RP2 Phenotype and Pathogenetic Correlations in X-Linked Retinitis Pigmentosa

Jayasundera, Thiran; Branham, Kari; Othman, Mohammad; Rhoades, William; Karoukis, Athanasios J.; Khanna, Hemant; Swaroop, Anand; Heckenlively, John R.

doi:10.1001/archophthalmol.2010.122

Cited by 67 publications

(85 citation statements)

References 27 publications

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“…Although the reasons for the association between RPGR mutations and high myopia remain unclear, a recent study analyzing refractive errors in inherited retinal dystrophies has postulated that the transport area between the inner and outer segment (i.e., the location of protein RPGR), is one of the critical sites for refractive error development. 28 Mutations in RP1 and RP2, encoding an outer segment protein and another connecting cilium protein, respectively, have also been linked to high myopia, 29,30 further corroborating this hypothesis. However, not all genes encoding connecting cilium proteins are associated with myopia, and some have been associated with hyperopia (e.g., CEP290 and RPGRIP1), and biallelic mutations in these are generally associated with much more extreme visual loss due to Leber congenital amaurosis.…”

Section: Discussionmentioning

confidence: 68%

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

Talib

Schooneveld

Cauwenbergh

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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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.

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Section: Discussionmentioning

confidence: 68%

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

Talib

Schooneveld

Cauwenbergh

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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“…Methods for RP2 mutational analysis were reported previously. 10 For RPGR mutation screening, the primer sequences were reported previously for the analysis of exons 1 through 19 25 and ORF15. 32 Accuprime high fidelity Taq polymerase (Invitrogen, Grand Island, NY) was used to amplify various RPGR exons.…”

Section: Mutational Analysismentioning

confidence: 99%

“…Some XLRP patients exhibit high myopia and decreased visual acuity even at an early age. 10 Heterozygous carrier females also manifest a range of phenotypes, varying from asymptomatic to mild fundus changes and pigment migration to some females showing a severe phenotype. 8,11 Although the presence of a tapetal-like reflex has been described as indicative of carrier status, this is not universally detected.…”

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confidence: 99%

Mutations inRPGRandRP2Account for 15% of Males with Simplex Retinal Degenerative Disease

Branham

Othman

Brumm

et al. 2012

Invest. Ophthalmol. Vis. Sci.

109

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PURPOSE.To determine the proportion of male patients presenting simplex retinal degenerative disease (RD: retinitis pigmentosa [RP] or cone/cone-rod dystrophy [COD/CORD]) with mutations in the X-linked retinal degeneration genes RPGR and RP2.METHODS. Simplex males were defined as patients with no known affected family members. Patients were excluded if they had a family history of parental consanguinity. Blood samples from a total of 214 simplex males with a diagnosis of retinal degeneration were collected for genetic analysis. The patients were screened for mutations in RPGR and RP2 by direct sequencing of PCR-amplified genomic DNA. RESULTS.We identified pathogenic mutations in 32 of the 214 patients screened (15%). Of the 29 patients with a diagnosis of COD/CORD, four mutations were identified in the ORF15 mutational hotspot of the RPGR gene. Of the 185 RP patients, three patients had mutations in RP2 and 25 had RPGR mutations (including 12 in the ORF15 region).CONCLUSIONS. This study represents mutation screening of RPGR and RP2 in the largest cohort, to date, of simplex males affected with RP or COD/CORD. Our results demonstrate a substantial contribution of RPGR mutations to retinal degenerations, and in particular, to simplex RP. Based on our findings, we suggest that RPGR should be considered as a first tier gene for screening isolated males with retinal degeneration. (Invest Ophthalmol Vis Sci. 2012;53:8232-8237)

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“…Nonetheless, recently, a comprehensive analysis of a large group of RP2 patients revealed interesting observations: a majority of RP2 patients seem to exhibit an early involvement of the macula (the central region of the retina) [68].…”

Section: Non-syndromic Retinal Ciliopathiesmentioning

confidence: 99%