Wilkie, Susan E.,
Liu, Yange,
Deery, Evelyne,
Newbold, Richard J.,
Garibaldi, Daniel,
Bateman, J. Bronwyn,
Zhang, Heidi,
Lin, Wei,
Zack, Donald J.,
Bhattacharya, Shomi S.,
and others.
Warren, Martin J.,
Hunt, David M.,
and
Zhang, Kang
(hide)
(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.
(doi:10.1086/323265)
(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)
(KAR id:11062)
|
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.
|
Official URL:
https://doi.org/10.1086/323265 |
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
|
| DOI/Identification number: |
10.1086/323265 |
| 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: |
Divisions > Division of Natural Sciences > Biosciences
|
| Depositing User: |
Martin Warren
|
| Date Deposited: |
12 Oct 2009 07:57
UTC
|
| Last Modified: |
05 Nov 2024 09:44
UTC
|
| Resource URI: |
https://kar.kent.ac.uk/id/eprint/11062 (The current URI for this page, for reference purposes) |
University of Kent Author Information
Deery, Evelyne.
Warren, Martin J..
- Depositors only (login required):
https://orcid.org/0000-0002-8189-678X
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