PRPH2-Related Retinal Diseases: Broadening the Clinical Spectrum and Describing a New Mutation.

Rosa M Coco-Martin,Ricardo Usategui-Martín,Carmen Desco,Juan J Tellería,Hortensia T Sanchez-Tocino

doi:10.3390/genes11070773

Abstract

Over 175 pathogenic mutations in the Peripherin-2 (PRPH2) gene are linked to various retinal diseases. We report the phenotype and genotype of eight families (24 patients) with retinal diseases associated with seven distinct PRPH2 gene mutations. We identified a new mutation, c.824_828+3delinsCATTTGGGCTCCTCATTTGG, in a patient with adult-onset vitelliform macular dystrophy (AVMD). One family with the p.Arg46Ter mutation presented with the already described AVMD phenotype, but another family presented with the same mutation and two heterozygous pathogenic mutations (p.Leu2027Phe and p.Gly1977Ser) in the ATP Binding Cassette Subfamily A Member 4 (ABCA4) gene that cause extensive chorioretinal atrophy (ECA), which could be a blended phenotype. The p.Lys154del PRPH2 gene mutation associated with the p.Arg2030Glu mutation in the ABCA4 gene was found in a patient with multifocal pattern dystrophy simulating fundus flavimaculatus (PDsFF), for whom we considered ABCA4 as a possible modifying gene. The mutation p.Gly167Ser was already known to cause pattern dystrophy, but we also found ECA, PDsFF, and autosomal-dominant retinitis pigmentosa (ADRP) as possible phenotypes. Finally, we identified the mutation p.Arg195Leu in a large family with common ancestry, which previously was described to cause central areolar choroidal dystrophy (CACD), but we also found ADRP and observed that it caused ECA more frequently than CACD in this family.

Highlights

Mutations in the Peripherin-2 (PRPH2) gene (OMIM: 179605) are among the most frequently found in inherited retinal diseases (IRD) [1], with an even higher percentage among diseases primarily involving the central retina [2]
Genes 2020, 11, 773 in age at onset, severity, and a range of clinical features including those limited to the macula, such as adult-onset vitelliform macular dystrophy (AVMD, MIM 608161), butterfly patterned dystrophy (PD, MIM 169150), or central areolar choroidal dystrophy (CACD, MIM 613105), and those with more widespread disorders, such as retinitis pigmentosa 7 (RP, MIM 608133) or retinitis punctata albescens (MIM 136880) or digenic RP caused by heterozygous mutations in Retinal Outer Segment
We present a detailed clinical characterization of 24 patients to broaden the spectrum of molecularly confirmed macular dystrophy due to PRPH2 mutations by disclosing new clinical presentations of known mutations, one new mutation, and one possible blended phenotype

Summary

Introduction

Mutations in the Peripherin-2 (PRPH2) gene (OMIM: 179605) are among the most frequently found in inherited retinal diseases (IRD) [1], with an even higher percentage among diseases primarily involving the central retina [2]. The mutations may differentially affect the gene’s protein product role as a structural component or as a functional protein that is key for organizing membrane domains for cellular signaling These roles may be different in the rods and cones, contributing to the phenotypic heterogeneity that characterizes this group of diseases [3]. Over 175 pathogenic mutations in the PRPH2 gene are linked to numerous human retinal diseases (summarized at http://www.retina-international.org/files/sci-news//rdsmut.htm) [4], which generally have an autosomal-dominant inheritance pattern.

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