HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (9) Citing Articles via Google Scholar Google Scholar Articles by Nishiguchi, K. M. Articles by Baehr, W. Search for Related Content PubMed PubMed Citation Articles by Nishiguchi, K. M. Articles by Baehr, W.

A Novel Mutation (I143NT) in Guanylate Cyclase-Activating Protein 1 (GCAP1) Associated with Autosomal Dominant Cone Degeneration

¹From the Ocular Molecular Genetics Institute, and ⁶Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts; the ²Departments of Ophthalmology, ⁴Pharmacology, and ⁵Chemistry, University of Washington, Seattle, Washington; and the ³Departments of Ophthalmology and Visual Sciences, ⁷Biology, and ⁸Neurobiology and Anatomy, University of Utah, Salt Lake City, Utah.

PURPOSE. To identify pathogenic mutations in the guanylate cyclase-activating protein 1 (GCAP1) and GCAP2 genes and to characterize the biochemical effect of mutation on guanylate cyclase (GC) stimulation.

METHODS. The GCAP1 and GCAP2 genes were screened by direct sequencing for mutations in 216 patients and 421 patients, respectively, with various hereditary retinal diseases. A mutation in GCAP1 segregating with autosomal dominant cone degeneration was further evaluated biochemically by employing recombinant proteins, immunoblotting, Ca²⁺-dependent stimulation of GC, fluorescence emission spectra, and limited proteolysis in the absence and presence of Ca²⁺.

RESULTS. A novel GCAP1 mutation, I143NT (substitution of Ile at codon 143 by Asn and Thr), affecting the EF4 Ca²⁺-binding loop, was identified in a heterozygote father and son with autosomal dominant cone degeneration. Both patients had much greater loss of cone function versus rod function; previous histopathologic evaluation of the father’s eyes at autopsy (age 75 years) showed no foveal cones but a few, scattered cones remaining in the peripheral retina. Biochemical analysis showed that the GCAP1-I143NT mutant adopted a conformation susceptible to proteolysis, and the mutant inhibited GC only partially at high Ca²⁺ concentrations. Individual patients with atypical or recessive retinitis pigmentosa (RP) had additional heterozygous GCAP1-T114I and GCAP2 gene changes (V85M and F150C) of unknown pathogenicity.

CONCLUSIONS. A novel GCAP1 mutation, I143NT, caused a form of autosomal dominant cone degeneration that destroys foveal cones by mid-life but spares some cones in the peripheral retina up to 75 years. Properties of the GCAP1-I143NT mutant protein suggested that it is incompletely inactivated by high Ca²⁺ concentrations as should occur with dark adaptation. The continued activity of the mutant GCAP1 likely results in higher-than-normal scotopic cGMP levels which may, in turn, account for the progressive loss of cones.

This article has been cited by other articles:

				M. L. Woodruff, E. V. Olshevskaya, A. B. Savchenko, I. V. Peshenko, R. Barrett, R. A. Bush, P. A. Sieving, G. L. Fain, and A. M. Dizhoor Constitutive Excitation by Gly90Asp Rhodopsin Rescues Rods from Degeneration Caused by Elevated Production of cGMP in the Dark J. Neurosci., August 15, 2007; 27(33): 8805 - 8815. [Abstract] [Full Text] [PDF]

				I. V. Peshenko and A. M. Dizhoor Activation and Inhibition of Photoreceptor Guanylyl Cyclase by Guanylyl Cyclase Activating Protein 1 (GCAP-1): THE FUNCTIONAL ROLE OF Mg2+/Ca2+ EXCHANGE IN EF-HAND DOMAINS J. Biol. Chem., July 27, 2007; 282(30): 21645 - 21652. [Abstract] [Full Text] [PDF]

				S. M. Hauck, P. A. R. Ekstrom, P. Ahuja-Jensen, S. Suppmann, F. Paquet-Durand, T. van Veen, and M. Ueffing Differential Modification of Phosducin Protein in Degenerating rd1 Retina Is Associated with Constitutively Active Ca2+/Calmodulin Kinase II in Rod Outer Segments Mol. Cell. Proteomics, February 1, 2006; 5(2): 324 - 336. [Abstract] [Full Text] [PDF]

				I. Sokal, W. J. Dupps, M. A. Grassi, J. Brown Jr, L. M. Affatigato, N. Roychowdhury, L. Yang, S. Filipek, K. Palczewski, E. M. Stone, et al. A Novel GCAP1 Missense Mutation (L151F) in a Large Family with Autosomal Dominant Cone-Rod Dystrophy (adCORD) Invest. Ophthalmol. Vis. Sci., April 1, 2005; 46(4): 1124 - 1132. [Abstract] [Full Text] [PDF]