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Izabela Sokal, William J. Dupps, Michael A. Grassi, Jeremiah Brown, Louisa M. Affatigato, Nirmalya Roychowdhury, Lili Yang, Sławomir Filipek, Krzysztof Palczewski, Edwin M. Stone, Wolfgang Baehr; A Novel GCAP1 Missense Mutation (L151F) in a Large Family with Autosomal Dominant Cone-Rod Dystrophy (adCORD). Invest. Ophthalmol. Vis. Sci. 2005;46(4):1124-1132. doi: https://doi.org/10.1167/iovs.04-1431.
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purpose. To elucidate the phenotypic and biochemical characteristics of a novel mutation associated with autosomal dominant cone–rod dystrophy (adCORD).
methods. Twenty-three family members of a CORD pedigree underwent clinical examinations, including visual acuity tests, standardized full-field ERG, and fundus photography. Genomic DNA was screened for mutations in GCAP1 exons using DNA sequencing and single-strand conformational polymorphism (SSCP) analysis. Function and stability of recombinant GCAP1-L151F were tested as a function of [Ca2+], and its structure was probed by molecular dynamics.
results. Affected family members experienced dyschromatopsia, hemeralopia, and reduced visual acuity by the second to third decade of life. Electrophysiology revealed a nonrecordable photopic response with later attenuation of the scotopic response. Affected family members harbored a C→T transition in exon 4 of the GCAP1 gene, resulting in an L151F missense mutation affecting the EF hand motif 4 (EF4). This change was absent in 11 unaffected family members and in 100 unrelated normal subjects. GCAP1-L151F stimulation of photoreceptor guanylate cyclase was not completely inhibited at high physiological [Ca2+], consistent with a lowered affinity for Ca2+-binding to EF4.
conclusions. A novel L151F mutation in the EF4 hand domain of GCAP1 is associated with adCORD. The clinical phenotype is characterized by early cone dysfunction and a progressive loss of rod function. The biochemical phenotype is best described as persistent stimulation of photoreceptor guanylate cyclase, representing a gain of function of mutant GCAP1. Although a conservative substitution, molecular dynamics suggests a significant change in Ca2+-binding to EF4 and EF2 and changes in the shape of L151F-GCAP1.
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