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http://purl.uniprot.org/citations/15790869http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/15790869http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/15790869http://www.w3.org/2000/01/rdf-schema#comment"

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."xsd:string
http://purl.uniprot.org/citations/15790869http://purl.org/dc/terms/identifier"doi:10.1167/iovs.04-1431"xsd:string
http://purl.uniprot.org/citations/15790869http://purl.org/dc/terms/identifier"doi:10.1167/iovs.04-1431"xsd:string
http://purl.uniprot.org/citations/15790869http://purl.uniprot.org/core/author"Yang L."xsd:string
http://purl.uniprot.org/citations/15790869http://purl.uniprot.org/core/author"Yang L."xsd:string
http://purl.uniprot.org/citations/15790869http://purl.uniprot.org/core/author"Baehr W."xsd:string
http://purl.uniprot.org/citations/15790869http://purl.uniprot.org/core/author"Baehr W."xsd:string
http://purl.uniprot.org/citations/15790869http://purl.uniprot.org/core/author"Stone E.M."xsd:string
http://purl.uniprot.org/citations/15790869http://purl.uniprot.org/core/author"Stone E.M."xsd:string
http://purl.uniprot.org/citations/15790869http://purl.uniprot.org/core/author"Palczewski K."xsd:string
http://purl.uniprot.org/citations/15790869http://purl.uniprot.org/core/author"Palczewski K."xsd:string
http://purl.uniprot.org/citations/15790869http://purl.uniprot.org/core/author"Affatigato L.M."xsd:string
http://purl.uniprot.org/citations/15790869http://purl.uniprot.org/core/author"Affatigato L.M."xsd:string
http://purl.uniprot.org/citations/15790869http://purl.uniprot.org/core/author"Sokal I."xsd:string
http://purl.uniprot.org/citations/15790869http://purl.uniprot.org/core/author"Sokal I."xsd:string
http://purl.uniprot.org/citations/15790869http://purl.uniprot.org/core/author"Filipek S."xsd:string
http://purl.uniprot.org/citations/15790869http://purl.uniprot.org/core/author"Filipek S."xsd:string
http://purl.uniprot.org/citations/15790869http://purl.uniprot.org/core/author"Brown J. Jr."xsd:string
http://purl.uniprot.org/citations/15790869http://purl.uniprot.org/core/author"Brown J. Jr."xsd:string
http://purl.uniprot.org/citations/15790869http://purl.uniprot.org/core/author"Dupps W.J."xsd:string
http://purl.uniprot.org/citations/15790869http://purl.uniprot.org/core/author"Dupps W.J."xsd:string
http://purl.uniprot.org/citations/15790869http://purl.uniprot.org/core/author"Grassi M.A."xsd:string
http://purl.uniprot.org/citations/15790869http://purl.uniprot.org/core/author"Grassi M.A."xsd:string
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