Phenotypic progression in X-linked retinitis pigmentosa secondary to a novel mutation in the RPGR gene

Al-Maskari, Ahmed; O'Grady, Anna; Pal, Bipin Chandra; McKibbin, Martin

doi:10.1038/eye.2008.427

Cited by 22 publications

(13 citation statements)

References 8 publications

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“…Moreover, the co-segregation analysis of this Caucasian family suggests the occurrence of a distinctive X-linked genotype-phenotype correlation between RP and PM, in which a possible complete penetrance of PM trait cannot be ruled out even considering the numerical pedigree’s limitation. In fact, just four female carriers suffered from bilateral myopic chorioretinal degenerations but all of them were heterozygous for ORF15-c.2091_2092insA, indicating that PM could represent the phenotypic expression of RP-related mutant heterozygosities located in various exons of RPGR gene, as previously observed in several pedigrees of both Asian and Caucasian descents202122232425262728. Focusing on the mutational hot spot exon ORF15 of RPGR gene10192930, RP-PM mutations have been hitherto reported exclusively in Asian pedigrees212326, with the exception of the c.2543del variant that has been recently discovered in a family of Caucasian Czech origin28.…”

Section: Discussionsupporting

confidence: 58%

Identification of novel X-linked gain-of-function RPGR-ORF15 mutation in Italian family with retinitis pigmentosa and pathologic myopia

Parmeggiani

Barbaro

Nadai

et al. 2016

Sci Rep

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The aim of this study was to describe a new pathogenic variant in the mutational hot spot exon ORF15 of retinitis pigmentosa GTPase regulator (RPGR) gene within an Italian family with X-linked retinitis pigmentosa (RP), detailing its distinctive genotype-phenotype correlation with pathologic myopia (PM). All members of this RP-PM family underwent a complete ophthalmic examination. The entire open reading frames of RPGR and retinitis pigmentosa 2 genes were analyzed by Sanger sequencing. A novel frame-shift mutation in exon ORF15 of RPGR gene (c.2091_2092insA; p.A697fs) was identified as hemizygous variant in the male proband with RP, and as heterozygous variant in the females of this pedigree who invariably exhibited symmetrical PM in both eyes. The c.2091_2092insA mutation coherently co-segregated with the observed phenotypes. These findings expand the spectrum of X-linked RP variants. Interestingly, focusing on Caucasian ethnicity, just three RPGR mutations are hitherto reported in RP-PM families: one of these is located in exon ORF15, but none appears to be characterized by a high penetrance of PM trait as observed in the present, relatively small, pedigree. The geno-phenotypic attributes of this heterozygosity suggest that gain-of-function mechanism could give rise to PM via a degenerative cell-cell remodeling of the retinal structures.

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Section: Discussionsupporting

confidence: 58%

Identification of novel X-linked gain-of-function RPGR-ORF15 mutation in Italian family with retinitis pigmentosa and pathologic myopia

Parmeggiani

Barbaro

Nadai

et al. 2016

Sci Rep

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“…Female carriers of X-linked retinal dystrophies have been reported to express RP characteristics, 21,22 sometimes partial or sectorial, albeit in small cohorts. 7,11,17,23 This variability has challenged the ability to identify the accurate disease inheritance mode in families with affected female patients.…”

Section: Discussionmentioning

confidence: 99%

“…Of the 125 included female carriers of pathogenic RPGR variants, 21 were from a large Dutch pedigree that has been previously described, 14 and additional follow-up data since the publication of that study were available in three subjects.…”

Section: Study Populationmentioning

confidence: 99%

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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“…15-19 The most dramatic example of this was demonstrated in a case report of dizygotic twins with an ORF15 mutation. 20 One patient had a clear cone-rod dysfunction, color vision deficits, macular atrophy, minimal peripheral constriction, and a cone-rod pattern on ERG, while his sibling exhibited foveal sparing, severe peripheral field loss, and a nonrecordable (NR) ERG.…”

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confidence: 98%

Phenotypic Conservation in Patients With X-Linked Retinitis Pigmentosa Caused byRPGRMutations

et al. 2013

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Phenotypic progression in X-linked retinitis pigmentosa secondary to a novel mutation in the RPGR gene

Cited by 22 publications

References 8 publications

Identification of novel X-linked gain-of-function RPGR-ORF15 mutation in Italian family with retinitis pigmentosa and pathologic myopia

Identification of novel X-linked gain-of-function RPGR-ORF15 mutation in Italian family with retinitis pigmentosa and pathologic myopia

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

Phenotypic Conservation in Patients With X-Linked Retinitis Pigmentosa Caused byRPGRMutations

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