Mutation Survey of the RP2 and RPGR Genes (Including ORF15) and Evidence for Genotype-Phenotype Correlations

Abstract

Abstract: : Purpose: To study the spectrum of mutations in RP2 and RPGR and to search for correlations between category of mutation and severity of retinitis pigmentosa (RP). Methods: We evaluated 189 unrelated male patients (137 with X-linked RP, 11 with probable X-linked RP, 30 isolate RP cases, and 11 with cone-rod degeneration). Mutation screening was done by single-strand conformation analysis and sequencing of all RP2 exons, RPGR exons 1-14, ORF15, and 15a. All patients were clinically evaluated with respect to refractive error, visual acuity, final dark-adaptation threshold, visual field area, and 30-Hz cone ERG amplitude. Results: We identified 10 mutations in RP2, including 6 novel mutations, in 11 unrelated patients. We identified 80 mutations in RPGR, including 55 novel mutations, in 98 patients; 65% of the mutations were within ORF15. After correcting for age, patients with RP2 mutations had, on average, lower visual acuity than patients with RPGR mutations. Patients with ORF15 mutations had, on average, larger visual field area than patients with RPGR mutations in exons 1-14. Regression analyses of patients with ORF15 mutations showed that the dark adaptation threshold became lower and 30-Hz ERG amplitude increased as the mutant codon number increased 5'-3'. Among patients with frameshift mutations in ORF15, as the length of the stretch of abnormal amino acid residues increased, the dark-adaptation threshold became higher and the 30-Hz ERG amplitude decreased when controlling for the mutant codon number. Conclusions: Our data indicate that the RP2 and RPGR genes together account for approximately 78% of cases with X-linked RP. For mutations affecting ORF15 the longer the wild-type ORF15 amino acid sequence, and the shorter the subsequent abnormal amino acid sequence, the milder the severity of disease at a given age. Despite some clinical average differences, there was substantial overlap in the clinical findings of patients with RP2 and RPGR mutations, so that we could not determine in a given patient, based on clinical findings, which of the X-linked RP genes is causative.

Keywords: retinal degenerations: hereditary • mutations • retina