Analysis of protein haplotypes in trans as factors modifying phenotypic variation of retinal dystrophies caused by a splice site mutation in the peripherin/RDS gene

Abstract

Abstract: : Purpose: To determine the effect of sequence variants in trans to a pathogenic mutation within the RDS gene. The sequence variants, which result in distinct protein haplotypes, may be responsible for the phenotypic variation seen among individuals who harbor an RDS donor splice site mutation, IVS2+3A→T. Methods: Forty–six affected individuals from eight putatively unrelated families with the RDS splice site mutation, IVS2+3A→T, were ascertained. The clinical diagnosis in these individuals ranged from autosomal dominant retinitis pigmentosa to pattern dystrophies and dominant macular degeneration. Sequence variants in exon 3 of the RDS gene that are in cis and trans to the pathogenic mutation were determined. Phenotypic categorization of the affected individuals was based on fundus photography, ERG, dark adaptometry and visual fields. Association between the different phenotypes and the protein haplotypes in trans was tested using chi–square methods. Results: Sequence analysis of RDS exon 3 showed segregation of a single haplotype, C–A–A, with the disease–causing mutation in all affected individuals. Three haplotypes, C–G–A, C–A–A and G–A–G, resulting in three different protein isoforms, were found in trans to the disease–causing mutation. Five phenotypes – retinitis pigmentosa, central areolar choroidal dystrophy, adult onset foveomacular vitelliform like dystrophy, fundus flavimaculatus like dystrophy, and butterfly pattern dystrophy – were determined. The association between these phenotypes and the protein haplotypes was not significant by chi–square analysis in the first subset of families analyzed. Conclusions: Protein haplotype analysis demonstrated a founder effect for the RDS, IVS2+3A→T mutation, with an origin from a common ancestor in all affected individuals from eight different families with distinct forms of autosomal dominant inherited retinopathy. The three distinct protein isoforms of the RDS gene in trans are not likely to be responsible for the marked phenotypic variation seen among these affected individuals. The phenotypic variation may be due to the modifying effects of other factors at the RDS locus, or due to sequence variants in other genes involved in the expression or function of RDS.

Keywords: gene modifiers • retinal degenerations: hereditary • photoreceptors