title: Identification of novel X-linked gain-of-function RPGR-ORF15 mutation in Italian family with retinitis pigmentosa and pathologic myopia.
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.
authors.affiliation: Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, Ferrara, 44121, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Parmeggiani
authors.affiliation: Fondazione Banca degli Occhi del Veneto, Venice, 30174, Italy.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Barbaro
authors.affiliation: Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, Ferrara, 44121, Italy.|Center for Retinitis Pigmentosa of Veneto Region, ULSS 15 Alta Padovana, Camposampiero, 35012, Italy.
authors.forename: Katia
authors.initials: K
authors.lastname: De Nadai
authors.affiliation: Department of Molecular Medicine, University of Padova, Padova, 35121, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Lavezzo
authors.affiliation: Department of Molecular Medicine, University of Padova, Padova, 35121, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Toppo
authors.affiliation: Center for Retinitis Pigmentosa of Veneto Region, ULSS 15 Alta Padovana, Camposampiero, 35012, Italy.
authors.forename: Marzio
authors.initials: M
authors.lastname: Chizzolini
authors.affiliation: Department of Molecular Medicine, University of Padova, Padova, 35121, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Palù
authors.affiliation: Department of Molecular Medicine, University of Padova, Padova, 35121, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Parolin
authors.affiliation: Department of Molecular Medicine, University of Padova, Padova, 35121, Italy.
authors.forename: Enzo
authors.initials: E
authors.lastname: Di Iorio
mesh_terms: D000328:Adult; D002648:Child; D004252:DNA Mutational Analysis; D005091:Exons; D005136:Eye Proteins / Q000737:chemistry / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation; D050172:Genes, X-Linked / Q000235:genetics*; D056726:Genetic Association Studies; D005838:Genotype; D057898:Hemizygote; D006579:Heterozygote; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D009216:Myopia / Q000235:genetics* / Q000473:pathology; D016366:Open Reading Frames / Q000235:genetics; D010375:Pedigree; D017434:Protein Structure, Tertiary; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000473:pathology; D044465:White People / Q000235:genetics*
chemical_list: D005136:Eye Proteins; C099929:RPGR protein, human