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

Francesco Parmeggiani,Vanessa Barbaro,Enzo Di Iorio,Katia De Nadai,Enrico Lavezzo,Marzio Chizzolini,Stefano Toppo,Cristina Parolin,Giorgio Palù

doi:10.1038/srep39179

Abstract

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.

Highlights

The linkage analyses, Retinitis pigmentosa (RP)-associated mutations are recognized in two main genes: retinitis pigmentosa GTPase regulator (RPGR or RP3; OMIM 312610) and retinitis pigmentosa 2 (RP2; OMIM 312600)
We report a Caucasian family with a novel pathogenic sequence alteration in the mutational hot spot exon ORF15 of RPGR gene underlying X-linked RP and pathologic myopia (PM)
Starting from 13 years of age, he reported the bilateral onset of mild-to-moderate myopic refractive error and, during his second decade of life, central visual deficiency with significant reduction of best-corrected visual acuity (BCVA)

Summary

Introduction

The linkage analyses, RP-associated mutations are recognized in two main genes: retinitis pigmentosa GTPase regulator (RPGR or RP3; OMIM 312610) and retinitis pigmentosa 2 (RP2; OMIM 312600). The majority of genetically solved X-linked RP can be explained by causative mutations in RPGR and RP2 genes accounting, respectively, for 75–80% and 10–15% of the genetically-solved cases of the disease[1,5,6,7,8,9,10,11]. We report a Caucasian family with a novel pathogenic sequence alteration in the mutational hot spot exon ORF15 of RPGR gene underlying X-linked RP and pathologic myopia (PM). Because of the distinctive genotype-phenotype correlation, characterized by a symmetrical presence of PM in both the retinas of all heterozygous female carriers, a speculative model of X-linked gain-of-function mutation with a high penetrance of the myopic trait is proposed

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