Genetics of the corneal endothelial dystrophies: an evidence-based review

Abstract

Purpose To provide an evidenced-based review of the genetic basis of the corneal endothelial dystrophies. Methods A review of the English-language peer-reviewed literature describing the molecular genetic basis of posterior polymorphous corneal dystrophy (PPCD), congenital hereditary endothelial dystrophy (CHED), Fuchs endothelial corneal dystrophy (FECD) and X-linked endothelial corneal dystrophy (XECD) was performed. Results Mutations in several genes have been implicated as playing a pathogenic role in the corneal endothelial dystrophies: VSX1 mutations in PPCD1; COL8A2 mutations in PPCD2 and FECD; ZEB1 mutations in PPCD3 and FECD; and SLC4A11 mutations in CHED2 and FECD. However, linkage, association and familial segregation analyses support a role of only one gene in each corneal endothelial dystrophy: ZEB1 in PPCD3, SLC4A11 in CHED2 and COL8A2 in FECD (early onset). In addition, insufficient evidence exists to consider the autosomal dominant form of CHED (CHED1) as distinct from PPCD. Conclusions An accurate classification of the corneal endothelial dystrophies requires a critical review of the evidence to support the role of each suggested chromosomal locus, gene and genetic mutation associated with a corneal endothelial dystrophy. Only after the separation of evidence from opinion is performed can a critical examination of the molecular pathways that lead to endothelial dysfunction in each of these disorders be accurately performed.

Human SLC4A11 Is a Novel NH3/H+ Co-transporter

“…Fig. 1B shows that NH 4 Cl application caused a rapid pH i rise in both SLC4A11-PS120 and EV-PS120 (labeled a) due to NH 3 gas diffusion and intracellular production of NH 4 ϩ and OH Ϫ (17). In phase b, pH i plateaued in EV-PS120 cells (Ϫ0.01 Ϯ 0.02 ⌬pH/⌬min), whereas a significant acidification occurred in SLC4A11-PS120 cells.…”

“…1A). Employing these two colonies of SLC4A11-PS120 cells, we examined the pH i response to extracellular 10 mM NH 4 Cl, relative to EV. Fig.…”

“…The bar graph on the right shows the density quantification of HA-SLC4A11 normalized to ␣-tubulin. B, pH i response to 10 mM NH 4 Cl pulse in EV and SLC4A11 PS120 cells. Each trace is the average of n ϭ 5 EV, n ϭ 3 SLC4A11 Col4, and n ϭ 3 SLC4A11 Col12, respectively.…”

“…Several SLC4A11 mutations have been implicated in the pathogenesis of Fuchs endothelial corneal dystrophy, congenital hereditary endothelial dystrophy, and Harboyan syndrome (corneal dystrophy with perceptive deafness) (4,5). Three strains of SLC4A11 knock-out mice exhibited variable phenotypes that included corneal endothelial dysfunction, perceptive deafness, and polyuria or low urine osmolality (6 -8).…”

“…To test this hypothesis, we generated two Na ϩ /H ϩ exchanger (NHE)-deficient Chinese hamster PS120 fibroblast cell lines stably expressing high or low levels of SLC4A11. Employing whole-cell patch clamp electrophysiology, we found that NH 4 Cl generated significant EIPA-and 4, 4Ј-diisothiocyanatostilbene-2,2Ј-disulfonic acid (DIDS)-insensitive currents in SLC4A11-expressing PS120 cells. These currents were sensitive to [NH 3 ] and [H atively unaffected by Na ϩ , K ϩ , or Cl Ϫ at physiological pH.…”