Human Molecular Genetics Advance Access originally published online on March 20, 2007
Human Molecular Genetics 2007 16(9):1030-1038; doi:10.1093/hmg/ddm048
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A heterozygous c-Maf transactivation domain mutation causes congenital cataract and enhances target gene activation
1 Academic 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, 2 Institute of Human Genetics, GSF-Research Centre for Environment and Health, D-85764 Neuherberg, Germany, 3 Department of Clinical Genetics, The Children's Hospital at Westmead, Sydney, Australia, 4 Centre for Molecular Medicine, Faculty of Medicine, University of Manchester, Manchester M13 9PT, UK and 5 Academic Unit of Ophthalmology, Manchester Royal Eye Hospital, Oxford Road Manchester, M13 9WH, UK
* To whom correspondence should be addressed. Tel: +44 1612766269; Fax: +44 1612766145; Email: gblack{at}manchester.ac.uk
MAF, one of a family of large Maf bZIP transcription factors, is mutated in human developmental ocular disorders that include congenital cataract, microcornea, coloboma and anterior segment dysgenesis. Expressed early in the developing lens vesicle, it is central to regulation of lens crystallin gene expression. We report a semi-dominant mouse c-Maf mutation recovered after ENU mutatgenesis which results in the substitution, D90V, at a highly conserved residue within the N-terminal 35 amino-acid minimal transactivation domain (MTD). Unlike null and loss-of-function c-Maf mutations, which cause severe runting and renal abnormalities, the phenotype caused by the D90V mutation is isolated cataract. In reporter assays, D90V results in increased promoter activation, a situation similar to MTD mutations of NRL that also cause human disease. In contrast to wild-type protein, the c-Maf D90V mutant protein is not inhibited by protein kinase A-dependent pathways. The MTD of large Maf proteins has been shown to interact with the transcriptional co-activator p300 and we demonstrate that c-Maf D90V enhances p300 recruitment in a cell-type dependent manner. We observed the same for the pathogenic human NRL MTD mutation S50T, which suggests a common mechanism of action.