X–linked Cone–rod Dystrophy (CORDX3) Is Caused by Mutation in CACNA1F

Abstract

Abstract: : Purpose:X–linked cone–rod dystrophy (CORDX) is a progressive retinal disease primarily showing cone photoreceptor dysfunction. The disease is genetically heterogeneous with three loci identified to date. CORDX1 is caused by mutations in the RPGR gene (Xp21.1), and CORDX2 is localized to Xq27.2–28. We recently localized CORDX3 to Xp11.4–q13.1 by linkage in a Finnish family (J Med Genet 2003, 40:418–423). This family includes ten affected males showing variable features including reduced visual acuity, high myopia, central scotomas and concentric constriction of visual fields, protan color vision defect, abnormal cone and rod dark adaptation, and altered cone ERG. The onset of the disease was at childhood or adulthood, and the progression was slow with respect to visual acuity, myopia, visual fields, and color vision. The purpose of this study was to determine the mutation behind the CORDX3 phenotype in our large Finnish family. Methods: All 48 exons and flanking intronic sequence of the CACNA1F gene were determined by direct sequencing. Segregation of the identified mutation in the family and analysis of controls were performed using Fnu4HI restriction endonuclease site analysis. RNA from cultured lymphoblasts was analyzed by RT–PCR and DNA sequencing. Results: A novel CACNA1F mutation, IVS28–1 GCGTC>TGG, in the splice acceptor site of intron 28 was identified in all affected CORDX3 family members, but not in 200 control chromosomes. RT–PCR analysis of lymphoblast RNA from CORDX3 patients revealed several aberrant splice variants. Conclusions: Mutations in CACNA1F are known to cause the incomplete form of X–linked congenital stationary night blindness (CSNB2), including an Åland Island eye disease–like phenotype, and retinal and optic disc atrophy. Our results indicate that CORDX3 is also caused by a mutation in CACNA1F. Support in part by Foundation Fighting Blindness – Canada (NTBH)

Keywords: retinal degenerations: hereditary • genetics • gene screening