Human Molecular Genetics Advance Access originally published online on May 4, 2006
Human Molecular Genetics 2006 15(12):1972-1983; doi:10.1093/hmg/ddl120
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Nance–Horan syndrome protein, NHS, associates with epithelial cell junctions
1Department of Ophthalmology, Flinders University, Bedford Park, SA 5042, Australia, 2Save Sight Institute, Sydney Eye Hospital, University of Sydney, Sydney 2001, Australia, 3Women's and Children's Hospital, North Adelaide, SA 5006, Australia, 4Centre for Eye Research Australia, Royal Victorian Ear and Eye Hospital, University of Melbourne, East Melbourne, Victoria 3002, Australia and 5Department of Paediatrics, University of Adelaide, Australia
* To whom correspondence should be addressed. Tel: +61 0882045892; Fax: +61 0882770899; Email: shiwani.sharma{at}flinders.edu.au
Received March 12, 2006; Accepted April 29, 2006
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.
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