MUTATIONS IN RPE65 CAUSE AUTOSOMAL RECESSIVE CHILDHOOD-ONSET SEVERE RETINAL DYSTROPHY

Autosomal recessive childhood-onset severe retinal dystrophy (arCSRD) designates a heterogeneous group of disorders affecting rod and cone p hotoreceptors simultaneously(1). The most severe cases are termed Lebe r congenital amaurosis (LCA), while the less aggressive forms are usua lly considered juvenile retinitis pigmentosa. Recently, mutations in t he retinal-specific guanylate cyclase gene were found in patients with LCA(2). Disease genes implicated in other forms of arCSRD are expecte d to encode proteins present in the neuroretina or in the retinal pigm ent epithelium (RPE). The RPE, a monolayer of cells separating the vas cular-rich choroid and the neuroretina, is in intimate contact with th e outer segments of rods and cones via the microvilli surrounding the photoreceptors. The RPE expresses a tissue-specific and evolutionarily 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 r ole in the RPE/photoreceptor vitamin-A cycle is suggested by the fact that RPE65 associates both with serum retino(-binding protein(7,8) and with the RPE-specific 11-cis retinol dehydrogenase, an enzyme active in the synthesis of the visual pigment chromophore 11-cis retinal(9). Here we report that the analysis of RPE65 in a collection of about 100 unselected retinal-dystrophy patients of different ethnic origin reve aled five that are likely to be pathogenic mutations, including a miss ense mutation (Pro363Thr), two point mutations affecting splicing (912 +1G-->T and 65+5G-->A) and two small re-arrangements (ins144T and 831d el8) on a total of nine alleles of five patients with arCSRD. In contr ast to other genes whose defects have been implicated in degenerative retinopathies, RPE65 is the first disease gene in this group of inheri ted disorders that is expressed exclusively in the RPE, and may play a role in vitamin-A metabolism of the retina.