A Mutation in Guanylate Cyclase Activator 1A (GUCA1A) in an Autosomal Dominant Cone Dystrophy Pedigree Mapping to a New Locus on Chromosome 6p21.1

• Published in: Human molecular genetics Vol. 7; no. 2; pp. 273 - 277
• Main Authors: Payne, Annette M., Downes, Susan M., Bessant, David A.R., Taylor, Rachel, Holder, Graham E., Warren, Martin J., Bird, Alan C., Bhattacharya, Shomi S.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.02.1998
• Subjects: Amino Acid Sequence; Biological and medical sciences; Calcium-Binding Proteins - chemistry; Calcium-Binding Proteins - genetics; Chromosomes, Human, Pair 6 - genetics; DNA Mutational Analysis; Eye Proteins; Female; Genes; Genes, Dominant; Guanylate Cyclase-Activating Proteins; Hippocalcin; Humans; Lipoproteins; Lod Score; Male; Medical sciences; Models, Molecular; Molecular Sequence Data; Nerve Tissue Proteins; Ophthalmology; Pedigree; Point Mutation; Polymerase Chain Reaction; Protein Conformation; Recoverin; Retinal Cone Photoreceptor Cells - pathology; Retinal Degeneration - enzymology; Retinal Degeneration - genetics; Retinopathies; Genetic mapping; Human; Retinopathy; Cone; Calcium; Enzyme; Family study; Phosphorus-oxygen lyases; Lyases; Chromosome C6; Guanylate cyclase; Genetic disease; Binding protein; Eye disease; Gene; Domain structure; Genetics; Dominant character; Dystrophy; Mutation
• DOI: 10.1093/hmg/7.2.273
• ISSN: 0964-6906; 1460-2083

We report a mutation (Y99C) in guanylate cyclase activator 1A (GUCA1A), the gene for guanylate cyclase activating protein (GCAP1), in a family with autosomal dominant cone dystrophy. Linkage analysis excluded all the known cone and cone-rod dystrophy loci, except the chromosome 6p21.1 region. This is known to contain the RDS gene, which is associated with dominant cone-rod dystrophy. Screening of the RDS gene by heteroduplex analysis and direct sequencing failed to demonstrate sequence changes in the coding region of this gene. The gene for GCAP1, a calcium binding protein which is highly expressed in photoreceptor outer segments, 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-cysteine change in the GCAP1 protein. This change was absent from 206 unrelated normal controls. We propose that this change would at least disrupt the EF3 hand of GCAP1 thereby preventing calcium binding and consequently interfere with activation. The resulting effect on cGMP production would predictably modify the number of open cGMP gated cation channels, and could explain the ultimate demise of cone photoreceptor cells.