Identification and functional consequences of a new mutation (E155G) in the gene for GCAP1 that causes autosomal dominant cone dystrophy

Wilkie, Susan E. and Liu, Yange and Deery, Evelyne and Newbold, Richard J. and Garibaldi, Daniel and Bateman, J. Bronwyn and Zhang, Heidi and Lin, Wei and Zack, Donald J. and Bhattacharya, Shomi S. and Warren, Martin J. and Hunt, David M. and Zhang, Kang (2001) Identification and functional consequences of a new mutation (E155G) in the gene for GCAP1 that causes autosomal dominant cone dystrophy. American Journal Humman Genetics, 69 (3). pp. 471-80. ISSN 0002-9297 . (The full text of this publication is not available from this repository)

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Abstract

Mutations in the gene for guanylate cyclase-activating protein-1 (GCAP1) (GUCA1A) have been associated with autosomal dominant cone dystrophy (COD3). In the present study, a severe disease phenotype in a large white family was initially shown to map to chromosome 6p21.1, the location of GUCA1A. Subsequent single-stranded conformation polymorphism analysis and direct sequencing revealed an A464G transition, causing an E155G substitution within the EF4 domain of GCAP1. Modeling of the protein structure shows that the mutation eliminates a bidentate amino acid side chain essential for Ca2+ binding. This represents the first disease-associated mutation in GCAP1, or any neuron-specific calcium-binding protein within an EF-hand domain, that directly coordinates Ca2+. The functional consequences of this substitution were investigated in an in vitro assay of retinal guanylate cyclase activation. The mutant protein activates the cyclase at low Ca2+ concentrations but fails to inactivate at high Ca2+ concentrations. The overall effect of this would be the constitutive activation of guanylate cyclase in photoreceptors, even at the high Ca2+ concentrations of the dark-adapted state, which may explain the dominant disease phenotype.

Item Type: Article
Uncontrolled keywords: Amino Acid Sequence Amino Acid Substitution Calcium-Binding Proteins/chemistry/*genetics/physiology Corneal Dystrophies, Hereditary/*genetics DNA/analysis Female Glutamic Acid/genetics Glycine/genetics Guanylate Cyclase-Activating Proteins Humans Male Models, Molecular Molecular Sequence Data Mutation Pedigree Protein Conformation Pyrimidines Sequence Homology, Amino Acid
Subjects: Q Science
Divisions: Faculties > Science Technology and Medical Studies > School of Biosciences
Depositing User: Martin Warren
Date Deposited: 12 Oct 2009 07:57
Last Modified: 25 Apr 2014 10:37
Resource URI: http://kar.kent.ac.uk/id/eprint/11062 (The current URI for this page, for reference purposes)
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