Abstract
Abstract: :
Purpose: To study the spectrum frequency of mutations of RPGR and RP2 genes and to evaluate the phenotype–genotype relationship in affected males as well as female carriers. Methods: Forty–two families with XLRP were collected by clinical characteristics and pedigree evaluation. Comprehensive molecular screenings of RPGR and RP2 were performed through direct PCR–sequencing. Clinical features of patients were evaluated by best–corrected visual acuity (Snellen chart), age of onset, refractive error (recorded as spherical equivalent), kinetic visual field (recorded here with average visual field area) and ERG and Student t test was applied. Distinct clinical features of Japanese XLRP female carriers were analyzed by pedigree structure using the Lyon Hypothesis on epigenetics, and the Lyon–ratio was evaluated by methylation–specific PCR. Results: Four novel pathogenic mutations of ORF15 of RPGR were identified in 6 unrelated families, and one additional family showed a nonsense mutation in RP2 gene. Three unrelated families shared the same mutation, deletion of GA at bases 651_652 in ORF15. Families F7, F9 and F15 had frameshift mutations at exon ORF15 (g.ORF15+1231_1232delGG, g.ORF15+672_673delGA and g.ORF15+482_483delAG, respectively), and family F11 have a mutation (Arg120Ter) in the RP2 gene. These mutations segregated together with XLRP disease in each family. In families with an RPGR or RP2 mutation, affected males showed typical RP, while obligate carrier females showed a wide spectrum of clinical features. Statistical analysis did not demonstrate any significant difference between affected males or female carriers regarding age (P=0.759), corrected visual acuity (P=0.180) or even visual field (P=0.135). However, affected males showed more severe reduction of ERG amplitude (a and b waves and 30–Hz flicker) and earlier onset age (P=0.024), while carrier females with more severe refractive error (P=0.02) were observed. It seemed that distinct symptoms in female carriers could be explained by the Lyon hypothesis. Conclusions: We identified 4 novel mutations of RPGR in 5 families, and one additional family with a mutation of RP2, which may also be the mutation hotspot in Japanese XLRP patients. Although we observed severe visual disturbance in affected males, there was no significant difference between affected males and female carriers, but it seemed that refractive error was a distinctive characteristic of carriers. The wide spectrum of clinical features in female carriers is due to X–chromosome inactivation.
Keywords: retinitis • genetics • retinal degenerations: hereditary