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Nature Genetics  17, 194 - 197 (1997)

Mutations in RPE65 cause autosomal recessive childhood−onset severe retinal dystrophy

Su-min Gu1, Debra A. Thompson2, C.R. Srisailapathy Srikumari3, Birgit Lorenz4, Ulrich Finckh1, Aileen Nicoletti2, K.R. Murthy5, Michaela Rathmann1, Govindasamy Kumaramanickavel6, Michael J. Denton7 & Andreas Gal1

  1Institut fü Humangenetik, Universitäts-Krankenhaus Eppendorf, Butenfeld 42, D-22529 Hamburg, Germany.

  2Departments of Ophthalmology and Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan, 48105, USA.

  3Department of Genetics, University Post-graduate Institute of Basic Medical Sciences, Chennai, India.

  4Abteilungfü pädiatrischeOphthalmologie, Strabismologie und Ophthalmogenetik, KlinikfüAugenheilkunde, Universität Regensburg, D-93042 Regensburg, Germany.

  5Praba Eye Clinic and Research Centre, Jayanagar, Bangalore-560070, India.

  6Sankara Nethralaya, Medical Research Foundation, 18 College Road, Chennai, India.

  7Department of Biochemistry, University of Otago, Dunedin, New Zealand.

Autosomal recessive childhood-onset severe retinal dystrophy (arCSRD) designates a heterogeneous group of disorders affecting rod and cone photoreceptors simultaneously1. The most severe cases are termed Leber congenital amaurosis (LCA), while the less aggressive forms are usually considered juvenile retinitis pigmentosa. Recently, mutations in the retinal-specific guanylate cyclase gene were found in patients with LCA2. Disease genes implicated in other forms of arCSRD are expected to encode proteins present in the neuroretina or in the retinal pigment epithelium (RPE). The RPE, a monolayer of cells separating the vascular-rich choroid and the neuroretina, is in intimate contact with the outer segments of rods and cones via the microvilli surrounding the photoreceptors. The RPE expresses a tissue-specific and evolutionary highly conserved 61 kD protein (RPE65) present at high levels in vivo 3−6. Although the function of RPE65 is not yet known, an important role in the RPE/photoreceptor vitamin-A cycle is suggested by the fact that RPE65 associates both with serum retinol-binding protein7,8 and with the RPE-specific 11-cis retinol dehydrogenase, an enzyme active in the synthesis of the visual pigment chromophore 11-cis retinal9. Here we report that the analysis of RPE65 in a collection of about 100 unselected retinal-dystrophy patients of different ethnic origin revealed five that are likely to be pathogenic mutations, including a missense mutation (Pro363Thr), two point mutations affecting splicing (912+1Gright arrowT and 65+5Gright arrowA) and two small re-arrangements (ins144T and 831del8) on a total of nine alleles of five patients with arCSRD. In contrast to other genes whose defects have been implicated in degenerative retinopathies, RPE65 is the first disease gene in this group of inherited disorders that is expressed exclusively in the RPE, and may play a role in vitamin-A metabolism of the retina.

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