Identification of a New Missense Mutation in crb1 Associated with Autosomal Recessive Retinitis Pigmentosa

Abstract

Abstract: : Purpose:To determine the molecular pathology of autosomal recessive retinitis pigmentosa (arRP) in a consanguineous pedigree linked to the RP12 locus. Methods:Ten members of a two generation consanguineous Pakistani pedigree were examined. The pedigree structure revealed disease segregation in a pattern consistent with autosomal recessive inheritance. The clinical history for all affected individuals was of severe disease, with poor visual acuity in the range PL to 3/24, and included the onset of progressive night blindness in early childhood. Examination revealed the presence of a marked pigmentary retinopathy without preservation of the para-arteriolar RPE, waxy pallor of the optic nerve head and attenuation of the retinal vasculature, which were all features consistent with retinitis pigmentosa. Also, one affected individual had a Coats-like exudative vasculopathy. Genomic DNA was extracted from peripheral blood leucocytes, and family members were typed using microsatellite markers spanning the RP12 locus and the other known arRP loci. Results:A maximal lod score of 3.2 confirmed linkage, and was generated with microsatellite marker D1S1660 at the crb1 gene on 1q31-q32.1. Sequence analysis was undertaken, and a new missense mutation was identified, Gly846Arg, which substitutes a large charged polar amino acid in place of a small nonpolar amino acid. Conclusions:This report describes a new allelic variant of the crb1 gene associated with retinitis pigmentosa, and by exhibiting a lack of preservation of the para-arteriolar RPE and a Coats-like response, highlights further clinical heterogeneity at the RP12 locus.

Keywords: retinal degenerations: hereditary • genetics