The Spectrum of Structural and Functional Abnormalities in Female Carriers of Pathogenic Variants in theRPGRGene

Abstract

PURPOSE. The purpose of this study was to investigate the phenotype and long-term clinical course of female carriers of RPGR mutations.METHODS. This was a retrospective cohort study of 125 heterozygous RPGR mutation carriers from 49 families.RESULTS. Eighty-three heterozygotes were from retinitis pigmentosa (RP) pedigrees, 37 were from cone-/cone-rod dystrophy (COD/CORD) pedigrees, and 5 heterozygotes were from pedigrees with mixed RP/CORD or unknown diagnosis. Mutations were located in exon 1-14 and in ORF15 in 42 of 125 (34%) and 83 of 125 (66%) subjects, respectively. The mean age at the first examination was 34.4 years (range, 2.1 to 86.0 years). The median follow-up time in heterozygotes with longitudinal data (n ¼ 62) was 12.2 years (range, 1.1 to 52.2 years). Retinal pigmentary changes were present in 73 (58%) individuals. Visual symptoms were reported in 51 (40%) cases. Subjects with both symptoms and pigmentary fundus changes were older than the other heterozygotes (P ¼ 0.01) and had thinner foveal outer retinas (P ¼ 0.006). Complete expression of the RP or CORD phenotype was observed in 29 (23%) heterozygotes, although usually in milder forms than in affected male relatives. Best-corrected visual acuity (BCVA) was <20/40 and <20/400 in at least one eye in 45 of 116 (39%) and 11 of 116 (9%) heterozygotes, respectively. Myopia was observed in 74 of 101 (73%) subjects and was associated with lower BCVA (P ¼ 0.006). Increasing age was associated with lower BCVA (P ¼ 0.002) and decreasing visual field size (P ¼ 0.012; I4e isopter).CONCLUSIONS. RPGR mutations lead to a phenotypic spectrum in female carriers, with myopia as a significantly aggravating factor. Complete disease expression is observed in some individuals, who may benefit from future (gene) therapeutic options.

Clinical Characteristics and Natural History of Rho-Associated Retinitis Pigmentosa

“…We and others have previously found that the PR + RPE complex has been suggested to be a good predictor of the visual acuity. 15,[28][29][30] Similar results were found in this study because the PR + RPE complex correlated strongly with the BCVA, and it was the only parameter that remained significant after correction for multiple testing. The PR + RPE complex can potentially be used to identify early structural changes before the visual acuity loss may be noticeable, which can be particularly useful in diseases with relatively slow disease progression such as RHO-associated RP.…”

RPGR-Associated Dystrophies: Clinical, Genetic, and Histopathological Features

“…It is believed that frameshift mutations in the exons that encode the N-terminal RCC1-like domain of RPGR are more prone to nonsense-mediated decay (NMD), leading to lower levels of the transcript and may therefore be more likely to cause severe RP phenotypes [4]. Furthermore, the N-terminal RCC1-like domain of RPGR is shared between RPGR ORF15 and RPGR [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] isoforms. Since RPGR [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] is also expressed in primary cilia, it is believed that mutations in the N-terminal RCC1-like domain may lead to retinal degeneration with ciliary abnormalities, as shown in previous studies [33][34][35].…”

“…Genomic DNA was extracted from peripheral blood samples according to standard protocols. Genetic analysis was performed at the Department of Clinical Genetics of the Amsterdam University Medical Centers (Amsterdam UMC, The Netherlands), the Netherlands, and methods used have been published previously [2,10,47]. The primers used in this study can be accessed upon reasonable request.…”

“…Symptom onset in affected males starts in childhood years and is described to reach blindness within the 4th decade of life [2,7,8]. Despite the X-linked inheritance of RPGR, female carriers may also be affected by XLRP [9,10].…”

“…The RPGR gene encodes the retinitis pigmentosa GTPase regulator (RPGR) protein and is able to express multiple isoforms through alternative splicing. The most common protein isoforms found in the retina are RPGR ORF15 and, to a lesser extent, the constitutive protein RPGR [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] [13,14]. The RPGR ORF15 transcript, which is believed to play a key role in intraflagellar transport processes, contains exon 1-14 and exon ORF15, which is formed by alternatively spliced exon 15 and intron 15 [15].…”