Mutations in the X-Linked Retinitis Pigmentosa GenesRPGRandRP2Found in 8.5% of Families with a Provisional Diagnosis of Autosomal Dominant Retinitis Pigmentosa

Abstract

PURPOSE. We determined the fraction of families in a wellcharacterized cohort with a provisional diagnosis of autosomal dominant retinitis pigmentosa (adRP) that have disease-causing mutations in the X-linked retinitis pigmentosa GTPase regulator (RPGR) gene or the retinitis pigmentosa 2 (RP2) gene. METHODS.Families with a provisional clinical diagnosis of adRP, and a pedigree consistent with adRP but no male-to-male transmission were selected from a cohort of 258 families, and tested for mutations in the RPGR and RP2 genes with di-deoxy sequencing. To facilitate testing of RPGR in ''adRP'' families that had no male members available for testing, the repetitive and purine-rich ORF15 of RPGR was subcloned and sequenced in heterozygous female subjects from 16 unrelated families.RESULTS. Direct sequencing of RPGR and RP2 allowed for identification of a disease-causing mutation in 21 families. Of these ''adRP'' families 19 had RPGR mutations, and two had RP2 mutations. Subcloning and sequencing of ORF15 of RPGR in female subjects identified one additional RPGR mutation. Of the 22 mutations identified, 15 have been reported previously.CONCLUSIONS. These data show that 8.5% (22 in 258) of families thought to have adRP truly have X-linked retinitis pigmentosa (XLRP). These results have substantive implications for calculation of recurrence risk, genetic counseling, and potential treatment options, and illustrate the importance of screening families with a provisional diagnosis of autosomal inheritance and no male-to-male transmission for mutations in X-linked genes. Mutations in RPGR are one of the most common causes of all forms of retinitis pigmentosa. (Invest Ophthalmol Vis Sci.

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

“…7,11,17,23 This variability has challenged the ability to identify the accurate disease inheritance mode in families with affected female patients. [24][25][26] In the early stages of genetic counseling of an RP pedigree, the presence of affected female subjects should raise suspicion of both an autosomal-dominant and an X-linked inheritance mode. In fact, typical RP fundus features, such as bonespicular or nummular intraretinal pigmentation, optic disc pallor, and vascular attenuation, were common in this cohort, expectedly more so in heterozygotes from RP pedigrees (49%, 44%, and 56%, respectively; Table) than in those from COD/ CORD pedigrees (18%, 18%, and 18%, respectively).…”

Prevalence of Mutations in eyeGENE Probands With a Diagnosis of Autosomal Dominant Retinitis Pigmentosa

“…All tests were validated by prior publications from this laboratory. [4][5][6][7][8] In some cases (RHO, PRPH2, and PRPF31) the entire gene was screened. In the remaining genes, only regions considered mutation hotspots were screened.…”

Loss of RPGR glutamylation underlies the pathogenic mechanism of retinal dystrophy caused by TTLL5 mutations

“…The disease etiology is highly heterogeneous, with mutations in more than 200 genes with diverse functions shown to underlie various forms of retinal dystrophy (https://sph.uth.edu/retnet/sum-dis.htm). Among these, mutations in the gene encoding retinitis pigmentosa GTPase regulator (RPGR) are a frequent cause, accounting for more than 70% of X-linked RP and up to 20% of all RP cases (2)(3)(4)(5). The disease associated with RPGR is severe and impacts central vision important for visual acuity (6).…”