Human Molecular Genetics, 2003, Vol. 12, No. 6 585-594
© 2003 Oxford University Press
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
1Mammalian Genetics Unit, Harwell, Didcot, OX11 0RD, UK, 2Academic Unit of Medical Genetics and Regional Genetics Service Department of Clinical Genetics, Central Manchester and Manchester Children's University Hospitals NHS Trust, St Mary's Hospital, Hathersage Road, Manchester M13 0JH, UK, 3Department of Clinical Genetics, The Children's Hospital at Westmead, Sydney, Australia, 4Institute of Animal Health, Compton, Newbury RG20 7NN, UK, 5Department of Immunology, Harvard School of Public Health, Boston MA 02115-6017, USA, 6Institute of Human Genetics, GSF-Research Centre for Environment and Health, D-85764 Neuherberg, Germany, 7Hopital Ophthalmique Jules Gonin, Center Hospitalier Universitaire Vaudois, Lausanne, Switzerland and 8Academic Unit of Ophthalmology, Manchester Royal Eye Hospital, Oxford Road, Manchester M13 9WH, UK
Received September 30, 2002; Accepted January 13, 2003
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.
* To whom correspondence should be addressed: Tel: +44 1235841000; Fax: +44 1235841200; Email: m.lyon{at}har.mrc.ac.uk
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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