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Susan M. Downes, FRCOphth; Graham E. Holder, PhD; Frederick W. Fitzke, PhD; Annette M. Payne, PhD; Martin J. Warren, PhD; Shomi S. Bhattacharya, PhD; Alan C. Bird, MD

Arch Ophthalmol. 2001;119:96-105.

Objective  To describe the phenotype in 3 families with dominantly inherited cone and cone-rod dystrophy with mutations in guanylate cyclase activator 1A (GUCA1A), the gene-encoding guanylate cyclase activator protein-1 (GCAP-1).

Methods  Phenotypic characterization with psychophysical and electrophysiological evaluation and confocal laser scanning ophthalmoscopy was performed in 2 families with a Tyr99Cys mutation and 1 family with a Pro50Leu mutation. Haplotype analysis was performed in the families with Tyr99Cys mutation.

Results  The families with a Y99C mutation were shown to be ancestrally related. Decreased visual acuity and loss of color vision occurred after the age of 20 years, followed by progressive atrophy of the central 5° to 10°. Electrophysiological testing revealed generalized loss of cone function, with preservation of rod function. Abnormal rod and cone sensitivities were confined to the central 5° to 10°. Confocal laser scanning ophthalmoscopy imaging showed abnormalities of autofluorescence in early disease. Subjects with a Pro50Leu mutation demonstrated marked variability in expressivity from minimal abnormalities of macular function to cone-rod dystrophy.

Conclusions  The phenotype associated with the Y99C mutation in GUCA1A is distinctive, with little variation in expression. By contrast, that associated with the P50L mutation demonstrates variable expressivity.

Clinical Relevance  Phenotype-genotype correlation in these 2 mutations demonstrates 2 different phenotypes.

From Moorfields Eye Hospital (Drs Downes, Holder, and Bird), and the Institute of Ophthalmology (Drs Downes, Fitzke, Payne, Warren, Bhattacharya, and Bird), London, England.

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