Sharma Shiwani, Ang Sharyn L, Shaw Marie, Mackey David A, Gécz Jozef, McAvoy John W, Craig Jamie E
Department of Opthalmology, Flinders University, Australia.
Hum Mol Genet. 2006 Jun 15;15(12):1972-83. doi: 10.1093/hmg/ddl120. Epub 2006 May 4.
Nance-Horan syndrome, characterized by congenital cataracts, craniofacial, dental abnormalities and mental disturbances, is an X-linked disorder with significant phenotypic heterogeneity. Affected individuals have mutations in the NHS (Nance-Horan syndrome) gene typically resulting in premature truncation of the protein. This report underlines the complexity of the regulation of the NHS gene that transcribes several isoforms. We demonstrate the differential expression of the two NHS isoforms, NHS-A and NHS-1A, and differences in the subcellular localization of the proteins encoded by these isoforms. This may in part explain the pleiotropic features of the syndrome. We show that the endogenous and exogenous NHS-A isoform localizes to the cell membrane of mammalian cells in a cell-type-dependent manner and that it co-localizes with the tight junction (TJ) protein ZO-1 in the apical aspect of cell membrane in epithelial cells. We also show that the NHS-1A isoform is a cytoplasmic protein. In the developing mammalian lens, we found continuous expression of NHS that became restricted to the lens epithelium in pre- and postnatal lens. Consistent with the in vitro findings, the NHS-A isoform associates with the apical cell membrane in the lens epithelium. This study suggests that disturbances in intercellular contacts underlie cataractogenesis in the Nance-Horan syndrome. NHS is the first gene localized at TJs that has been implicated in congenital cataracts.
南斯-霍兰综合征以先天性白内障、颅面及牙齿异常和精神障碍为特征，是一种具有显著表型异质性的X连锁疾病。受影响个体的NHS（南斯-霍兰综合征）基因发生突变，通常导致蛋白质过早截断。本报告强调了转录多种异构体的NHS基因调控的复杂性。我们证明了两种NHS异构体NHS-A和NHS-1A的差异表达，以及这些异构体编码的蛋白质在亚细胞定位上的差异。这可能部分解释了该综合征的多效性特征。我们表明，内源性和外源性NHS-A异构体以细胞类型依赖的方式定位于哺乳动物细胞的细胞膜，并且在上皮细胞细胞膜顶端与紧密连接（TJ）蛋白ZO-1共定位。我们还表明，NHS-1A异构体是一种细胞质蛋白。在发育中的哺乳动物晶状体中，我们发现NHS持续表达，在出生前和出生后的晶状体中局限于晶状体上皮。与体外研究结果一致，NHS-A异构体与晶状体上皮细胞的顶端细胞膜相关联。这项研究表明，细胞间接触的紊乱是南斯-霍兰综合征白内障形成的基础。NHS是第一个定位于紧密连接且与先天性白内障有关的基因。
