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We have identified a novel gene (WBSCR9) within the common Williams-Beuren syndrome (WBS) deletion by interspecies sequence conservation. The WBSCR9 gene encodes a roughly 7-kb transcript with an open reading frame of 1483 amino acids and a predicted protein product size of 170.8 kDa. WBSCR9 is comprised of at least 20 exons extending over 60 kb. The transcript is expressed ubiquitously throughout development and is subject to alternative splicing. Functional motifs identified by sequence homology searches include a bromodomain; a PHD, or C4HC3, finger; several putative nuclear localization signals; four nuclear receptor binding motifs; a polyglutamate stretch and two PEST sequences. Bromodomains, PHD motifs and nuclear receptor binding motifs are cardinal features of proteins that are involved in chromatin remodeling and modulation of transcription. Haploinsufficiency for WBSCR9 gene products may contribute to the complex phenotype of WBS by interacting with tissue-specific regulatory factors during development.
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- Aasland R, Gibson TJ, Stewart AF: The PHD finger: implications for chromatin-mediated transcriptional regulation. Trends Biochem Sci 20:56–59 (1995).
- Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ: Basic local alignment search tool. J Mol Biol 215:403–410 (1990).
- Altschul SF, Madden TL, Schaffer AA, Zhang J, Zhang Z, Miller W, Lipman DJ: Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucl Acids Res 25:3389–3402 (1997).
- Ashkenas J: Williams syndrome starts making sense. Am J hum Genet 59:756–761 (1996).
- Attwood TK, Beck ME, Flower DR, Scordis P, Selley J: The PRINTS protein fingerprint database in its fifth year. Nucl Acids Res 26:304–308 (1998).
- Bairoch A, Bucher P, Hofmann K: The PROSITE database, its status in 1997. Nucl Acids Res 25:217–221 (1997).
- Barlev NA, Poltoratsky V, Owen-Hughes T, Ying C, Liu L, Workman JL, Berger SL: Repression of GCN5 histone acetyltransferase activity via bromodomain-mediated binding and phosphorylation by the Ku-DNA-dependent protein kinase complex. Mol Cell Biol 18:1349–1358 (1998).
- Baumer A, Dutly F, Balmer D, Riegel M, Tükel T, Krajewska-Walasek M, Schinzel AA: High level of unequal meiotic crossovers at the origin of the 22q11.2 and 7q11.23 deletions. Hum Mol Genet 7:887–894 (1998).
- Blackwood EM, Kadonaga JT: Going the distance: a current view of enhancer action. Science 281:60–63 (1998).
- Brownell JE, Allis CD: Special HATs for special occasions: linking histone acetylation to chromatin assembly and gene activation. Curr Opin Genet Develop 6:176–184 (1996).
- Burley S, Roeder R: Biochemistry and structural biology of transcription factor IID (TFIID). Ann Rev Biochem 65:769–799 (1996).
- De Zeeuw CI, Hoogenraad CC, Goedknegt E, Hertzberg E, Neubauer A, Grosveld F, Galjart N: CLIP-115, a novel brain-specific cytoplasmic linker protein, mediates the localization of dendritic lamellar bodies. Neuron 19:1187–1199 (1997).
- Dib C, Faure S, Fizames C, Samson D, Drouot N, Vignal A, Millasseau P, Marc S, Hazan J, Seboun E, Lathrop M, Gyapay G, Morissette J, Weissenbach J: A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature 380:152–154 (1996).
- Dilts CV, Morris CA, Leonard CO: Hypothesis for development of a behavioral phenotype in Williams syndrome. Am J Med Genet Suppl 6:126–131 (1990).
- Dingwall C, Laskey RA: Nuclear targeting sequences – a consensus? Trends Biochem Sci 16:478–481 (1991).
- Dutly F, Schinzel A: Unequal interchromosomal rearrangements may result in elastin gene deletions causing the Williams-Beuren syndrome. Hum Mol Genet 5:1893–1898 (1996).
- Ewart A, Morris CA, Atkinson D, Jin W, Sternes K, Spallone P, Stock AD, Leppert M, Keating MT: Hemizygosity at the elastin locus in a developmental disorder, Williams syndrome. Nature Genet 5:11–16 (1993).
- Farkas G, Gausz J, Galloni M, Reuter G, Gyurkovics H, Karch F: The Trithorax-like gene encodes the Drosophila GAGA factor. Nature 371:806–808 (1994).
- Francke U, Taggart RT: Assignment of the gene for cytoplasmic superoxide dismutase (Sod-1) to a region of chromosome 16 and of Hprt to a region of the X chromosome in the mouse. Proc Natl Acad Sci, USA 76:5230–5233 (1979).
- Frangiskakis JM, Ewart AK, Morris CA, Mervis CB, Bertrand J, Robinson BF, Klein BP, Ensing GJ, Everett LA, Green ED, Pröschel C, Gutowski NJ, Noble M, Atkinson DL, Odelberg SJ, Keating MT: LIM-kinase1 hemizygosity implicated in impaired visuospatial constructive cognition. Cell 86:1–20 (1996).
- Garnier J, Gibrat JF, Robson B: GOR method for predicting protein secondary structure from amino acid sequence. Methods Enzymol 266:540–553 (1996).
- Gibbons RJ, Bachoo S, Picketts DJ, Aftimos S, Asenbauer B, Bergoffen JA, Berry SA, Dahl N, Fryer A, Keppler K, Kurosawa K, Levin ML, Masuno M, Neri G, Pierpont ME, Slaney SF, Higgs DR: Mutations in transcriptional regulator ATRX establish the functional significance of a PHD-like domain. Nature Genet 17:146–148 (1997).
- Guarente L: Transcriptional coactivators in yeast and beyond. Trends Biochem Sci 20:517–521 (1995).
- Haynes SR, Dollard C, Winston F, Beck S, Trowsdale J, Dawid IB: The bromodomain: a conserved sequence found in human, Drosophila and yeast proteins. Nucl Acids Res 20:2603 (1992).
- Heery DM, Kalkhoven E, Hoare S, Parker MG: A signature motif in transcriptional co-activators mediates binding to nuclear receptors. Nature 387:733–736 (1997).
- Henikoff S, Henikoff JG: Protein family classification based on searching a data base of blocks. Genomics 19:97–107 (1994).
- Higgins DG, Thompson JD, Gibson TJ: Using CLUSTAL for multiple sequence alignments. Methods Enzymol 266:383–402 (1996).
- Horton P, Nakai K: Better prediction of protein cellular localization sites with the k nearest neighbors classifier. Intelligent Systems Mol Biol 5:147–152 (1997).
- Jeanmougin F, Wurtz JM, Le Douarin B, Chambon P, Losson R: The bromodomain revisited. Trends Biochem Sci 22:151–153 (1997).
- Kawasaki H, Song J, Eckner R, Ugai H, Chiu R, Taira K, Shi Y, Jones N, Yokoyama KK: p300 and ATF-2 are components of the DRF complex, which regulates retinoic acid- and E1A-mediated transcription of the c-jun gene in F9 cells. Genes Develop 12:233–245 (1998).
- Khan AS, Wilcox AS, Polymeropoulos MH, Hopkins JA, Stevens JJ, Robinson M, Orpana AK, Sikela JM: Single pass sequencing and physical and genetic mapping of human brain cDNAs. Nature Genet 2:180–185 (1992).
- Kim UJ, Birren BW, Slepak T, Mancino V, Boysen C, Kang HL, Siman MI, Shizuya H: Construction and characterization of a human bacterial artificial chromosome library. Genomics 34:213–218 (1996).
- Kozak M: Point mutations define a sequence flanking the AUG initiator codon that modulates translation by eukaryotic ribosomes. Cell 44:283–292 (1986).
- Le Douarin B, Nielsen AL, Garnier JM, Ichinose H, Jeanmougin F, Losson R, Chambon P: A possible involvement of TIF1α and TIF1β in the epigenetic control of transcription by nuclear receptors. EMBO J 15:6701–6715 (1996).
- Li DY, Toland AE, Boak BB, Atkinson DL, Ensing GJ, Morris CA, Keating MT: Elastin point mutations cause an obstructive vascular disease, supravalvular aortic stenosis. Hum Mol Genet 6:1021–1028 (1997).
- Lonie A, D’Andrea R, Paro R, Saint R: Molecular characterization of the Polycomblike gene of Drosophila melanogaster, a trans-acting negative regulator of homeotic gene expression. Development 120:2629–2636 (1994).
- Mao X, Jones TA, Williamson J, Gutkowski NJ, Pröschel C, Noble M, Sheer D: Assignment of the human and mouse LIM-kinase genes (LIMK1; Limk1) to chromosome bands 7q11.23 and 5G1. Cytogenet Cell Genet 74:190–191 (1996).
- Monaco AP: Human genetics: dissecting Williams syndrome. Curr Biol 6:1396–1398 (1996).
- Nagamine K, Peterson P, Scott HS, Kudoh J, Minoshima S, Heino M, Krohn KJE, Lalioti MD, Mullis PE, Antonarakis SE, Kawasaki K, Asakawa S, Ito F, Shimizu N: Positional cloning of the APECED gene. Nature Genet 17:393–398 (1997).
- Nevill-Manning CG, Wu TD, Brutlag DL: Highly specific protein sequence motifs for genome analysis. Proc natl Acad Sci, USA 95:5865–5871 (1998).
- Ogryzko VV, Schiltz RL, Russanova V, Howard BH, Nakatani Y: The transcriptional coactivators p300 and CBP are histone acetyltransferases. Cell 87:953–959 (1996).
- Osborne LR, Martindale D, Scherer SW, Shi XM, Huizenga J, Heng HHQ, Costa T, Pober B, Lew L, Brinkman J, Rommens J, Koop B, Tsui LC: Identification of genes from a 500-kb region at 7q11.23 that is commonly deleted in Williams syndrome patients. Genomics 36:328–336 (1996).
- Osborne LR, Soder S, Shi XM, Pober B, Costa T, Scherer SW, Tsui LC: Hemizygous deletion of the syntaxin 1A gene in individuals with Williams syndrome. Am J hum Genet 61:449–452 (1997).
- Peoples R, Pérez-Jurado L, Wang Y-K, Kaplan P, Francke U: The gene for replication factor C subunit 2 (RFC2) is within the 7q11.23 Williams syndrome deletion. Am J hum Genet 58:1370–1373 (1996).
- Pérez-Jurado LA, Peoples R, Kaplan P, Hamel BCJ, Francke U: Molecular definition of the chromosome 7 deletion in Williams syndrome and parent-of-origin effects on growth. Am J hum Genet 59:781–792 (1996).
- Pérez-Jurado LA, Wang Y-K, Peoples R, Coloma A, Cruces J, Francke U: A duplicated gene in the breakpoint regions of the 7q11.23 Williams-Beuren syndrome deletion encodes the initiator binding protein TFII-I and BAP-135, a phosphorylation target of BTK. Hum Mol Genet 7:325–334 (1998).
- Petrij F, Giles RH, Dauwerse HG, Saris JJ, Henekam RCM, Masuno M, Tommerup N, van Ommen GB, Goodman RH, Peters DJM, Breuning MH: Rubinstein-Taybi syndrome caused by mutations in the transcriptional coactivator CBP. Nature 376:348–351 (1995).
- Riley J, Butler R, Ogilvie D, Finniear R, Jenner D, Powell S, Anand R, Smith JC, Markham AF: A novel, rapid method for the isolation of terminal sequences from yeast artificial chromosome (YAC) clones. Nucl Acids Res 18:2887–2890 (1990).
- Rodgers S, Wells R, Rechsteiner M: Amino acid sequences common to rapidly degraded proteins: the PEST hypothesis. Science 234:364 (1986).
- Roth SY, Allis CD: Histone acetylation and chromatin assembly: a single escort, multiple dances? Cell 87:5–8 (1996).
- Smith RF, Wiese BA, Wojzynski MK, Davison DB, Worley KC: BCM Search Launcher – an integrated interface to molecular biology data base search and analysis services available on the world wide web. Genome Res 6:454–462 (1996).
- Struhl K: Chromatin structure and RNA polymerase II connection: implications for transcription. Cell 84:179–182 (1996).
- Struhl K, Moqtaderi Z: The TAFs in the HAT. Cell 94:1–4 (1998).
- Sugano K, Kyogoku A, Fukayama N, Ohkura H, Shimosato Y, Sekiya T, Hayashi K: Rapid and simple detection of c-Ki-ras2 gene codon 12 mutations by nonradioisotopic single-strand conformation polymorphism analysis. Methods Lab Invest 65:361–366 (1993).
- Tamkun JW, Deuring R, Scott MP, Kissinger M, Pattatucci AM, Kaufman TC, Kennison JA: Brahma: a regulator of Drosophila homeotic genes structurally related to the yeast transcriptional activator SNF2/SWI2. Cell 68:561–572 (1992).
- Tassabehji M, Metcalfe K, Fergusson WD, Carette MJA, Dore JK, Donnai D, Read AP, Pröschel C, Gutowski NJ, Mao X, Sheer D: LIM-kinase deleted in Williams syndrome. Nature Genet 13:272–273 (1996).
- Tassabehji M, Metcalfe K, Donnai D, Hurst J, Reardon W, Burch M, Read AP: Elastin: genomic structure and point mutations in patients with supravalvular aortic stenosis. Hum Mol Genet 6:1029–1036 (1997a).
- Tassabehji M, Karmiloff-Smith A, Grant J, Donnai D, Dennis N, Splitt M, Reardon W, Osborne L, Read AP, Metcalfe K: Genotype phenotype correlations in Williams syndrome. Am J hum Genet 61:A4 (1997b).
- The Finnish-German APECED Consortium: An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nature Genet 17:399–403 (1997).
- Tijan R, Maniatis T: Transcriptional activation: a complex puzzle with few easy pieces. Cell 77:5–8 (1994).
- Torchia J, Rose DW, Inostroza J, Kamei Y, Westin S, Glass CK, Rosenfeld MG: The transcriptional co-activator p/CIP binds CBP and mediates nuclear-receptor function. Nature 387:677–684 (1997).
- Voegel JJ, Heine MJS, Tini M, Vivat V, Chambon P, Gronemeyer H: The coactivator TIF2 contains three nuclear receptor-binding motifs and mediates transactivation through CBP binding-dependent and independent pathways. EMBO J 17:507–519 (1998).
- Wade PA, Wolffe AP: Chromatin: histone acetyltransferases in control. Curr Biol 7:R82–R84 (1997).
- Wang PP, Bellugi U: Williams syndrome, Down syndrome and cognitive neuroscience. Am J Dis Child 147:1246–1251 (1993).
- Wang PP, Doherty S, Rourke SB, Bellugi U: Unique profile of visuo-perceptual skills in a genetic syndrome. Brain Cognition 29:54–65 (1995).
- Wang Y-K, Harryman Samos C, Peoples R, Pérez-Jurado LA, Nusse R, Francke U: A novel human homologue of the Drosophila frizzled wnt receptor gene binds wingless protein and is in the Williams syndrome deletion at 7q11.23. Hum Mol Genet 6:465–472 (1997).
- Wang Y-K, Pérez-Jurado LA, Francke U: A mouse single-copy gene, Gtf2i, the homolog of human GTF2I, that is duplicated in the Williams-Beuren syndrome deletion region. Genomics 48:163–170 (1998).
- Wolffe AP, Pruss D: Targeting chromatin disruption: transcription regulators that acetylate histones. Cell 84:817–819 (1996).
- Worley KC, Wiese BA, Smith RF: BEAUTY: an enhanced BLAST-based search tool that interprets multiple biological information resources into sequence similarity search results. Genome Res 5:173–184 (1995).
- Wu YQ, Sutton R, Nickerson E, Lupski JR, Potocki L, Korenberg JR, Greenberg F, Tassabehji M, Shaffer LG: Delineation of the common critical region in Williams syndrome and clinical correlation of growth, heart defects, ethnicity and parental origin. Am J Med Genet 78:82–89 (1998).
- Wydner KS, Sechler JL, Boyd CD, Passmore HC: Use of an intron length polymorphism to localize the tropoelastin gene to mouse chromosome 5 in a region of linkage conservation with human chromosome 7. Genomics 23:125–131 (1994).