Age-related macular degeneration (AMD) is a multifactorial disorder affecting the visual system with a high prevalence among the elderly population but with no effective therapy available at present. To better understand the pathogenesis of this disorder, the identification of the genetic factors and the determination of their contribution to AMD is needed. Towards this goal, we are pursuing a strategy that makes use of the EST data processed in the UniGene database and aims at the generation of a comprehensive catalogue of genes preferentially active in the human retina. Subsequently, these genes will be systematically assessed in AMD. We performed a retina EST sampling and obtained a total of 673 clusters containing only retina ESTs as well as 568 clusters with at least 30% of the ESTs in each cluster originating from retina cDNA libraries. Of these, 180 representative EST clusters with varying retina and non-retina EST contents were analyzed for their in vitro expression. This approach identified 39 transcripts with retina-specific expression. One of these genes (C18orf2) mapping to chromosome 18 was further characterized. Multiple C18orf2 transcripts display a complex pattern of differential splicing in the human retina. The various isoforms encode hypothetical polypeptides with no homologies to known proteins or protein motifs.   

Allikmets R, Singh N, Sun H, Shroyer NF, Hutchinson A, Chidambaram A, Gerrard B, Baird L, Stauffer D, Peiffer A, Rattner A, Smallwood P, Li Y, Anderson KL, Lewis RA, Nathans J, Leppert M, Dean M, Lupski JR: A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nature Genet 15:236–246 (1997a).
Allikmets R, Shroyer NF, Singh N, Seddon JM, Lewis RA, Bernstein PS, Peiffer A, Zabriskie NA, Li Y, Hutchinson A, Dean M, Lupski JR, Leppert M: Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration. Science 277:1805–1807 (1997b).
Allikmets R, Seddon JM, Bernstein PS, Hutchinson A, Atkinson A, Sharma S, Gerrard B, Li W, Metzker ML, Wadelius C, Caskey CT, Dean M, Petrukhin K: Evaluation of the Best disease gene in patients with age-related macular degeneration and other maculopathies. Hum Genet 104:449–453 (1999).
Allikmets R, The International ABCR Screening Consortium: Further evidence for an association of ABCR alleles with age-related macular degeneration. Am J hum Genet 67:487–491 (2000).
Bascom RA, Manara S, Collins L, Molday RS, Kalnins VI, McInnes RR: Cloning of the cDNA for a novel photoreceptor membrane protein (rom-1) identifies a disk rim protein family implicated in human retinopathies. Neuron 8:1171–1184 (1992).
Bernstein SL, Borst DE, Neuder ME, Wong P: Characterization of a human fovea cDNA library and regional differential gene expression in the human retina. Genomics 32:301–308 (1996).
Boguski MS, Lowe TM, Tolstoshev CM: dbEST – database for “expressed sequence tags”. Nature Genet 4:332–333 (1993).
Bortoluzzi S, d’Alessi F, Romualdi C, Danieli GA: The human adult skeletal muscle transcriptional profile reconstructed by a novel computational approach. Genome Res 10:344–349 (2000).
Bouck J, Yu W, Gibbs R, Worley K: Comparison of gene indexing databases. Trends Genet 15:159–162 (1999).
Bracey LT, Paigen K: Changes in translational yield regulate tissue-specific expression of beta-glucuronidase. Proc natl Acad Sci, USA 84:9020–9024 (1987).
Den Hollander AI, van Driel MA, de Kok YJ, van de Pol DJ, Hoyng CB, Brunner HG, Deutman AF, Cremers FP: Isolation and mapping of novel candidate genes for retinal disorders using suppression subtractive hybridization. Genomics 58:240–249 (1999).
Donohue SJ, Roseboom PH, Illnerova H, Weller JL, Klein DC: Human hydroxyindole-O-methyltransferase: presence of LINE-1 fragment in a cDNA clone and pineal mRNA. DNA Cell Biol 12:715–727 (1993).
Evans J, Wormald R: Is the incidence of registrable age-related macular degeneration increasing? Br J Ophthalmol 80:9–14 (1996).
Ewing RM, Claverie JM: EST databases as multi-conditional gene expression datasets. Pac Symp Biocomput 12:430–442 (2000).
Felbor U, Doepner D, Schneider U, Zrenner E, Weber BH: Evaluation of the gene encoding the tissue inhibitor of metalloproteinases-3 in various maculopathies. Invest Ophthalmol Vis Sci 38:1054–1059 (1997).
Furukawa T, Morrow EM, Cepko CL: Crx, a novel otx-like homeobox gene, shows photoreceptor-specific expression and regulates photoreceptor differentiation. Cell 91:531–541 (1997).
Hwang DM, Dempsey AA, Lee CY, Liew CC: Identification of differentially expressed genes in cardiac hypertrophy by analysis of expressed sequence tags. Genomics 66:1–14 (2000).
Klaver CC, Wolfs RC, Assink JJ, van Duijn CM, Hofman A, de Jong PT: Genetic risk of age-related maculopathy. Population-based familial aggregation study. Arch Ophthalmol 116:1646–1651 (1998).
Klein ML, Mauldin WM, Stoumbos VD: Heredity and age-related macular degeneration. Observations in monozygotic twins. Arch Ophthalmol 112: 932–937 (1994).
Kozak M: Interpreting cDNA sequences: some insights from studies on translation. Mammal Genome 7:563–574 (1996).
Kramer F, White K, Pauleikhoff D, Gehrig A, Passmore L, Rivera A, Rudolph G, Kellner U, Andrassi M, Lorenz B, Rohrschneider K, Blankenagel A, Jurklies B, Schilling H, Schutt F, Holz FG, Weber BHF: Mutations in the VMD2 gene are associated with juvenile-onset vitelliform macular dystrophy (Best disease) and adult vitelliform macular dystrophy but RI not age-related macular degeneration. Eur J hum Genet 8:286–292 (2000).
Mares-Perlman JA, Brady WE, Klein R, Van den Langenberg GM, Klein BE, Palta M: Dietary fat and age-related maculopathy. Arch Ophthalmol 113:743–748 (1995).
Marquardt A, Stohr H, Passmore LA, Kramer F, Rivera A, Weber BHF: Mutations in a novel gene, VMD2, encoding a protein of unknown properties cause juvenile-onset vitelliform macular dystrophy (Best’s disease). Hum molec Genet 7:1517–1525 (1998).
Miller RD, Hoffmann JW, Powell PP, Kyle JW, Shipley JM, Bachinsky DR, Sly WS: Cloning and characterization of the human beta-glucuronidase gene. Genomics 7:280–283 (1990).
Penotti FE: Human pre-mRNA splicing signals. J Theor Biol 150:385–420 (1991).
Petrukhin K, Koisti MJ, Bakall B, Li W, Xie G, Marknell T, Sandgren O, Forsman K, Holmgren G, Andreasson S, Vujic M, Bergen AA, McGarty-Dugan V, Figueroa D, Austin CP, Metzker ML, Caskey CT, Wadelius C: Identification of the gene responsible for Best macular dystrophy. Nature Genet 19:241–247 (1998).
Rodriguez IR, Mazuruk K, Schoen TJ, Chader GJ: Structural analysis of the human hydroxyindole-O-methyltransferase gene. Presence of two distinct promoters. J biol Chem 269:31969–31977 (1994).
Schoen TJ, Mazuruk K, Chader GJ, Rodriguez IR: Isolation of candidate genes for macular degeneration using an improved solid-phase subtractive cloning technique. Biochem biophys Res Commun 213:181–188 (1995).
Schmitt AO, Specht T, Beckmann G, Dahl E, Pilarsky CP, Hinzmann B, Rosenthal A: Exhaustive mining of EST libraries for genes differentially expressed in normal and tumour tissues. Nucl Acids Res 27:4251–4260 (1999).
Schuler GD: Pieces of the puzzle: expressed sequence tags and the catalog of human genes. J Mol Med 75:694–698 (1997).
Seddon JM, Ajani UA, Mitchell BD: Familial aggregation of age-related maculopathy. Am J Ophthalmol 123:199–206 (1997).
Smit AF, Toth G, Riggs AD, Jurka J: Ancestral, mammalian-wide subfamilies of LINE-1 repetitive sequences. J Mol Biol 246:401–417 (1995).
Smith W, Mitchell P, Leeder SR: Smoking and age-related maculopathy. The Blue Mountains Eye Study. Arch Ophthalmol 114:1518–1523 (1996).
Stöhr H, Marquardt A, White K, Weber BHF: cDNA cloning and genomic structure of a novel gene (C11orf9) localized to chromosome 11q12→q13.1 which encodes a highly conserved, potential membrane-associated protein. Cytogenet Cell Genet 88:211–216 (2000).
Stone EM, Lotery AJ, Munier FL, Heon E, Piguet B, Guymer RH, Vandenburgh K, Cousin P, Nishimura D, Swiderski RE, Silvestri G, Mackey DA, Hageman GS, Bird AC, Sheffield VC, Schorderet DF: A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy. Nature Genet 22:199–202 (1999).
Swaroop A, Xu JZ, Agarwal N, Weissman SM: A simple and efficient cDNA library subtraction procedure: isolation of human retina-specific cDNA clones. Nucl Acids Res 19:1954 (1991).
Thylefors B, Negrel AD, Pararajasegaram R, Dadzie KY: Global data on blindness. Bull World Health Organ 73:115–121 (1995).
Vasmatzis G, Essand M, Brinkmann U, Lee B, Pastan I: Discovery of three genes specifically expressed in human prostate by expressed sequence tag database analysis. Proc natl Acad Sci, USA 95:300–304 (1998).
Weber BHF, Vogt G, Pruett RC, Stohr H, Felbor U: Mutations in the tissue inhibitor of metalloproteinases-3 (TIMP3) in patients with Sorsby’s fundus dystrophy. Nature Genet 8:352–356 (1994).
Wolfsberg TG, Landsman D: A comparison of expressed sequence tags (ESTs) to human genomic sequences. Nucl Acids Res 25:1626–1632 (1997).
Zhao X, Huang J, Khani SC, Palczewski K: Molecular forms of human rhodopsin kinase (GRK1). J biol Chem 273:5124–5131 (1998).
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