SLC4A11 – Congenital Hereditary Endothelial Dystrophy of Cornea (CHED2)

Autosomal recessive congenital hereditary endothelial dystrophy (CHED2) is characterized by bilateral corneal clouding and nystagmus presenting at or shortly after birth. CHED2 is caused by biallelic loss-of-function variants in SLC4A11 ([HGNC:16438]), encoding a membrane transporter critical for corneal endothelial fluid homeostasis (PMID:17679935; PMID:17397048). Affected individuals often exhibit early-onset edema leading to vision impairment, and misdiagnoses as primary congenital glaucoma have been reported in infancy ([PMID:36833236]).

Genetic evidence for SLC4A11–CHED2 includes seven families with novel missense and splice site variants in the initial report of recessive CHED2 (PMID:17397048), followed by mutational screening in 42 families identifying 27 distinct mutations—including 13 missense, 5 nonsense, 7 deletions, and 1 splice variant—in 49 affected individuals (PMID:17679935). Segregation of homozygous or compound heterozygous alleles in consanguineous and outbred pedigrees further supports pathogenicity.

The variant spectrum encompasses missense (e.g., c.2024A>C (p.Glu675Ala) ([PMID:36833236])), nonsense (e.g., p.Trp224Ter), frameshift (e.g., c.859_862delGAGAinsCCT (p.Glu287fsTer21) ([PMID:17262014])), and splice site changes. The c.2024A>C (p.Glu675Ala) allele appears as a founder mutation in Pakistani CHED2 families and was associated with secondary glaucoma, underscoring the need for genomic screening to avoid misdiagnosis.

Functional assays demonstrate that CHED2-associated SLC4A11 mutants are misfolded, retained in the endoplasmic reticulum, and exhibit markedly reduced water and H+ transport activity. Rescue of certain ER-retained mutants by low-temperature incubation or pharmacological chaperones (e.g., glafenine) restores cell surface expression and transporter function, confirming a loss-of-function mechanism (PMID:24916015).

Mechanistically, SLC4A11 deficiency leads to impaired endothelial pump function and corneal edema. Concordant in vitro models and the reproducible association of biallelic loss-of-function variants with CHED2 establish a definitive gene–disease relationship. Early molecular diagnosis informs prognosis, guides genetic counseling, and enables potential therapeutic interventions such as folding-correction therapy.

Key Take-home: Biallelic pathogenic SLC4A11 variants cause AR-CHED2 via loss of transporter function, and genetic testing is essential for accurate diagnosis and management.

References

• Human mutation • 2007 • Novel SLC4A11 mutations in patients with recessive congenital hereditary endothelial dystrophy (CHED2). PMID:17397048
• Molecular Vision • 2007 • Mutational spectrum of the SLC4A11 gene in autosomal recessive congenital hereditary endothelial dystrophy. PMID:17679935
• Genes • 2023 • Exome Sequencing Reveals SLC4A11 Variant Underlying Congenital Hereditary Endothelial Dystrophy (CHED2) Misdiagnosed as Congenital Glaucoma. PMID:36833236
• Molecular Vision • 2007 • Genetic analysis of two Indian families affected with congenital hereditary endothelial dystrophy: two novel mutations in SLC4A11. PMID:17262014
• Human Mutation • 2014 • Corneal dystrophy-causing SLC4A11 mutants: suitability for folding-correction therapy. PMID:24916015

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