Dominant cone and cone-rod dystrophies: functional analysis of mutations in retGC1 and GCAP1

Hunt, David M. and Wilkie, Susan E. and Newbold, Richard J. and Deery, Evelyne and Warren, Martin J. and Bhattacharya, Shomi S. and Zhang, Kang (2004) Dominant cone and cone-rod dystrophies: functional analysis of mutations in retGC1 and GCAP1. In: Bock, Gregory and Chader, Gerry and Goode, Jamie, eds. Retinal Dystrophies: Functional Genomics to Gene Therapy. Novartis Foundation Symposia, 255 . John Wiley & Sons, pp. 37-49. ISBN 9780470853573. (The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided)

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The regulation of cGMP levels is central to the normal process of phototransduction in both cone and rod photoreceptor cells. Two of the proteins involved in this process are the enzyme, retinal guanylate cyclase (retGC), and its activating protein (GCAP) through which activity is regulated via changes in cellular Ca2+ levels. Dominant cone-rod dystrophies arising from changes in retGC1 are essentially restricted to mutations in codon 838 and result in the replacement of a conserved arginine residue with either cysteine, histidine or serine. In all three cases, the effect of the substitution on the in vitro cyclase activity is a loss of Ca2+ sensitivity arising from an increased stability of the coiled-coil domain of the protein dimer and retention of cyclase activity. In contrast, mutations in the Ca2+-coordinating EF hands of GCAP1 result in dominant cone dystrophy; the consequences of these mutations is a reduced ability of the mutant protein to regulate retGC activity in response to changes in Ca2+ levels. Functionally therefore, the retGC2 and GCAP2 mutations are similar in reducing the feedback inhibition of Ca2+ on cyclase activity and thereby on cGMP levels in the photoreceptors.

Item Type: Book section
Additional information: 1528-2511 (Print) discussion 49
Uncontrolled keywords: Calcium Calcium-Binding Proteins/genetics/metabolism DNA Mutational Analysis Guanylate Cyclase/*genetics/metabolism Guanylate Cyclase-Activating Proteins Humans Mutation *Receptors, Cell Surface Retinal Diseases/*genetics/metabolism Structure-Activity Relationship
Subjects: Q Science
Divisions: Faculties > Science Technology and Medical Studies > School of Biosciences
Depositing User: Martin Warren
Date Deposited: 09 Oct 2009 12:01
Last Modified: 25 Apr 2014 11:13
Resource URI: (The current URI for this page, for reference purposes)
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