Hiroyuki Morimura, Gerald A. Fishman, Sandeep A. Grover, Anne B. Fulton, Eliot L. Berson, Thaddeus P. Dryja | PNAS | 17 May 1998 | Vol. 95 (6) | pgs. 3088–3093 | doi: 10.1073/pnas.95.6.3088
Abstract
RPE65 is a protein of unknown function expressed specifically by the retinal pigment epithelium. We examined all 14 exons of this gene in 147 unrelated patients with autosomal recessive retinitis pigmentosa (RP), in 15 patients with isolate RP, and in 45 patients with Leber congenital amaurosis (LCA). Sequence anomalies that were likely to be pathogenic were found in two patients with recessive RP, in one patient with isolate RP recategorized as recessive, and in seven patients with LCA. Cosegregation analysis in each available family showed that all affected individuals were either homozygotes or compound heterozygotes and that all unaffected individuals were either heterozygote carriers or homozygous wild type. In one family, there was one instance of a new mutation not present in either parent of the affected individual. In another family, affected members with recessive RP in three branches (i.e., three distinct pairs of parents) were compound heterozygotes for the same two mutations or homozygous for one of them. Based on our results, mutations in the RPE65 gene appear to account for ≈2% of cases of recessive RP and ≈16% of cases of LCA.
Over 40 loci for human hereditary retinal degenerations involving the photoreceptors and retinal pigment epithelium are known (http://utsph.sph.uth.tmc.edu/www/utsph/RetNet/home.htm). Most of these loci are unidentified genes that have been recognized by linkage studies alone. Our group is engaged in identifying genes responsible for this set of diseases primarily through a candidate gene-based approach (1). In this report, we describe an analysis of the RPE65 gene, which has been assigned to chromosome 1p31 (2). This gene was discovered through its protein product that forms a complex with an antibody raised against human retinal pigment epithelium (3). The cDNA sequence predicts a protein with 533 amino acid residues and a molecular mass of ≈61 kDa (4). The protein is associated with the endoplasmic reticulum of the retinal pigment epithelium in vertebrates (3, 5). Although the biochemical function of the protein product is currently obscure, the tissue-specific expression of the RPE65 gene made it an attractive candidate as a cause for some retinal degenerations because the retinal pigment epithelium has an essential role in maintaining the viability of the neighboring photoreceptor cells. In particular, enzymes in the endoplasmic reticulum are responsible for the recycling of the chromophore used by photoreceptor opsins.
To explore the possible role that defects in RPE65 might play in the etiology of retinal degenerations, we screened a large cohort of unrelated patients with retinitis pigmentosa or Leber congenital amaurosis for mutations. Because RPE65 is expressed specifically in the eye, the study focused on patients with nonsyndromic forms of these diseases. This study was carried out contemporaneously with studies from two other groups that recently have been published (6, 7).
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