Human Molecular Genetics, Vol 7, 273-277, Copyright © 1998 by Oxford University Press
AM Payne, SM Downes, DA Bessant, R Taylor, GE Holder, MJ Warren, AC Bird and SS Bhattacharya
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.
ARTICLES
A mutation in guanylate cyclase activator 1A (GUCA1A) in an autosomal dominant cone dystrophy pedigree mapping to a new locus on chromosome 6p21.1
Institute of Ophthalmology, Department of Molecular Genetics, 11-43 Bath Street, London EC1V 9EL, UK.
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