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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 EF3handof 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.

Original publication

DOI

10.1093/hmg/7.2.273

Type

Journal article

Journal

Human Molecular Genetics

Publication Date

02/1998

Volume

7

Pages

273 - 277

Addresses

Institute of Ophthalmology, Department of Molecular Genetics, 11-43 Bath Street, London EC1V 9EL, UK.

Keywords

Chromosomes, Human, Pair 6, Humans, Retinal Degeneration, Lipoproteins, Calcium-Binding Proteins, Eye Proteins, Nerve Tissue Proteins, Polymerase Chain Reaction, Pedigree, DNA Mutational Analysis, Amino Acid Sequence, Protein Conformation, Genes, Dominant, Lod Score, Point Mutation, Genes, Models, Molecular, Molecular Sequence Data, Female, Male, Hippocalcin, Recoverin, Guanylate Cyclase-Activating Proteins, Retinal Cone Photoreceptor Cells