Cone structure in retinal degeneration associated with mutations in the peripherin/RDS gene.

Peripherin/RDS is an integral membrane glycoprotein involved in photoreceptor outer segment formation.1 peripherin/RDS mutations on chromosome 6p were first reported to cause autosomal dominant retinitis pigmentosa (RP)2,3 but have since been shown to cause a wide variety of retinal phenotypes including pattern dystrophy,4,5 cone-rod dystrophy,6 adult vitelliform macular dystrophy,7 central areolar choroidal dystrophy,8,9 and autosomal dominant macular dystrophy.10 Peripherin/RDS forms a complex with ROM1, which also plays a role in photoreceptor outer segment disc formation, and heterozygous mutations in peripherin/RDS and ROM1 may produce a digenic form of RP.11 The highly conserved second intradiscal loop is thought to be integral for peripherin/RDS protein function and, thus, for outer segment disc generation and stabilization.6,12 More than 90 different mutations in the peripherin/RDS gene have been associated with retinal degeneration, and mutations at the same amino acid position have been associated with diverse clinical phenotypes (http://www.retina-international.org/sci-news/rdsmut.htm). Mutations affecting the intradiscal D2 domain of peripherin/RDS manifest a variety of different retinal degeneration phenotypes, supporting the importance of this region for normal photoreceptor outer segment structure and survival. Altering the DNA from cysteine to thymidine at position 514 of the peripherin/RDS cDNA causes an arginine to tryptophan substitution at position 172 (R172W), which has been associated with macular dystrophy, central areolar choroidal dystrophy, cone dystrophy, and cone rod dystrophy.6,10,13–23 Changing guanine to adenosine at position 623 alters the amino acid at position 208 from glycine to aspartic acid (G208D) and is thought to alter the secondary structure of the protein.24 The G208D mutation has been associated with atypical autosomal dominant RP,25 pattern macular dystrophy,10 and central areolar dystrophy.13 Substituting guanine for cysteine at position 629 changes the amino acid at position 210 from proline to arginine (P210R)23,26 and produces adult foveomacular dystrophy26 and both macular and peripheral retinal degeneration, including cone-rod degeneration and RP.23,27 Finally, substituting guanine for adenosine at position 637 changes the amino acid at position 213 from cysteine to tyrosine and causes pattern dystrophy.4 This cysteine is thought to play an important role in intrachain or interchain disulfide bond formation, and mutations at this location may disrupt photoreceptor disc membrane integrity, resulting in photoreceptor degeneration and lipofuscin accumulation in RPE cells.4 Given the dramatic phenotypic variation observed within and between families with the same mutation, the effect of peripherin/RDS mutations on cone structure in living eyes is not clearly understood. Adaptive optics scanning laser ophthalmoscopy (AOSLO) uses adaptive optics to overcome optical imperfections in living eyes and can be used to obtain retinal images with lateral resolution of approximately 2 μm, allowing direct visualization of photoreceptors.28–31 Direct visualization of the cone mosaic in patients with retinal degeneration allows comparison of cone spacing, density, and regularity with healthy subjects.32–35 In combination with other imaging and diagnostic modalities, measures of cone structure provide insight into the effect different types of retinal degeneration have on macular cones.32,33,36–38 Here we present high-resolution retinal images for four patients with mutations in the peripherin/RDS gene, allowing direct in vivo genotype-phenotype correlation of cone photoreceptor structure and function at the cellular level.