Identification of a novel locus for autosomal dominant butterfly–shaped macular dystrophy on 5q21.2–q33.2

Abstract

Abstract: : Purpose: Butterfly–shaped macular dystrophy (BSMD) is characterized by bilateral accumulation of pigmented or yellowish material at the level of the retinal pigment epithelium (RPE). Lesions consist of 3 to 5 "wings", resembling the wings of a butterfly. Fundamental for the diagnosis are a subnormal electrooculogram (EOG), normal or slightly diminished visual acuity, and an autosomal dominant inheritance pattern. BSMD has so far only been associated with mutations in the peripherin/RDS gene. We ascertained 20 members of a BSMD family originally described by Deutman et al in 1970. We excluded peripherin/RDS as the causative gene in this family, as well as the ROM–1 gene, 4 genes expressed in cone photoreceptors, all known non–syndromic macular, RPE and choroidal dystrophy loci, all known Leber congenital amaurosis loci and all known non–syndromic congenital and stationary retinal disease loci (van Lith–Verhoeven et al 2003, Mol Vis 9:138–143). The aim of this study was to identify the locus responsible for BSMD in this family with a genome–wide scan. Methods: Genomic DNA samples of 9 affected individuals and 11 unaffected individuals of the BSMD family were subjected to a genome–wide scan. Genotyping of 400 CA–repeat markers with an average spacing of 10 cM was conducted by the Genotyping Service for Linkage Analysis at the Department of Human Genetics, Nijmegen. Two–point parametric linkage analysis of the genotyping data was performed with LINKAGE. Multipoint analysis was performed with LINKMAP. Results: The BSMD disease locus was mapped to a 44–cM region at 5q21.2–q33.2 with a multipoint lodscore of 4.05 between markers D5S433 and D5S410. A candidate gene in the region, PDE6A, encoding the α subunit of cGMP phosphodiesterase, was excluded by sequence analysis. Conclusions: This study provides evidence for genetic heterogeneity of BSMD. A novel locus for BSMD was identified on 5q21.2–q33.2. The critical interval will be refined with additional CA–repeat markers.

Keywords: linkage analysis • retinal degenerations: hereditary • macula/fovea