MUTATIONS AND POLYMORPHISMS IN THE HUMAN PERIPHERIN-RDS GENE AND THEIR INVOLVEMENT IN INHERITED RETINAL DEGENERATION

The RDS gene codes for the protein peripherin-RDS, which is an integra l membrane glycoprotein found in the outer segment of both rod and con e photoreceptor cells. It is thought to function as a structural prote in involved in the maintenance of the flattened form of the disc lamel lae. The RDS gene has been implicated in the mouse phenotype retinal d egeneration slow, and mutations in the human homologue are now known t o be associated with both central and peripheral retinal degenerations . In all, 43 sequence variants have been described in the human gene, including 30 missense mutations, two single base substitutions produci ng termination codons, 7 small in-frame deletions, and 4 insertion/ de letion events, which break the reading frame. Of these, 39 are associa ted with retinal phenotypes, which can be grouped into four broad cate gories: dominant retinitis pigmentosa, progressive macular degeneratio n, digenic RP, and pattern dystrophies. The mutations underlying domin ant RP and severe macular degeneration are largely missense or small i n-frame deletions in a large intradiscal loop between the third and fo urth transmembrane domains. In contrast, those associated with the mil der pattern phenotypes or with digenic RP are scattered more evenly th rough the gene and are often nonsense mutations. This observation corr elates with the hypothesis that the large loop is an important site of interaction between RDS molecules and other protein components in the disc. (C) 1996 Wiley-Liss, Inc.