Jamieson Robyn V, Perveen Rahat, Kerr Bronwyn, Carette Martin, Yardley Jill, Heon Elise, Wirth M Gabriela, van Heyningen Veronica, Donnai Di, Munier Francis, Black Graeme C M
University Department of Medical Genetics and Regional Genetic Service, St Mary's Hospital, Manchester, M13 0JH, UK.
Hum Mol Genet. 2002 Jan 1;11(1):33-42. doi: 10.1093/hmg/11.1.33.
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.
人类先天性白内障和眼前节发育异常均表现出广泛的遗传和表型异质性。我们鉴定了一个家族，其中眼部发育异常（白内障、眼前节发育异常和小眼症）以平衡和不平衡形式与一种易位，即t(5;16)(p15.3;q23.2) 共同分离。我们推测这改变了在人类晶状体和眼前节中具有发育意义的一个基因的表达。克隆16q23.2断点表明它切断了MAF的基因组控制域，MAF是一种碱性区域亮氨酸拉链（bZIP）转录因子，最初被鉴定为一种癌基因，在脊椎动物晶状体发育中表达并调节眼晶状体晶状体蛋白的表达。纯合无效突变体Maf小鼠胚胎表现出晶状体形成缺陷和小眼症。通过对一组遗传性先天性白内障患者进行突变筛查，我们在一个患有白内障、小角膜和虹膜缺损的三代家族中鉴定出MAF中的一个突变。该突变导致MAF DNA结合域碱性区域第288位残基（R288P）处一个进化上高度保守的精氨酸被脯氨酸取代。我们的发现进一步表明MAF/Maf在哺乳动物晶状体发育中的作用，并突出了晶状体在眼前节发育中的作用。16q23.2断点切断了常见脆性位点FRA16D，提供了一个常见脆性位点种系断裂的分子证据。
