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W.J. Dupps, M.P. Rauen, J.A. Andorf, K.M. Schrum, K.A. Melendez, E.M. Stone; A Novel GCAP1 Missense Mutation in a Family with Autosomal Dominant Cone-Rod Dystrophy . Invest. Ophthalmol. Vis. Sci. 2003;44(13):1527.
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Purpose: Guanylate cyclase activating protein 1 (GCAP1) is a calcium-dependent photoreceptor regulatory protein that has been localized to human cones and rods. Two GCAP1 mutations have previously been reported in association with autosomal dominant cone dystrophy (Y99C) and cone-rod dystrophy (P50L). In this study, a pedigree affected with autosomal dominant cone-rod dystrophy previously linked to a chromosome 6p21 locus was screened for disease-causing sequence variations in the GCAP1 gene. Methods: Twenty-three members of a CRD pedigree underwent clinical examination and genetic analysis. Clinical testing included visual acuity, color testing, Goldmann perimetry, standardized full-field ERG, dark adaptometry and fundus photography. DNA prepared from peripheral blood of family members, 3 unaffected spouses and 200 normal subjects was screened for mutations in the coding sequence of the GCAP1 gene using automated DNA sequencing and SSCP analysis. Results: Affected family members (12/23) experienced dyschromatopsia, photophobia and/or reduced visual acuity by the second decade of life. Characteristic features included a pigmentary maculopathy with central and paracentral scotomas, abnormal dark adaptation, and eventual progression to non-recordable cone responses on ERG (with attenuated rod responses). Linkage was demonstrated between the CRD phenotype and genetic markers from 6p21. Direct sequencing of the RDS gene revealed no disease-causing sequence variations. Sequencing of the GCAP1 gene in the proband detected a C to T missense mutation that would be expected to cause a Leu151Phe change in the GCAP1 protein. This change was present in all 12 affected family members, but absent from 11 unaffected family members, 3 unaffected spouses and 200 unrelated normal subjects. Conclusions: A novel mutation (L151F) in the predicted calcium-binding EF4 hand domain of GCAP1 is associated with autosomal dominant cone-rod dystrophy.
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