Identification of mutations in GCAP1 in autosomal dominant cone dystrophy

Abstract

Abstract: : Purpose: The cone dystrophies are a heterogeneous group of hereditary retinal degenerations characterized by progressive dysfunction of the photopic (cone–mediated) system, presenting with photophobia, loss of color vision and reduced central visual acuity. This phenotype is in contrast to that of retinitis pigmentosa (RP) which is characterized by abnormalities in scotopic (rod–mediated) functions, manifesting as night blindness and also a decrease of peripheral vision. Cone dystrophy is genetically heterogeneous and may present as an autosomal dominant, autosomal recessive, or X–linked recessive trait. Autosomal loci have been localized to 6p21.1 (COD3, OMIM 602093), 6q25–q26 (OMIM 180020), and 17p12–13 (OMIM 601251). In the case of COD3, mutations have been identified in the GUCA1A gene encoding GCAP1, a Ca²⁺–binding protein involved in regulation of rod and cone phototransduction. X–linked cone dystrophy maps to loci on Xp11.4 (COD1, OMIM 304020) and Xq27 (COD2, OMIM 303800). Mutations in RPGR have been identified in X–linked cone dystrophy linked COD1. The purpose of this study is to investigate clinical features and gene mutations in two families with an autosomal dominant form of cone dystrophy. Methods: Ophthalmologic examinations were performed and genomic DNA extracted. DNA samples were amplified by the polymerase chain reaction using primers corresponding to each exon of GCAP1. The PCR products were screened for mutations by DHPLC (WAVE® System, Transgenomic, Omaha, NE) and by direct sequencing. Results: Clinical finding in these families including photophobia, decreased visual acuity and color vision abnormalities typical of cone dystrophy. We identified two mutations Tyr99Cys and Leu151Pro respectively in two families with autosomal dominant cone dystrophy. Conclusions:We identified two mutations in the GCAP1 gene in 21 patients of 2 independent families with cone dystrophy. Identification and functional studies of genes causing cone dystrophy will facilitate development of DNA diagnostic tools and new treatment strategies.

Keywords: retinal degenerations: hereditary • mutations • gene screening