A MUTATION IN GUANYLATE-CYCLASE ACTIVATOR 1A (GUCA1A) IN AN AUTOSOMAL-DOMINANT CONE DYSTROPHY PEDIGREE MAPPING TO A NEW LOCUS ON CHROMOSOME6P21.1

We report a mutation (Y99C) in guanylate cyclase activator 1A(GUCA1A), the gene for guanylate cyclase activating protein (GCAP1), in a famil y with autosomal dominant cone dystrophy. Linkage analysis excluded al l the known cone and cone-rod dystrophy loci, except the chromosome 6p 21.1 region, This is known to contain the RDS gene, which is associate d with dominant cone-rod dystrophy. Screening of the RDS gene by heter oduplex analysis and direct sequencing failed to demonstrate sequence changes in the coding region of this gene, The gene for GCAP1, a calci um binding protein which is highly expressed in photoreceptor outer se gments, is also located in 6p21.1, It was screened for mutations, and all affected individuals showed a single base pair missense mutation ( A-->G) at codon 99 in exon 2 of this gene generating a tyrosine-to-cys teine change in the GCAP1 protein, This change was absent from 206 unr elated normal controls, We propose that this change would at least dis rupt the EF3 hand of GCAP1 thereby preventing calcium binding and cons equently interfere with activation, The resulting effect on cGMP produ ction would predictably modify the number of open cGMP gated cation ch annels, and could explain the ultimate demise of cone photoreceptor ce lls.