SLC4A11 mutations in Fuchs endothelial corneal dystrophy

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...

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Bibliographic Details
Published in:	Human molecular genetics 2008-03, Vol.17 (5), p.656-666
Main Authors:	Vithana, Eranga N., Morgan, Patricio E., Ramprasad, Vedam, Tan, Donald T.H., Yong, Victor H.K, Venkataraman, Divya, Venkatraman, Anandalakshmi, Yam, Gary H.F., Nagasamy, Soumittra, Law, Ricky W.K., Rajagopal, Rama, Pang, Chi P., Kumaramanickevel, Govindsamy, Casey, Joseph R., Aung, Tin
Format:	Article
Language:	eng
Subjects:	Adult Aged Aged, 80 and over Amino Acid Sequence Amino Acid Substitution Anion Transport Proteins - genetics Antiporters - genetics Asian Continental Ancestry Group - genetics Biological and medical sciences Case-Control Studies Cohort Studies Conserved Sequence Female Frameshift Mutation Fuchs' Endothelial Dystrophy - diagnosis Fuchs' Endothelial Dystrophy - etiology Fuchs' Endothelial Dystrophy - genetics Fuchs' Endothelial Dystrophy - pathology Fundamental and applied biological sciences. Psychology Gene Deletion Genetic Testing Genetics of eukaryotes. Biological and molecular evolution Heterozygote Humans Male Middle Aged Models, Molecular Molecular and cellular biology Molecular Sequence Data Mutation, Missense Sequence Homology, Amino Acid Statistics as Topic
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Summary:	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.
ISSN:	0964-6906 1460-2083