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.