V76D mutation in a conserved γD-crystallin region leads to dominant cataracts in mice

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Item Type:	Article
Title:	V76D mutation in a conserved γD-crystallin region leads to dominant cataracts in mice
Creators Name:	Graw, J., Loester, J., Soewarto, D., Fuchs, H., Reis, A., Wolf, E., Balling, R. and de Angelis, M.H.
Abstract:	During a large-scale ENU mutagenesis screen, a mouse mutant with a dominant cataract was detected and referred to as Aey4. Aim of this study was the morphological description of the mutant, the mapping of the mutation, and the characterization of the underlying molecular lesion. The slit-lamp examination revealed a strong nuclear cataract surrounded by a homogeneous milky opacity in the inner cortex. The histological analysis demonstrated remnants of cell nuclei throughout the entire lens. The mutation was mapped to Chromosome 1 by a genome-wide linkage making the six {gamma}-crystallin encoding genes and the closely linked {beta}A2-crystallin encoding gene to relevant candidate genes. Finally, a T→A exchange in exon 2 of the {gamma}D-crystallin encoding gene (symbol: Crygd) was demonstrated to be causative for the cataract phenotype; this particular mutation is, therefore, referred to CrygoAey4. The alteration in codon 76 leads to an amino acid exchange of Val→Asp. Val at this position is highly conserved; it is found in all mouse and rat {gamma}D/E/F-crystallins as well as in the human {gamma}A- and {gamma}D-crystallins. It may be replaced solely by Ile, which is present in all bovine {gamma}-crystallins, in the rat and mouse {gamma}A/B/C-crystallins, as well as in the human {gamma}B/C-crystallins. It is predicted that the exchange of a hydrophobic side chain by a polar and acidic one might influence the microenvironment by a dramatic decrease of the isoelectric point by 1.5 pH units in the 10 amino acids surrounding position 76. The CrygdAey4 additionally demonstrates the importance of the integrity of the Cryg gene cluster for lens transparency.
Keywords:	Amino Acid Substitution, Cataract, Chromosome Mapping, Crystallins, DNA Sequence Analysis, Dominant Genes, Mutation, Non-U.S. Gov't Support, Protein Folding, Animals, Mice
Source:	Mammalian Genome
ISSN:	0938-8990
Publisher:	Springer
Volume:	13
Number:	8
Page Range:	452-455
Date:	August 2002
Official Publication:	https://doi.org/10.1007/s00335-002-3021-6
PubMed:	View item in PubMed

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