Novel GCAP1 missense mutation (L151F) in a large family with autosomal dominant cone-rod dystrophy (adCORD)

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Publication Type Journal Article
School or College School of Medicine
Department Ophthalmology
Creator Baehr, Wolfgang
Other Author Sokal, Izabela; Dupps, William J; Grassi, Michael A; Brown, Jeremiah Jr; Affatigato, Louisa M; Roychowdhury, Nirmalya; Yang, Lili; Filipek, Slawomir; Palczewski, Krzysztof; Stone, Edwin M
Title Novel GCAP1 missense mutation (L151F) in a large family with autosomal dominant cone-rod dystrophy (adCORD)
Date 2005
Description 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 [Ca(2+)], 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 [Ca(2+)], consistent with a lowered affinity for Ca(2+)-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 Ca(2+)-binding to EF4 and EF2 and changes in the shape of L151F-GCAP1.
Type Text
Publisher Association for Research in Vision and Ophthalmology
Volume 46
Issue 4
First Page 1124
Last Page 1132
Subject Polymorphism, Single-Stranded Conformational; Guanylate Cyclase-Activating Proteins; DNA Mutational Analysis
Subject MESH Calcium-Binding Proteins; Photoreceptors, Vertebrate; Mutation, Missense
Language eng
Bibliographic Citation Sokal I, Dupps WJ, Grassi MA, Brown J Jr, Affatigato LM, Roychowdhury N, Yang L, Filipek S, Palczewski K, Stone EM, Baehr W. (2005). A novel GCAP1 missense mutation (L151F) in a large family with autosomal dominant cone-rod dystrophy (adCORD). Invest Ophthalmol Vis Sci, 46(4), 1124-32
Rights Management (c) Association for Research in Vision and Ophthalmology
Format Medium application/pdf
Identifier ir-main,1742
ARK ark:/87278/s64q8ck6
Setname ir_uspace
Date Created 2012-06-13
Date Modified 2021-05-06
ID 707039
Reference URL
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