Paper Citing NAMD - Abstract
Sokal, I.; Dupps, W.J.; Grassi, M.A.; Brown, J.; Affatigato, L.M.; Roychowdhury, N.; Yang, L.L.; Filipek, S.; Palczewski, K.; Stone, E.M.; Baehr, W.
A novel GCAP1 missense mutation (L151F) in a large family with autosomal dominant cone-rod dystrophy (adCORD)
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 46:1124-1132, APR 2005
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.
