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SLC4A11 mutations in Fuchs endothelial corneal dystrophy
Eranga N Vithana1, Patricio E Morgan, Vedam Ramprasad
1Singapore Eye Research Institute, 11 Third Hospital Avenue, Singapore 168751, Singapore. evithana@yahoo.co.uk
Human Molecular Genetics
|November 21, 2007
Summary
Heterozygous mutations in the SLC4A11 gene cause late-onset Fuchs endothelial corneal dystrophy (FECD). This discovery links SLC4A11 gene defects to FECD, impacting corneal endothelial cell viability.
Area of Science:
- Ophthalmology
- Genetics
- Cell Biology
Background:
- Endothelial (posterior) corneal dystrophies, including Fuchs endothelial corneal dystrophy (FECD), arise from primary endothelial dysfunction.
- Mutations in the SLC4A11 gene are known to cause recessive congenital hereditary endothelial dystrophy (CHED2).
Purpose of the Study:
- To investigate the role of heterozygous mutations in the SLC4A11 gene in the pathogenesis of late-onset FECD.
- To identify specific SLC4A11 mutations associated with FECD and analyze their functional consequences.
Main Methods:
- Screening of 89 FECD patients for mutations in the SLC4A11 gene.
- Analysis of mutation conservation, protein localization via immunoblotting, cell surface assays, and confocal immunolocalization.
- Comparison of identified mutations against ethnically matched controls.
Main Results:
- Four heterozygous SLC4A11 mutations (three missense, one deletion) were identified in FECD patients and absent in controls.
- Missense mutations affected highly conserved amino acid residues, suggesting deleterious effects.
- Mutant SLC4A11 proteins exhibited defective cell surface localization, indicating impaired function.
Conclusions:
- Heterozygous SLC4A11 mutations are associated with late-onset FECD.
- SLC4A11 haploinsufficiency and misfolded protein accumulation may contribute to FECD pathology.
- Reduced SLC4A11 levels negatively impact the long-term viability of corneal endothelial cells.
