SLC4A11 mutations in Fuchs endothelial corneal dystrophy

Abstract

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.

Slc4a11 Gene Disruption in Mice

“…Our results demonstrate that Slc4a11 Ϫ/Ϫ mice are an important new model system for addressing the underlying pathophysiology of the sensory abnormalities in patients with NaBC1 mutations (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). Prior to the current study, there was no information regarding the expression of NaBC1 protein in the inner ear.…”

“…Therefore, the corneal phenotype in Slc4A11 Ϫ/Ϫ mice differ significantly from the severe corneal phenotype described in patients with mutations in the SLC4A11 gene (5)(6)(7)(8)(9)(10)(11)(12)(13)(14).…”

“…Heterozygous single nucleotide polymorphisms for SLC4A11 have also been identified in Chinese and Indian patients with Fuchs dystrophy, the most common dystrophic cause of endothelial failure in the adult population. However, the mutations in the SLC4A11 gene may only be responsible for about 5% of Fuchs cases, and causality has not yet been firmly established (13). No patients with SLC4A11 mutations have been described with isolated hearing abnormalities.…”

“…Mutations in the SLC4A11 gene are responsible for corneal hereditary dystrophy type 2 (CHED2) 4 and Harboyan syndrome (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). In addition to corneal dystrophy, patients with Harboyan syndrome have perceptive hearing loss and nystagmus (7,14).…”

What does the future hold for the treatment of Fuchs endothelial dystrophy; will ‘keratoplasty’ still be a valid procedure?

“…When we take a look at what is currently known about the genetic background of FECD, mutated genes have only been found in inherited cases and some sporadic cases. For instance, FECD has been associated with rare mutations in SLC4A11 (solute carrier family 4, sodium borate transporter, member 11), 18,19 TCF4 (transcription factor 4), [20][21][22][23][24][25] TCF8 (transcription factor 8), 26,27 CLU (clusterin), 24 and LOXHD1 (lipoxygenase homology domains 1). 28 These mutations, however, are not identified in every cohort of FECD patients.…”