A dominant mutation within the DNA-binding domain of the bZIP transcription factor Maf causes murine cataract and results in selective alteration in DNA binding

Details

Ressource 1Download: serval:BIB_A20F85169B74.P001 (1506.84 [Ko])
State: Public
Version: author
License: Not specified
It was possible to publish this article open access thanks to a Swiss National Licence with the publisher.
Serval ID
serval:BIB_A20F85169B74
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
A dominant mutation within the DNA-binding domain of the bZIP transcription factor Maf causes murine cataract and results in selective alteration in DNA binding
Journal
Human Molecular Genetics
Author(s)
Lyon  M. F., Jamieson  R. V., Perveen  R., Glenister  P. H., Griffiths  R., Boyd  Y., Glimcher  L. H., Favor  J., Munier  F. L., Black  G. C.
ISSN
0964-6906 (Print)
Publication state
Published
Issued date
03/2003
Volume
12
Number
6
Pages
585-94
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Mar 15
Abstract
The murine autosomal dominant cataract mutants created in mutagenesis experiments have proven to be a powerful resource for modelling the biological processes involved in cataractogenesis. We report a mutant which in the heterozygous state exhibits mild pulverulent cataract named 'opaque flecks in lens', symbol Ofl. By molecular mapping, followed by a candidate gene approach, the mutant was shown to be allelic with a knockout of the bZIP transcription factor, Maf. Homozygotes for Ofl and for Maf null mutations are similar but a new effect, renal tubular nephritis, was found in Ofl homozygotes surviving beyond 4 weeks, which may contribute to early lethality. Sequencing identified the mutation as a G-->A change, leading to the amino-acid substitution mutation R291Q in the basic region of the DNA-binding domain. Since mice heterozygous for knockouts of Maf show no cataracts, this suggests that the Ofl R291Q mutant protein has a dominant effect. We have demonstrated that this mutation results in a selective alteration in DNA binding affinities to target oligonucleotides containing variations in the core CRE and TRE elements. This implies that arginine 291 is important for core element binding and suggests that the mutant protein may exert a differential downstream effect amongst its binding targets. The cataracts seen in Ofl heterozygotes and human MAF mutations are similar to one another, implying that Ofl may be a model of human pulverulent cortical cataract. Furthermore, when bred onto a different genetic background Ofl heterozygotes also show anterior segment abnormalities. The Ofl mutant therefore provides a valuable model system for the study of Maf, and its interacting factors, in normal and abnormal lens and anterior segment development.
Keywords
Alleles Amino Acid Sequence Animals Arginine/chemistry Bacterial Proteins/*metabolism Cataract/*genetics/metabolism Crosses, Genetic DNA/metabolism DNA Mutational Analysis *Genes, Dominant Heterozygote Homozygote Humans Mice Mice, Knockout Molecular Sequence Data *Mutation Phenotype Precipitin Tests Protein Binding Protein Biosynthesis Protein Structure, Tertiary Sequence Homology, Amino Acid
Pubmed
Web of science
Open Access
Yes
Create date
28/01/2008 13:54
Last modification date
25/09/2019 7:10
Usage data