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 integral membrane glycoprotein found in the outer segment of both rod and cone photoreceptor cells. It is thought to function as a structural protein involved in the maintenance of the flattened form of the disc lamellae. The RDS gene has been implicated in the mouse phenotype retinal degeneration slow, and mutations in the human homologue are now known to 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 producing termination codons, 7 small in-frame deletions, and 4 insertion/ deletion events, which break the reading frame. Of these, 39 are associated with retinal phenotypes, which can be grouped into four broad categories: dominant retinitis pigmentosa, progressive macular degeneration, digenic RP, and pattern dystrophies. The mutations underlying dominant RP and severe macular degeneration are largely missense or small in-frame deletions in a large intradiscal loop between the third and fourth transmembrane domains. In contrast, those associated with the milder pattern phenotypes or with digenic RP are scattered more evenly through the gene and are often nonsense mutations. This observation correlates with the hypothesis that the large loop is an important site of interaction between RDS molecules and other protein components in the disc.