NovelSLC4A11mutations in patients with recessive congenital hereditary endothelial dystrophy (CHED2)

Abstract

Autosomal recessive congenital hereditary endothelial dystrophy (CHED2) is a severe and rare corneal disorder that presents at birth or shortly thereafter, characterized by corneal opacification and nystagmus. Recently the gene for CHED2 was identified and seven different mutations in the SLC4A11 gene were reported. Here, we report seven novel mutations and two previously identified mutations in families from India and the United Kingdom with recessive CHED. The novel changes include two nonsense (p.Trp240X; p.Gln800X) three missense (p.Glu143Lys; p.Cys386Arg; p.Arg755Trp) and two splice site mutations (c.2240+1G>A; c.2437-1G>A). Interestingly, the c.2398C>T (p.Gln800X) and c.2437-1G>A identified in two affected siblings represent the first compound heterozygous mutations in the SLC4A11 gene.

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

“…As such, SLC4A11 should be considered when examining ammonia: H ϩ balance along with other recently identified NH 3 channels/transporters, namely selected AQPs (AQP8, AQP3, AQP7, AQP9, and AQP10) (14), Amt proteins, methylamine permease (22), and rhesus protein (23). In addition, our findings may also provide insight into the pathophysiology of corneal endothelial dystrophy (24,25) and an explanation for altered renal function in SLC4A11 knock-out mice (7,8).…”

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).…”

“…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).…”

SLC4A11 Prevents Osmotic Imbalance Leading to Corneal Endothelial Dystrophy, Deafness, and Polyuria

“…Expression of the CHED2 A269V point mutation and the F672del deletion (27,28) in Madin-Darby canine kidney epithelial cells resulted in aberrant subcellular localizations. Both mutant proteins resided in the cytoplasm and did not demonstrate the typical membrane localization characteristic for wild type SLC4A11 (supplemental Fig.…”