Human Molecular Genetics Advance Access originally published online on November 16, 2007
Human Molecular Genetics 2008 17(5):656-666; doi:10.1093/hmg/ddm337
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SLC4A11 mutations in Fuchs endothelial corneal dystrophy
1 Singapore Eye Research Institute, 11 Third Hospital Avenue, Singapore 168751, Singapore 2 Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore 3 Department of Physiology and 4 Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada 5 ONGC Department of Genetics & Molecular biology, Vision Research Foundation and 6 Department of Cornea, Medical Research Foundation, Sankara Nethralaya, 18 College Road, Chennai 600 006, Tamilnadu, India 7 Singapore National Eye Centre, Singapore 168751, Singapore and 8 Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong Eye Hospital, 147K Argyl Street, Kowloon, Hong Kong
* To whom correspondence should be addressed. Tel: +65 6322 4542; Fax: +65 6322 4599; Email: evithana{at}yahoo.co.uk, eranga.n.v{at}seri.com.sg
Received July 12, 2007; Revised October 18, 2007; Accepted November 14, 2007
The endothelial (posterior) corneal dystrophies, which result from primary endothelial dysfunction, include Fuchs endothelial corneal dystrophy (FECD), posterior polymorphous corneal dystrophy (PPCD) and congenital hereditary endothelial dystrophy (CHED). Mutations in SLC4A11 gene have been recently identified in patients with recessive CHED (CHED2). In this study, we show that heterozygous mutations in the SLC4A11 gene also cause late-onset FECD. Four heterozygous mutations [three missense mutations (E399K, G709E and T754M) and one deletion mutation (c.99-100delTC)] absent in ethnically matched controls were identified in a screen of 89 FECD patients. Missense mutations involved amino acid residues showing high interspecies conservation, indicating that mutations at these sites would be deleterious. Accordingly, immunoblot analysis, biochemical assay of cell surface localization and confocal immunolocalization showed that missense proteins encoded by the mutants were defective in localization to the cell surface. Our data suggests that SLC4A11 haploinsufficiency and gradual accumulation of the aberrant misfolded protein may play a role in FECD pathology and that reduced levels of SLC4A11 influence the long-term viability of the neural crest derived corneal endothelial cells.
The authors wish it to be known that, in their opinion, the first 2 authors should be regarded as joint First Authors.