The spectrum of retinal dystrophies caused by mutations in the peripherin/RDS gene

doi:10.1016/j.preteyeres.2008.01.002

Progress in Retinal and Eye Research

Volume 27, Issue 2, March 2008, Pages 213-235

https://doi.org/10.1016/j.preteyeres.2008.01.002 Get rights and content

Abstract

Peripherin/rds is an integral membrane glycoprotein, mainly located in the rod and cone outer segments. The relevance of this protein to photoreceptor outer segment morphology was first demonstrated in retinal degeneration slow (rds) mice. Thus far, over 90 human peripherin/RDS gene mutations have been identified. These mutations have been associated with a variety of retinal dystrophies, in which there is a remarkable inter- and intrafamilial variation of the retinal phenotype. In this paper, we discuss the characteristics of the peripherin/RDS gene and its protein product. An overview is presented of the broad spectrum of clinical phenotypes caused by human peripherin/RDS gene mutations, ranging from various macular dystrophies to widespread forms of retinal dystrophy such as retinitis pigmentosa. Finally, we review the proposed genotype–phenotype correlation and the pathophysiologic mechanisms underlying this group of retinal dystrophies.

Introduction

The retinal degeneration slow (rds) mouse is one of the oldest animal models of retinal degeneration. The abnormal photoreceptor outer segment formation in the rds mouse is caused by mutations in the peripherin/Rds gene and results in a slowly progressive photoreceptor degeneration (van Nie et al., 1978; Hawkins et al., 1985; Travis et al., 1989; Connell et al., 1991).

The role of mutations in the human homologue of peripherin/Rds, the peripherin/RDS gene, in human retinal dystrophies was first recognized in autosomal dominant retinitis pigmentosa (adRP) in two simultaneous reports (Kajiwara et al., 1991; Farrar et al., 1991). Subsequent reports identified peripherin/RDS mutations not only in adRP, but also in a variety of macular dystrophies, such as adult-onset foveomacular vitelliform dystrophy (AFVD) and butterfly-shaped pigment dystrophy of the fovea (Wells et al., 1993; Nichols et al., 1993b). Other retinal dystrophies that have been found in association with peripherin/RDS mutations are central areolar choroidal dystrophy (CACD) (Hoyng et al., 1996; Klevering et al., 2002b), retinitis punctata albescens (RPA) (Kajiwara et al., 1993), cone–rod dystrophy (Nakazawa et al., 1994a), multifocal pattern dystrophy simulating autosomal recessive Stargardt disease (STGD1)/fundus flavimaculatus (Boon et al., 2007b), age-related macular degeneration (AMD)-like late-onset maculopathy (Khani et al., 2003) and other unspecified autosomal dominant macular dystrophies (Downes et al., 1999; van Lith-Verhoeven et al., 2003b). The combination of a specific mutation in peripherin/RDS (Leu185Pro) and a mutation in the ROM1 gene causes a digenic form of retinitis pigmentosa (RP) (Bascom et al., 1992; Kajiwara et al., 1994; Dryja et al., 1997).

Several studies showed that a striking inter- and intrafamilial phenotypic variation may be observed in association with peripherin/RDS mutations (Weleber et al., 1993; Apfelstedt-Sylla et al., 1995; Gorin et al., 1995). Mutations in this gene not only account for a broad spectrum of retinal disorders, but causative peripherin/RDS mutations are also relatively frequent in patients with retinal dystrophies. Peripherin/RDS mutations are present in up to 25% of the central retinal dystrophies, depending on the inclusion criteria, methods of mutation analysis, and ethnic background of the patient population (Kohl et al., 1997; Felbor et al., 1997b; Milla et al., 1998; Fujiki et al., 1998; Budu et al., 2001; Gamundi et al., 2007). Furthermore, peripherin/RDS is one of the most frequently involved genes in patients with adRP (Sohocki et al., 2001; Sullivan et al., 2006).

This paper aims to review the characteristics of the peripherin/RDS gene, as well as the broad spectrum of retinal dystrophies caused by mutations in this gene. In addition, in vitro studies and transgenic animal models are discussed, which add to the insight in the pathogenesis of peripherin/RDS-related retinal dystrophies and improve the genotype–phenotype correlations. Finally, future therapeutic perspectives are discussed.

Section snippets

The peripherin/RDS gene

Two years prior to the identification of the human peripherin/RDS gene, the murine ortholog was found (Travis et al., 1989). Since abnormalities in this gene result in a slowly progressive degeneration of photoreceptors, the gene was named retinal degeneration slow (rds) (Van Nie et al., 1978). The phenotype in rds mice is due to haploinsufficiency and is dose-dependent: retinal degeneration is faster and more pronounced in rds(−/−) mice compared to rds(+/−) mice (Sanyal et al., 1980; Hawkins

Peripherin/RDS mutations and protein structure

Phenotypes associated with peripherin/RDS mutations do not show a straightforward dependence on the position of the mutation in the primary protein sequence or the type of mutation (Goldberg, 2006). Moreover, a single mutation may cause a spectrum of phenotypes ranging from a number of different macular dystrophies to adRP (Weleber et al., 1993; Apfelstedt-Sylla et al., 1995; Piguet et al., 1996; Ekstrom et al., 1998a; Michaelides et al., 2005; Boon et al., 2007b). Clearly, this remarkable

Future perspectives

A better understanding of the underlying mechanisms of retinal dystrophies, such as the peripherin/RDS-related disorders in this review, is necessary for the future development of effective therapeutic strategies. Information from animal model research is indispensable to demonstrate the efficacy and safety of such treatments (Chader, 2002; Farjo and Naash, 2006; Ding and Naash, 2006). Detailed studies on retinal dystrophies caused by peripherin/RDS mutations are mandatory, not only to provide

Acknowledgement

The authors would like to thank Muna I. Naash for her expert advice.

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