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Human Molecular Genetics, 2002, Vol. 11, No. 1 33-42
© 2002 Oxford University Press

Domain disruption and mutation of the bZIP transcription factor, MAF, associated with cataract, ocular anterior segment dysgenesis and coloboma

Robyn V. Jamieson1,2,+, Rahat Perveen1, Bronwyn Kerr3, Martin Carette1, Jill Yardley4, Elise Heon5, M. Gabriela Wirth6, Veronica van Heyningen7, Di Donnai1, Francis Munier8 and Graeme C. M. Black1,4

1University Department of Medical Genetics and Regional Genetic Service, St Mary’s Hospital, Manchester, M13 0JH, UK, 2Department of Clinical Genetics, The Children’s Hospital at Westmead, Sydney, NSW, Australia, 3Royal Manchester Children’s Hospital, Manchester, UK, 4University Department of Ophthalmology, Manchester Royal Eye Hospital, Manchester, M13 9WH, UK, 5Department of Ophthalmology, The Hospital for Sick Children, Toronto, Ontario, Canada, 6Department of Ophthalmology, Royal Children’s Hospital, Melbourne, Victoria, Australia, 7MRC Human Genetics Unit, Western General Hospital, Edinburgh EH4 2XU, UK and 8Hopital Ophtalmique Jules Gonin, Center Hospitalier Universitaire Vaudois, Lausanne, Switzerland

Human congenital cataract and ocular anterior segment dysgenesis both demonstrate extensive genetic and phenotypic heterogeneity. We identified a family where ocular developmental abnormalities (cataract, anterior segment dysgenesis and microphthalmia) co-segregated with a translocation, t(5;16)(p15.3;q23.2), in both balanced and unbalanced forms. We hypothesized that this altered the expression of a gene of developmental significance in the human lens and ocular anterior segment. Cloning the 16q23.2 breakpoint demonstrated that it transected the genomic-control domain of MAF, a basic region leucine zipper (bZIP) transcription factor, first identified as an oncogene, which is expressed in vertebrate lens development and regulates the expression of the eye lens crystallins. The homozygous null mutant Maf mouse embryo demonstrates defective lens formation and microphthalmia. Through mutation screening of a panel of patients with hereditary congenital cataract we identified a mutation in MAF in a three-generation family with cataract, microcornea and iris coloboma. The mutation results in the substitution of an evolutionarily highly conserved arginine with a proline at residue 288 (R288P) in the basic region of the DNA-binding domain of MAF. Our findings further implicate MAF/Maf in mammalian lens development and highlight the role of the lens in anterior segment development. The 16q23.2 breakpoint transects the common fragile site, FRA16D, providing a molecular demonstration of a germline break in a common fragile site.

+ To whom correspondence should be addressed. Tel: +44 161 276 6264; Fax: +44 161 276 6145; Email: robynj@central.cmht.nwest.nhs.uk


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