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D. J. Sidjanin, K. Schneck, E. Reese, A. Iannaccone; Novel Mutations in the RDS-Peripherin Gene in Adult-Onset Macular Dystrophies. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3699.
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To determine if mutations in the RDS gene are responsible for various forms of adult-onset macular dystrophies in patients with and without family history of the disease.
A 41-year old Egyptian-American male (PT1), a 58-year old Caucasian female (PT2), and a 66-year old Italian-American male (PT3) underwent clinical and functional studies, including electroretinogram (ERG) and electro-oculogram [EOG] testing. Genomic DNA was extracted from peripheral blood. For exons scanning, RDS and ROM1 exons were evaluated (http://genome.ucsc.edu), and primers were designed to anneal 50 bp away from intron-exon junctions. PCRs and sequencing were performed using standard methods.
We identified a novel heterozygous 2 bp-deletion del964-965 in the RDS gene in PT1 and PT2, who had negative family history. Haplotype analysis of the RDS exonic polymorphisms showed that this mutation arose twice independently. Clinically, PT1 showed bilateral, asymmetric adult-onset multifocal vitelliform lesions, with borderline low EOG Arden ratios (~1.5) and delayed photopic ERG responses. The lesions progressed to the vitelliruptive and atrophic stage, resulting in <20/100 acuity by age 43. PT2 presented with adult-onset vitelliform foveal dystrophy (AOFVD), resulting in <20/63 acuity, but normal EOGs (Arden ratio ~2.6) and normal ERGs. In PT3, who had positive family history for macular degeneration (MD) but presented with visual acuity loss from a late-onset macular pattern dystrophy (MPD), a Tyr258X RDS mutation was identified. Cone and rod ERGs were both moderately reduced and delayed in PT3. Sequencing of ROM1 did not identify any mutations.
Mutations in the RDS gene have been associated with various retinal phenotypes such as dominant retinitis pigmentosa (RP), digenic RP, progressive MD, vitelliform macular dystrophies and MPDs. We identified a 2-bp deletion in the RDS gene in two unrelated probands with a different vitelliform phenotype. In addition, in a patient with MPD we identified a Tyr258X mutation, which had been previously reported in a patient with AOFVD. Although phenotypic heterogeneity has been previously established for the RDS mutation, our data further show that the same RDS mutations result in distinct adult-onset phenotypes. This finding confirms that as of yet unidentified genetic modifiers play an essential role in the onset and progression of RDS-associated phenotypes.
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