Human Molecular Genetics Advance Access published online on May 4, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl120
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1 Department of Ophthalmology, Flinders University, Bedford Park, SA 5042, Australia
* To whom correspondence should be addressed. The Nance-Horan syndrome characterised 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 localisation 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 localises to the cell membrane of mammalian cells in a cell type dependent manner, and that it localises with the tight junction 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 post-natal 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 localised at tight junctions that has been implicated in congenital cataracts.
Received March 12, 2006
Revised April 29, 2006
Accepted April 29, 2006
Article
Nance-Horan Syndrome protein, NHS, associates with epithelial cell junctions
Shiwani Sharma 1 *,
Sharyn L. Ang 2,
Marie Shaw 3,
David A. Mackey 4,
Jozef Gécz 5,
John W. McAvoy 2,
and
Jamie E. Craig 1
2 Save Sight Institute, Sydney Eye Hospital, University of Sydney, Sydney 2001, Australia
3 Women's and Children's Hospital, North Adelaide, SA 5006, Australia
4 Centre for Eye Research Australia, University of Melbourne, Royal Victorian Ear and Eye Hospital, East Melbourne, Victoria 3002, Australia; Department of Paediatrics, University of Adelaide, Australia
5 Women's and Children's Hospital, North Adelaide, SA 5006, Australia; Department of Paediatrics, University of Adelaide, Australia
Shiwani Sharma, E-mail: shiwani.sharma{at}flinders.edu.au
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