Autosomal dominant cone dystrophy caused by a novel mutation in the GCAP1 gene (GUCA1A).
OBJECTIVE
To describe the clinical features and genetic analysis of a family with an autosomal dominant cone dystrophy (adCD).


METHODS
Selected members of a family with an autosomal dominant cone dystrophy underwent ophthalmic evaluation. Blood samples were obtained, genomic DNA was isolated, and genomic fragments were amplified by PCR. Linkage to locus D6S1017 was established. DHPLC mutational analysis and direct sequencing were used to identify a mutation in GUCA1A, the gene encoding the guanylate cyclase activating protein 1 (GCAP1).


RESULTS
Of 24 individuals who are at risk of the disease in a five generation family, 11 members were affected. Clinical presentations included photophobia, color vision defects, central acuity loss, and legal blindness with advanced age. The disease phenotype was observed in the second and third decades of life and segregated in an autosomal dominant fashion. An electroretinogram performed on one proband revealed profoundly subnormal and prolonged photopic and flicker responses, but preserved scotopic ERGs, consistent with a cone dystrophy. Mutational analysis and direct sequencing revealed a C451T transition in GUCA1A, corresponding to a novel L151F mutation in GCAP1. Like the E155G mutation, this mutation occurs in the EF4 hand domain, a region of GCAP1 critical in conferring calcium sensitivity to the protein. The leucine at this position is highly conserved among vertebrate guanylate cyclase activating proteins.


CONCLUSIONS
A novel L151F missense mutation in the EF4 high affinity Ca2+ binding site of GCAP1 is linked to adCD in a large pedigree. The cone dystrophy in this family shares clinical and electrophysiologic characteristics with other previously described adCD caused by mutations in GUCA1A.
Jiang
Li
L
Department of Ophthalmology and Visual Sciences, University of Utah Health Sciences Center, Salt Lake City, UT 84132, USA.
Katz
Bradley J
BJ
Yang
Zhenglin
Z
Zhao
Yu
Y
Faulkner
Nathan
N
Hu
Jianbin
J
Baird
Jennifer
J
Baehr
Wolfgang
W
Creel
Donnell J
DJ
Zhang
Kang
K
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001766:Blindness / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000235:genetics*; D002648:Child; D003117:Color Vision Defects / Q000235:genetics; D004252:DNA Mutational Analysis; D004596:Electroretinography; D005260:Female; D005451:Fluorescein Angiography; D005799:Genes, Dominant; D005838:Genotype; D006162:Guanylate Cyclase / Q000235:genetics*; D051604:Guanylate Cyclase-Activating Proteins; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D016133:Polymerase Chain Reaction; D017949:Retinal Cone Photoreceptor Cells / Q000503:physiopathology*; D012162:Retinal Degeneration / Q000235:genetics* / Q000503:physiopathology
D002135:Calcium-Binding Proteins; C496736:GUCA1A protein, human; D051604:Guanylate Cyclase-Activating Proteins; D006162:Guanylate Cyclase