Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or leber congenital amaurosis

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 approximately 2% of cases of recessive RP and approximately 16% of cases of LCA.

Figure 1

DNA sequence of mutations found in patients with RP (A) and patients with LCA (B). In each panel, the left sequence with the heading “control” is the wild type and the right sequence is that of an index patient whose identification number is at the top and the mutation at the bottom. All sequences are in the sense direction going from bottom to top, except the sequence showing the frameship mutation E404(4-bp ins) in patient 003–117, which is in the antisense direction from bottom to top. Patients 003–117, 003–119, and 003–179 are the index patients with RP from families 7828, 0356, and E070, respectively. Patients 048–040, 048–017, 048–054, 048–011, 048–033, 048–041, and 048–008 are the index patients with LCA from families 9404, 9148, 7775, 3867, 9190, 0748, and 9145, respectively.

Figure 2

Pedigrees segregating mutations in the families of index patients having RP (A) or LCA (B). Filled symbols are affected, open symbols unaffected. Underneath each family member’s symbol is the RPE65 genotype with small letters indicating the alleles designated at the bottom of each pedigree and “+” indicating the wild-type sequence. Arrows point to index patients. In family 0748, the index patient has LCA and her two parents have RP by history.

Figure 3

Schematic model of the exons of the human RPE65 locus with the locations of the mutations found in patients with RP (top) and LCA (bottom).