Domain disruption and mutation of the bZIP transcription factor, MAF, associated with cataract, ocular anterior segment dysgenesis and coloboma
Domain disruption and mutation of the bZIP transcription factor, MAF, associated with cataract, ocular anterior segment dysgenesis and coloboma
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DOI：
10.1093/hmg/11.1.33
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发表时间：
2002-01-01
影响因子：
3.5
通讯作者：
Black, GCM
中科院分区：
文献类型：
--
作者：
Jamieson, RV;Perveen, R;Black, GCM
人类先天性白内障和眼前段发育不全都表现出广泛的遗传和表型异质性。我们确定了一个家族，其中眼发育异常（白内障，眼前段发育不良和小眼）共分离易位，t（5;16）（p15.3;q23.2），在平衡和不平衡的形式。我们假设这改变了人类透镜和眼前节中具有发育意义的基因的表达。克隆16 q23.2断裂点表明，它横切MAF的基因组控制结构域，MAF是一种碱性区亮氨酸拉链（bZIP）转录因子，首先被鉴定为癌基因，在脊椎动物透镜发育中表达，并调节眼透镜晶状体蛋白的表达。纯合子无效突变Maf小鼠胚胎表现出透镜形成缺陷和小眼畸形。通过对一组遗传性先天性白内障患者进行突变筛查，我们在一个三代患有白内障、小角膜和虹膜缺损的家族中发现了MAF突变。该突变导致MAF的DNA结合结构域的碱性区域中的残基288（R288 P）处进化上高度保守的精氨酸被脯氨酸取代。我们的研究结果进一步牵连MAF/Maf在哺乳动物透镜的发展和突出的作用，透镜在眼前段的发展。16q23.2断裂点横切常见的脆性位点FRA 16 D，提供了常见脆性位点中生殖系断裂的分子证据。
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.