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.
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.
authors.affiliation: Mammalian Genetics Unit, Harwell, Didcot, OX11 0RD, UK. m.lyon@har.mrc.ac.uk
authors.forename: Mary F
authors.initials: MF
authors.lastname: Lyon
authors.forename: Robyn V
authors.initials: RV
authors.lastname: Jamieson
authors.forename: Rahat
authors.initials: R
authors.lastname: Perveen
authors.forename: Peter H
authors.initials: PH
authors.lastname: Glenister
authors.forename: Robert
authors.initials: R
authors.lastname: Griffiths
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Boyd
authors.forename: Laurie H
authors.initials: LH
authors.lastname: Glimcher
authors.forename: Jack
authors.initials: J
authors.lastname: Favor
authors.forename: Francis L
authors.initials: FL
authors.lastname: Munier
authors.forename: Graeme C M
authors.initials: GC
authors.lastname: Black
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001120:Arginine / Q000737:chemistry; D001426:Bacterial Proteins / Q000378:metabolism*; D002386:Cataract / Q000235:genetics* / Q000378:metabolism; D003433:Crosses, Genetic; D004247:DNA / Q000378:metabolism; D004252:DNA Mutational Analysis; D005799:Genes, Dominant; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D011233:Precipitin Tests; D011485:Protein Binding; D014176:Protein Biosynthesis; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid
chemical_list: D001426:Bacterial Proteins; C081169:Maf protein, Bacillus subtilis; D004247:DNA; D001120:Arginine