTCI'C`i'G OCAGTOCAAG 2400 AA'I'OGCC'.ACA TCTGITGCTC AGZGC'~ATCCA C~IGTGCCT'I'C AGGAACTG 2448 (2) INFORMATION FOR SEQ ID NO:39:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 3198 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA(genomic) (iii) HYPOTHETICAL: NO

(iv) ANTI-SENSE: NO
(vii) IMMEDIATE SOURCE:
(A) LIBRARY: Human fetal brain cDNA library (B) CLONE: GEN-093E05 (ix) FEATURE:
(A) NAME/KEY: CDS
(B) LOCATION: 97..2544 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:39:

TTOG("~AGCAG CAGPCTCi'CC GCPOGZC.'ZCC CGGAGGTT'I'C ZC('~ATTGi'CT CTGCCTI'TAC

AACAGAGGGA GAOGATGGAC TGAGC."I'GATC CGCACC ATG GAG TCT COG GTC TTA 114 Met Glu Ser Arg Val Leu CTG AGA ACA TTC ZGT TTG ATC TPC GGT CTC GGA GCA GTT TGG GGG G'TT 162 Leu Arg Thr Phe Cys Leu Ile Phe Gly Leu Gly Ala Val Trp Gly Leu Gly Val Asp Pro Ser Leu Gln Ile Asp Val Leu Thr Glu Leu Glu Lau GGG GAG TCC AAG AOC GGA GTG WT CAG GTC OOG GflG CTG CAT AAT GGG 258 Gly Glu Ser Thr Thr Gly Val Arg Gln Val Pro Gly Leu His Asn Gly Thr Lys Ala Phe Leu Phe Gin Asp Thr Pro Arg Ser Ile Lys Ala Ser ACT GL'T ACA GCT GAA CAG TTT TTT CAG AAIG CTG AGA AAT AAA CAT GAA 354 Thr Ala Thr Ala Glu Gln Phe Phe Gln Lys Leu Arg Asn Lys His Glu Phe Thr Ile Leu Val Thr LSu Lys Gln Thr His Leu Asn Ser Gly Val ATT CTC TCA ATT CAC CAC TTG GAT CAC AGG TAC CZG GAA CZ'G GAA AG'T 450 Ile Leu Ser Ile His His Leu Asp His Arg Tyr Leu Glu Leu Glu Ser AGT GGC CAT aGG AAT GAA GTC AGA C'I'G CAT TAC OGC TGA GGC AGT CAC 498 Ser Gly His Arg Asn Glu Val Arg Leu His Tyr Arg Ser Gly Ser His CGC OGT CAC ACA GAA GTG TRT CCT TAC ATT Ti'G GCT GAT GAC AAG TGG 546 Arg Pro His Thr Glu Val Phe Pro Tyr Ile Leu Ala Asp Asp Lys Trp CAC AAG CTC TCC TTA GCC ATC AG'P GCT TCC CAT TTG ATT TTA CAC ATT 594 His Lys Leu Ser Leu Ala Ile Ser Ala Ser His Leu Ile Leu His Ile Asp Cys Asn Lys Ile Tyr Glu Arg Val Val Glu Lys Pro Ser Thr Asp TTG (7C'I' CTA GGC ACA ACA T'1'T TaG CTA GGA CAG AGA AAT AAT GGG CAT 690 Leu Pro Leu Gly Thr Thr Phe Trp Leu Gly Gln Arg Asn Asn Ala His GGA TAT T'IT AAG GGT ATA AZG CAA GAT GTC CAA TTA CTT GTC ATG MC 738 Gly Tyr Pitie Lys Gly Ile Met Gln Asp Val Gln Leu Leu Val Met Pro CAG GGA TTT ATT GCT CAG ZGC CCA GAT C.'TI' AAT tJGC ACC TGT CCA AC.T 786 Gin Gly Phe Ile Ala Gln Cys Pro Asp Leu Asn Arg Thr Cys Pro Thr Cys Asn Asp Phe His Gly Leu Val Gin Lys Ile Met Glu Leu Gln Asp ATT TTA QOC AAA ACA TCA GOC AAG CPG TZ.T OGA GCT GAA CAG GGA ATG 882 Ile Leu Ala Lys Thr Ser Ala Lys Leu Ser Arg Ala Glu Gln Arg Met Asn Arg Leu Asp Gln Cys Tyr Cys Glu Arg Thr Cys Thr Met Lys Gly AOC AIOC TAC dGA GAA TTT GAG TCC TGG ATA GAC GGC TGT AAG AAC TGC 978 Thr Thr Tyr Arg Glu Rie Glu Ser Trp Ile Asp Gly Cys Lys Asn Cys Thr Cys Leu Asn Gly Tthr Ile Gln Cys Glu Thr Leu Ile Cys Pro Asn OL'I' GAC TGC CX'A CTT AAG TCG Gt,"T CIT GCG TAT GTG GAT GGC AAA TGC 1074 Pro Asp Cys Pro Leu Lys Ser Ala ILeu Ala Tyr Val Asp Gly Lys Cys TGT AAG GAA TGC AAA TM ATA TaC CAA TTT CAA GGA OGA AQC TAC TTT 1122 Cys Lys Glu Cys Lys Ser Ile Cys Gln Phe Gln Gly Arg Thr Tyr Phe GAA GGA GAA AGA AAT ACA GTC TAT TQC TGT TGY' GGA GTA TGT GTT CrC 1170 Glu Gly Glu Arg Asn Thr Val Tyr Ser Ser Ser Gly Val Cys Val Leu Tyr Glu Cys Lys Asp Gln Thr Met Lys Leu Val. Glu Ser Ser Gly Cys Pro Ala Leu Asp Cys Pro Glu Ser His Gln Ile Thr Leu Ser His Ser TG'P TGC AAA GTT TGT AAA GGT TAT GAC TTT TGT TCT GAA AGG CAT AAC 1314 Cys Cys Lys Val qis Lys Gly Tyr Asp Phe Cys Ser Glu Arg His Asn TW ATG GAG AAT TOC ATC TGC AGA AAT C'IG AAT GAC AGG GCT GTP ZGT 1362 Cys Met Glu Asn Ser Ile Cys Arg Asn LSu Asn Asp Arg Ala Val Cys AGC TGT CGA GAT GGT TTT AGG GGT C'I'I' CGA GAG GAT AAT GOC TAC TGT 1410 Ser Cys Arg Asp Gly Phe Arg Ala Leu Arg Glu Asp Asn Ala Tyr Cys Glu Asp Ile Asp Glu Cys Ala Glu Gly Arg His Tyr Cys Arg Glu Asn Thr Met Cys Val Asn Thr Pro Gly Ser Ptye Met Gys Ile Cys Lys Thr Gly Tyr Ile Arg Ile Asp Asp Tyr Ser Cys Thr Glu His Asp Glu Cys Ile Thr Asn Gin His Asn Cys Asp Glu Asn Ala Lau Cys Phe Asn Thr Val Gly Gly His Asn Cys Val Cys Lys Pro Gly Tyr Thr Giy Asn Gly Thr Thr Cys Lys Ala Phe Cys Lys Asp Gly Cys Arg Asn Gly Gly Ala Cys Ile Ala Ala Asn Val Cys Ala Cys Pro Gin Gly Phe Thr Gly Pro Ser Cys Glu Thr Asp Ile Asp Glu Cys Ser Asp Gly Phe Val Gln Cys GAC AGT C:GT GC.T AAT TGC ATT AAC CTG CCT GGA TGG TAC CAC TGT GAG 1842 Asp Ser Arg Ala Asn Cys Ile Asn Leu Pro Gly Trp Tyr His Cys Glu Cys Arg Asp Gly Tyr His Asp Asn Gly Met Phe Ser Pro Ser Gly Glu Ser Cys Glu Asp Ile Asp Glu Cys Gly Thr Gly Arg His Ser Cys Ala AAT GP-T ACC ATT TGC TTC AAT TTG GAT GGO GGA TAT GP,T TGT (7GA TG'I' 1986 Asn Asp Thr Ile Cys Phe Asn Leu Asp Gly Gly Tyr Asp Cys Arg Cys Pro His Gly Lys Asn Cys Thr Gly Asp Cys Ile His Asp Gly Lys Val AAG CAC AAT WT CAG ATT TGG GTG T1'G G;AA AAT GAC AGG TGC TG'T GTG 2082 Lys His Asn Gly Gln Ile Trp V&l. ieu Glu Asn Asp Arg Cys Ser Val Cys Ser Cys Gln Asn Gly Phe Val Met Cys Arg Arg Met Val Cys Asp TGT GAG AAT GOC ACA GTT GAT CTT TTT TGC TOC aCT GAA TGT GAC OCA 2178 qs Glu Asn Pro Thr Val. Asp Leu Phe Cys Cys Pro Glu Cys Asp Pro AGG CTT AGT AGT CAG TGC CTC CAT CAA AAT GGG GAA ACT TTG TAT AAiC 2226 Arg Leu Ser Ser Gln Cys Leu His Gln Asn Gly Glu Thr Leu Tyr Asn AGT GGT GAC ACC TGG GTC CAG AAT TGT CAA CAG TGC C:OC TGC TTG CAA 2274 Ser Gly Asp Thr Trp Val Gln Asn Cys Gln Gln Cys Arg Cys Leu Gln Gly Glu Val Asp Cys Trp Pro Leu Pro Cys Pro Asp Val Glu Cys Glu TTC AOC ATT CTC OCA GAG AAT GAG TGC TGC QOG aGC TGT GTG ACA GAC 2370 Phe Ser Ile Leu Pro Glu Asn Glu Cys Cys Pro Arg Cys Val Thr Asp OCT TaC CAG GCT GAC ACC ATC aCC AAT GAC ATC ACC AAG ACT TGC CIG 2418 Pro Cys Gln Ala Asp Thr Ile Arg Asn Asp Ile Thr Lys Thr Cys Leu GAC GAA ATG AAT GZG GTT OOC TTC A(JC GOG TOC TCT TC3G ATC AAA CAT 2466 Asp Glu Met Asn Val Val Arg Phe Thr Gly Ser Ser Trp Ile Lys His Gly Thr Glu Cys Thr Leu Cys Gln Cys Lys Asn Gly His Ile Cys Cys TCA GTG GAT CCA CAG TGC C'IT CAG GAA CIG ZGAAGT'rAAC TG'IC'I'CATGG 2564 Ser Val Asp Pro Gin Cys Leu Gln Glu Leu GAGATTZC,'IG ZTAAAAGAAT GTTCTITCAT TAAAAGAOCA AAAAGAAG'TT AAAACTTAAA 2624 TTG(~GI'GATT TGi'GGGCA10C TAAATGCAGC TTI'G`ITAATA GCTGAGIY'yAA CTT`1'C'.AATTA

ZGAAAZ'I'IGr GGAGCTPC',ArC AAAATCA('AA AAQC''AAAATT ACTGGGGCAA AATTACACGT 2744 CAAG'I'C7I'GOC TCTArCZC3TGT CTCACATCAC CATGTAGAAG AATGGGCGTA CAGI'ATATAC 2804 CGTGACATCC TGAAOCL'TOG ATAGAAADCJC TGAOOOCATT GGATCTG'IGA AAGCC,R'CTAG 2864 CT1C'.A~.'iC~T GCAC'aAAAATT TPOC'!'CI'AGA TC'AGAATLZ'T C.AC'aAATCAGT
TA~OGTTOCIC 2924 ACTGC.AAGAA ATAAAATGIC AGGC=AGI'GAA TGAATTATAT TTTCAGAAGr AAAGCAAA('1 2984 AGCTATAACA TGTTATGTAC AIGTACAC'PG'P G1?AAAGAAAT Ci''aAAAC.AAC' TTATTGTAAT 3044 GATAAAAATA ATGCACAGOC ATG(7ITAC'iT AATATTTTCP AACAOGAAAA GTCATCOC'PA 3104 TTI'IOCTI'GZT TTAC'iYGC.ACT TAATATTATT TGGT'I'GAATT TGTTC.AGPAT AAGCTCGTIC

TTC'IG('.AAAA TTAAATAAAT ATT'i~CICTTA CC'iT 3198 (2) INFORMATION FOR SEQ ID N0:40:

(i) SEQUENCE.CHARACTERISTICS:
(A) LENGTH: 499 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:40:

Met Glu Leu Ser Glu Pro Val Val Glu Asn Gly Glu Val Glu Met Ala Leu Glu Glu Ser Trp Glu His Ser Lys Glu Val Ser Glu Ala Glu Pro Gly Gly Gly Ser Ser Gly Asp Ser Gly Pro Pro Glu Glu Ser Gly Gln Glu Met Met Glu Glu Lys Glu Glu Ile Arg Lys Ser Lys Ser Val Ile Val Pro Ser Gly Ala Pro Lys Lys Glu His Val Asn Val Val Phe I1e Gly His Val Asp Ala Gly Lys Ser Thr Ile Gly Gly Gln Ile Met Phe Leu Thr Gly Met Ala Asp Lys Arg Thr Lau Glu Lys Tyr Glu Arg Glu Ala Glu Glu Lys Asn Arg Glu Tthr Trp Tyr Leu Ser Trp Ala Leu Asp Thr Asn Gln Glu Glu Arg Asp Lys Gly Lys Thr Val Glu Val Gly Arg Ala Tyr Phe Glu Thr Glu Arg Lys His Phe Thr Ile Leu Asp Ala Pro Gly His Lys Ser Phe Val Pro Asn Met Ile Gly Gly Ala Ser Gln Ala Asp Leu Ala Val Leu Val Ile Ser Ala Arg Lys Gly Glu Phe Glu Thr Gly Phe Glu Lys Gly Gly Gln Thr Arg Glu His Ala Met Phe Gly Lys Thr Ala Gly Val Lys His Leu Ile Val Lau Ile Asn Lys Met Asp Asp Pro Thr Val Asn Trp Gly Ile Glu Arg Tyr Glu Glu Cys Lys Glu Lys Leu Val Pro Phe Lau Lys Lys Val Gly Phe Ser Pro Lys Lys Asp Ile His Phe Met Pro Cys Ser Gly Lau Thr Gly Ala Asn Ile Lys Glu Gln 260 265 270.
Ser Asp Phe Cys Pro Trp Tyr Thr Gly Lsu Pro Phe Ile Pro Tyr Lsu . 275 280 285 Asn Asn Lsu Pro Asn Phe Asn Arg Ser Ile Asp Gly Pro Ile Arg Lau Pro Ile Val Asp Lys Tyr Lys Asp Met Gly Thr Val Val Leu Gly Lys Leu Glu Ser Gly Ser Ile Phe Lys Gly Gln Gln Leu Val Met Met Pro Asn Lys His Asn Val Glu Val Leu Gly Ile Leu Ser Asp Asp Thr Glu Thr Asp Phe Val Ala Pro Gly Glu Asn Leu Lys Ile Arg Leu Lys Gly Ile Glu- Glu Glu Glu Ile Leu Pro Glu Phe Ile Leu Cys Asp Pro Ser Asn Leu Cys His Ser Gly Arg Thr Phe Asp Val Gln Ile Val Ile Ile Glu His Lys Ser Ile Ile Cys Pro Gly Tyr Asn Ala Val Leu His Ile His Thr Cys Ile Glu Glu Val Glu Ile Thr Ala Leu Ile Ser Leu Val Asp Lys Lys Ser Gly Glu Lys Ser Lys Thr Arg Pro Arg Phe Val Lys Gln Asp Gln Val Cys Ile Ala Arg Leu Arg Thr Ala Gly Thr Ile Cys Leu Glu Thr Phe Lys Asp Phe Pro Gln Met Gly Arg Phe Thr Leu Arg Asp Glu Gly Lys Thr Ile Ala Ile Gly Lys Val Leu Lys LSu Val Pro Glu Lys Asp (2) INFORMATION FOR SEQ ID NO:41:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 1497 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA(genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID N0:41:

AT'GGAACTTT CAGAP-OCTGT TGTACAAP-AT GGAIGAGGI'GG AAATGOIXX.T AGAAGAATCA 60 TGGGAGCACA GTAAAGAAG'P AAGT('~AAQOC GAGCCTOC'GG GI'OG'I"IC7C'PC GGGAGATTCA 120 OGGCCCCCAG AAGAAAGZ'OG CCAaGAAATG ATGGAGGAAA AAGAOGAAAT AA~C'aAAAATCC 180 AAATCTGTGA TCGPACCC'I'C AGGTGCACCT AAC''AAAGAAC ACGI'AAATGT AGPATTCATT 240 GGCX'.ATGTAG ACGC,'ZCGCAA GTCAACCATC GGAIGGACAGA TAATGTPTIT GACTGGAATG 300 GCTGACAAAA GAACACTOGA GAAATATC'aAA AGAGAAGCTG AOGAAAAAAA CAG:AC'~AACC 360 ZTATGT 1C1 T AGATAC,AAAT CAGC',oAGGAAC GAGACAAGGG TAAAACAGIC 420 GAAGTGGI'C GTGCC.'TATTT TGAAACAGAA AOGAAAICATT TCACAATTTI' AGATGCOCC,T 480 COGCCACAAGik GTTTT(~i'OCC AAP-TA'I'GATT uG1wI'C~CIT C'iC',AAGCi'GA
TPICaGCi~GIC` 540 CTaGTCATCT CTGCCAIGGAA AGCAGAGTTT GAAAC,'TGGAT TTGAAAAAOG TOGACAGACA 600 AGAC'aAAf'.ATG CGAZGrrTGG CAAAACOGC',A GGAGPAAAAIG ATTTAATAGr GCI'TATTAAT 660 C'IC~GI'OOOC.'T TTTTGAAAAA AGTA GCPIT AQi'CCAAAAA AGGACATZCA CTTTA'IG:CC 780 TGCPC'AOGAC 'i'GACCGGAGC AAATATTAAA GAGCAGICAG ATTTCTGOCC TZGCZ'ACACr' 840 GGATTACCAT TTATTCCGrA TTTt3AATAAC TTGOC'AAACT TCAACA[3ATC AATTGATGGA 900 CCAATAAGAC TGCf'.AATTGT GGATAAOTAC AAAiGATATOG OCAGTGTGGT CCTGGGAAPdG 960 CPCGAAT= GGTCX".ATTTT TAAAGGCCAG CAGCTCGTGA TGATOCCAAA CAAGCACAAT 1020 GTAlGAAGITC TTGC'~AATACT TTCTC'rATGAT ACZGAAAL.'TG ATI"I'I'GTAOC CCC'.AIOGrGAA

AAOCTCAAAA TCAGACTGAA G'OGAATIGAA GAAGAAGAC'aF- TTCZ'PCC1AC'aA ATTCATACZT 1140 TGTGATCCrA GTAACCI'CTG CCAT'PC'PGGA COCACGITIG ATGTIC'Af'aAT AGi'GATTATT 1200 GACY'A,C'AAAT CCATCATCTG CCCAGGT'rAT AATGCGGTaC TCGCACATTCA TAGTTGTATT 1260 C;AGGAAGT'iG AGATAACAGC GTTAATCTCC TTOGTAGAf'A AAAAAT('.AOG aGAAAAAAIG'T 1320 AAGACACGAC CCIX'CTPOGT GAAAOAAOAT CAAGrATGCA TT{~CrCG!'t'T AAGGACAGCA 1380 GGAAOCATCT GOCI'CGAGAC GPTC,AAAGAT TTTCCPCAGA TOOGTOGI'IT TACTTTAAGA 1440 GATGAGGGTA AGACCATTGC AATTG('aAAAA G'I'I'CTGAAAT TGGTCCCAGA GAAGGAC 1497 (2) INFORMATION FOR SEQ ID N0:42:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 2057 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA(genomic) (iii) HYPOTHETICAL: NO

(iv) ANTI-SENSE: NO

( vii ) IMMEDIATE SOURCE:
(A) LIBRARY: Human fetal brain cDNA library (B) CLONE: GEN-077A09 (ix) FEATURE:
(A) NAME/KEY: CDS
(B) LOCATION: 144..1640 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:42:

Ta00GGCCOG CTCOGGC'.AGC AAL7C`AZGW OCrOCACCGG CGCGOf'aATAIC aCTCAA[OGTA 60 AAAGGATaGG ACGGGGGGCA CC,`I'G7GGAAC CIZC00f'AGA GGAAOOGTTA GiG'POOClTG 120 AAOGPIMAA Ti'C.AGOOGPT ACC ATG GAA CT'T TCA GAA CCT GTT GTA GAA 170 Met Glu Leu Ser Glu Pro Val Val Glu Asn Gly Glu Val Glu Met Ala Leu Glu Glu Ser Txp Glu His Ser Lys Glu Val Ser Glu Ala Glu Pro Gly Gly Gly Ser Ser Gly Asp Ser Gly Pro Pro Glu Glu Ser Gly Gln Glu Met Met Glu Glu Lys Glu Glu Ile Arg Lys Ser Lys Ser Val Ile Val Pro Ser Gly Ala Pro Lys Lys Glu His Val Asn Val Val Phe Ile Gly His Val Asp Ala Gly Lys Ser Thr Ile Gly Gly Gln Ile Met Phe L8u Thr Gly Met Ala Asp Lys Arg Thr Leu Glu Lys Tyr Glu Arg Glu Ala Glu Glu Lys Asn Arg Glu Thr Trp TAT Tt'G TCC TGG GOC TTA GAT ACA AAT CAG GAG GAA CGA GAC AAG GGT 554 Tyr Leu Ser Trp Ala Leu Asp Thr Asn Gln Glu Glu Arg Asp Lys Gly Lys Thr Val Glu Val Gly Arg Ala Tyr Phe Glu Thr Glu Arg Lys His TTC ACA ATT TPA GAT GflC CCT GGC CAC AAG AGT TTT GTC CCA AAT ATG 650 Phe Thr Ile Leu Asp Ala Pro Gly His Lys Ser Phe Val Pro Asn Met ATT GGr GGT GCT TC'T CAA GCT GAT TTG GLT GTG CIG GIC ATC TCT GOC 698 Ile Gly Gly Ala Ser Gln Ala Asp Leu Ala Val Leu Val Ile Ser Ala Arg Lys Gly Glu Phe Glu Thr Gly Phe Glu Lys Gly Gly Gln Thr Arg GAA CAT GCG ATG TTT GOC AAA AIOG a'.A GGA G'TA AAA CAT TTA ATA GTG 794 Glu His Ala Met Phe Gly Lys Thr Ala Gly Val Lys His Leu Ile Val Leu Ile Asn Lys Met Asp Asp Pro Thr Val Asn Trp Gly Ile Glu Arg TAT'GAA GAA TGT AAA GAA AAA CIG GIG CCC TTT TTG AAA AAA GTA GGC 890 Tyr Glu Glu Cys Lys Glu Lys Leu Val Pro Phe Leu Lys Lys Val Gly Phe Ser Pro Lys Lys Asp Ile His Phe Met Pro Cys Ser Gly Leu Thr GGA GCA AAT ATT AAA GAG CAG 'ICA GAT TTC TGC CCT TOG TAC ACT GGA 986 Gly Ala Asn Ile Lys Glu Gln Ser Asp Phe Cys Pro Trp Tyr Thr Gly TTA CCA TTT AZT CCG TAT TTG AAT AAC TTG CCA AAC TZC AAC AGA '1CA 1034 Leu Pro Phe Ile Pro Tyr Leu Asn Asn Leu Pro Asn Phe Asn Arg Ser ATT GAT GGA Cf_'A ATA AGA C'1G CCA ATT GTG GAT AAG TAC AAA GAT ATG 1082 Ile Asp Gly Pro Ile Arg Leu Pro Ile Val Asp Lys Tyr Lys Asp Met GOC ACT GTG GTC C't'G GGA AAG C'I'G GAA TOC GGG TOC ATT TTT AP-P- GGC 1130 Gly Thr Val Val Leu Gly Lys Leu Glu Ser Gly Ser Ile Phe Lys Gly CAG CAG CTC GTG ATG ATG OGA AAIC AAL", CAC AAT GTA GAA GTT C'!T GGA 1178 Gln Gl.n. Leu Val Met Met Pro Asn Lys His Asn Val Glu Val Leu Gly ATA CI'T TCT GAT GAT ACT GAA ACT GAT TTT GTA GCC OCA GGT GAA AAC 1226 Ile Leu Ser Asp Asp Thr Glu Thr Asp Phe Val Ala Pro Gly Glu Asn CTC AAA ATC AGA C'IG AAIG GGA ATT GAA GAA GAA GAG ATT CIT CCA GAA 1274 Leu Lys Ile Arg Leu Lys Gly Ile Glu Glu Glu Glu Ile Leu Pro Glu Phe Ile Leu Cys Asp Pro Ser Asn Leu Cys His Ser Gly Arg Thr Phe Asp Val Gln Ile Val Ile Ile Glu His Lys Ser Ile Ile Cys Pro Gly Tyr Asn Ala Val Leu His Ile His Thr Cys Ile Glu Glu Val Glu Ile Thr Ala Lau Ile Ser Leu Val Asp Lys Lys Ser Gly Glu Lys Ser Lys Thr Arg Pro Arg Phe Val Lys Gin Asp Gin Val Cys Ile Ala Arg Leu AGG ACA GCA GGA AOC ATC TGC CPC GAG ACG TTC AAA GAT TTT C)CT CAG 1562 Arg Thr Ala Gly Thr Ile Cys Leu Glu Thr Phe Lys Asp Phe Pro Gln ATG GGT CG'I' TTT ACT ZTA AGA GAT GAG GGT AA+G AOC ATT GCA ATT GGA 1610 Met Gly Arg Phe Thr Leu Arg Asp Glu Gly Lys Thr Ile Ala Ile Gly w M

AAA GTT CTG AAA TTG GTC aCA GAG AAG GAC TAAGCAATTT TGT'IC'~AZGC.C 1660 Lys Val Leu Lys Leu Val Pro Glu Lys Asp TCZGCAAGAT ACTGIC'~AlaGA GAATTGACAG CAAAAGTTCA OCAQCTAC'I'C TTATTTACZG 1720 CCOC'.ATTGATT GACT'ITTCTT CATAT'I'Pl'OC AAAGAGAAAT TTCACAGCAA AAATTCAZGT 1780 TTZGTC'AGCT TTG'PC'ATGTT GAGATCTG'TT A'I'GTCIACZGA TGAATTTAOC CI'CAAGP'i'TC

GTTaCTCTGT AOCACTCTGC TTOCrTGGAC AATATCAGTA ATAGCTTTGT AAGI'GATG'1G 1900 GAOGPAATTG CCTACAU`PAA TAAAAAAATA AT6TACPITA ATPPTPCATT TI'CPT'ITAGG 1960 ATATTTAGAIC CAOOCTrGTT aCAOGC'.AAAC CAGAGTGPGT CAGTG'TTTGT GZ'GTGICTTA 2020 AAATGATAAC TAACATGt'GA ATAAAATACT OCATTTG 2057

Claims (7)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. An isolated polypeptide consisting of the amino acid sequence of SEQ ID NO:22.

2. An isolated DNA molecule consisting of the nucleotide sequence of SEQ ID NO:23 or a sequence complementary thereto.

3. An expression vector harbouring the isolated DNA
molecule as defined in claim 2.

4. A host cell transformed with the expression vector as defined in claim 3.

5. A method of producing a recombinant polypeptide having ubiquitin-conjugating activity, the method comprising growing the host cell defined in claim 4 in a culture medium, and harvesting the polypeptide from the resulting culture.

6. A recombinant polypeptide obtained by the method as defined in claim 5.

7. An antibody having a binding affinity for the polypeptide as defined in claim 1 or the recombinant polypeptide as defined in claim 6.