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

Abstract

Autosomal recessive childhood-onset severe retinal dystrophy (arCSRD) designates a heterogeneous group of disorders affecting rod and cone photoreceptors simultaneously. 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 LCA. 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 evolutionarily highly conserved 61 kD protein (RPE65) present at high levels in vivo. 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 protein and with the RPE-specific 11-cis retinol dehydrogenase, an enzyme active in the synthesis of the visual pigment chromophore 11-cis retinal. 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 + 1G-->T and 65 + 5G-->A) 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.

Why photoreceptors die (and why they don't)

“…It is therefore essential for the formation of rhodopsin, and animals without it are almost completely incapable of producing normal visual pigment. Mutations in the Rpe65 gene are thought to be responsible for several human retinal degenerations, including Lebers congenital amaurosis, (36,39) autosomal recessive retinitis pigmentosa (38) and rod-cone dystrophy. (40) In Rpe65 À/À mice kept in normal room light (12 hours on and 12 hours off), the outer segments of the rods have very little rhodopsin but abundant opsin.…”

Gene therapy in the second eye of RPE65-deficient dogs improves retinal function

“…LCA type II results from mutations in the RPE65 gene, and accounts for 10-15% of LCA cases. 2,3 RPE65 encodes a protein that forms an essential component of the visual cycle and is expressed within the retinal pigment epithelium. 3 The visual cycle is responsible for the supply of the chromophore, 11-cis-retinal, to the photoreceptor cells for combination with the rod and cone opsins to form the visual pigments.…”

Retinal degeneration is delayed by tissue factor pathway inhibitor-2 in RCS rats and a sodium-iodate-induced model in rabbits

“…16 In some groups of retinal degeneration, the RPE is affected primarily, and the degeneration in the neural retina is the secondary process. 17,18 So it is possible that TFPI-2 can ameliorate the progressive loss of visual function due to the loss or dysfunction of the RPE. In this study, we investigated the effects of TFPI-2 on the RPE function after the retinal degeneration was induced by sodium iodate(SI) in Dutch rabbits, using the electrophysiological analysis.…”