Journal article
A novel GCAP1 missense mutation (L151F) in a large family with autosomal dominant cone-rod dystrophy (adCORD)
Investigative ophthalmology & visual science, Vol.46(4), pp.1124-1132
04/2005
DOI: 10.1167/iovs.04-1431
PMCID: PMC1352313
PMID: 15790869
Abstract
To elucidate the phenotypic and biochemical characteristics of a novel mutation associated with autosomal dominant cone-rod dystrophy (adCORD). 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. 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. 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.
Details
- Title: Subtitle
- A novel GCAP1 missense mutation (L151F) in a large family with autosomal dominant cone-rod dystrophy (adCORD)
- Creators
- Izabela Sokal - Department of Ophthalmology, University of Washington, Seattle, Washington, USAWilliam J DuppsMichael A GrassiJeremiah Brown Jr - University of IowaLouisa M AffatigatoNirmalya RoychowdhuryLili Yang - University of UtahSlawomir FilipekKrzysztof PalczewskiEdwin M StoneWolfgang Baehr
- Resource Type
- Journal article
- Publication Details
- Investigative ophthalmology & visual science, Vol.46(4), pp.1124-1132
- DOI
- 10.1167/iovs.04-1431
- PMID
- 15790869
- PMCID
- PMC1352313
- NLM abbreviation
- Invest Ophthalmol Vis Sci
- ISSN
- 0146-0404
- eISSN
- 1552-5783
- Publisher
- United States
- Grant note
- R01 EY009339 / NEI NIH HHS R01 EY008123 / NEI NIH HHS EY08123 / NEI NIH HHS EY09339 / NEI NIH HHS
- Language
- English
- Date published
- 04/2005
- Academic Unit
- The University of Iowa Institute for Vision Research; Iowa Neuroscience Institute; Ophthalmology and Visual Sciences
- Record Identifier
- 9983980295002771
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