Autosomal dominant cone and cone-rod dystrophy with mutations in the guanylate cyclase activator 1A gene-encoding guanylate cyclase activating protein-1

Objective: To describe the phenotype in 3 families with dominantly inherite d 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 electrophysiol ogical evaluation and confocal laser scanning ophthalmoscopy was performed in 2 families with a Tyr99Cys mutation and 1 family with a Pro50Leu mutatio n. Haplotype analysis was performed in the families with Tyr99Cys mutation. Results: The families with a Y99C mutation were shown to be ancestrally rel ated. Decreased visual acuity and loss of color vision occurred after the a ge of 20 years, followed by progressive. atrophy of the central 5 degrees t o 10 degrees. Electrophysiological testing revealed generalized loss of con e function, with preservation of rod function. Abnormal rod and cone sensit ivities were confined to the central 5 degrees to 10 degrees. Confocal lase r scanning ophthalmoscopy imaging, showed abnormalities of autofluorescence in tarry disease. Subjects with a Pro50Leu mutation demonstrated marked va riability in expressivity from minimal abnormalities of macular function to cone-rod dystrophy. Conclusions: The phenotype associated with the Y99C mutation in GUCA1A is d istinctive, with little variation in expression. By contrast, that associat ed with the P50L mutation demonstrates variable expressivity. Clinical Relevance: Phenotype-genotype correlation in these 2 mutations dem onstrates 2 different phenotypes.