Purchase this article with an account.
Izabela Sokal, William J. Dupps, Michael A. Grassi, Jeremiah Brown, Jr, 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: 10.1167/iovs.04-1431.
Download citation file:
© 2016 Association for Research in Vision and Ophthalmology.
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.
This PDF is available to Subscribers Only