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A Novel GCAP1 Missense Mutation (L151F) in a Large Family with Autosomal Dominant Cone-Rod Dystrophy (adCORD)

Izabela Sokal,¹ William J. Dupps,² Michael A. Grassi,² Jeremiah Brown, Jr,^2,3 Louisa M. Affatigato,² Nirmalya Roychowdhury,⁴ Lili Yang,⁴ Sawomir Filipek,⁵ Krzysztof Palczewski,^1,6,7 Edwin M. Stone,^2,8 and Wolfgang Baehr^4,9,10

¹From the Departments of Ophthalmology, ⁶Pharmacology, and ⁷Chemistry, University of Washington, Seattle, Washington; the ²Department of Ophthalmology and Visual Sciences, and the ⁸Howard Hughes Medical Institute, University of Iowa Carver College of Medicine, Iowa City, Iowa; the ⁴Departments of Ophthalmology and Visual Sciences, ⁹Biology, and ¹⁰Neurobiology and Anatomy, University of Utah, Salt Lake City, Utah; and the ⁵International Institute of Molecular and Cell Biology, Warsaw, Poland.

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 CT 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.

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