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SLC4A11 encodes a sodium borate–like transporter critical for corneal endothelial pump function. Heterozygous mutations in SLC4A11 have been implicated in late-onset Fuchs endothelial corneal dystrophy (FECD), a progressive disorder characterized by endothelial cell loss, guttae formation, and corneal edema. FECD typically presents in the fifth to seventh decade, leading to glare, reduced visual acuity, and the need for corneal transplantation. While homozygous variants cause congenital hereditary endothelial dystrophy (CHED), the dominant FECD phenotype arises from haploinsufficiency or dominant-negative effects of mutant alleles. Genetic screening across multiple cohorts has established SLC4A11 as a bona fide FECD gene, supporting its integration into diagnostic panels and therapeutic research.
Genetic evidence for SLC4A11 in FECD includes heterozygous variants identified in 89 unrelated patients ([PMID:18024964]) and seven novel missense alleles in 192 additional sporadic and familial cases ([PMID:20848555]), totaling over 280 probands. Four distinct mutation classes were observed: missense, small deletions, splice‐site, and frameshift. One representative FECD allele, c.2213C>T (p.Thr738Met) ([PMID:18024964]), disrupts a highly conserved residue. Segregation analysis in a three-generation pedigree demonstrated co-segregation of a heterozygous missense mutation with FECD in one additional affected relative ([PMID:20848555]). No recurrent founder variants have been described, reflecting allelic heterogeneity.
Functional studies reveal that FECD‐associated SLC4A11 mutants often misfold or impair plasma membrane localization, leading to reduced NH₃-stimulated H⁺ conductance. Immunoblot and confocal analyses showed defective cell surface trafficking for several missense alleles. Electrophysiological assays confirmed decreased H⁺ flux in mutants, supporting a loss-of-function mechanism. Rescue experiments using the NSAID glafenine partially restored mutant trafficking and water-flux activity in HEK293 cells ([PMID:26641551]). Similarly, diclofenac eye drops corrected cell surface expression and water transport of SLC4A11 mutants, suggesting therapeutic potential ([PMID:30140924]).
Dominant inheritance may be explained by mutant–wild-type oligomerization: FECD alleles form heteromers with wild-type SLC4A11, reducing overall transporter processing and activity. Oligomerization assays revealed impaired dimer assembly and dominant-negative effects of FECD mutants on wild-type trafficking. Animal and cellular knock-out models recapitulate endothelial dysfunction and edema, further corroborating pathogenicity. No conflicting evidence has refuted SLC4A11’s role in FECD, although rare studies in specific populations have reported benign variants.
Integration of genetic and functional data supports a Strong gene–disease association. The combination of >280 unrelated probands, segregation in multi-generational families, concordant loss-of-function assays, and rescue by small molecules meets ClinGen criteria for a Strong classification. Genetic testing for SLC4A11 variants enhances diagnostic precision, and NSAID–based therapies hold promise for personalized treatment. Key Take-home: Heterozygous SLC4A11 mutations cause autosomal dominant FECD through haploinsufficiency and dominant-negative mechanisms, with actionable functional rescue by repurposed drugs.
Gene–Disease AssociationStrongOver 280 probands, segregation in 3-generation pedigree, concordant functional and rescue studies Genetic EvidenceStrong
Functional EvidenceModerateMutant misfolding and impaired H+ transport in cellular assays; rescue by glafenine and diclofenac |