Missense mutations in the sodium borate cotransporter SLC4A11 cause late-onset Fuchs corneal dystrophya

Abstract

Homozygous mutations in the Borate Cotransporter SLC4A11 cause two early-onset corneal dystrophies: congenital hereditary endothelial dystrophy (CHED) and Harboyan syndrome. More recently, four sporadic patients with late-onset Fuchs corneal dystrophy (FCD), a common age-related disorder, were also reported to harbor heterozygous mutations at this locus. We therefore tested the hypothesis that SLC4A11 contributes to FCD and asked whether mutations in SLC4A11 are responsible for familial cases of late-onset FCD. We sequenced SLC4A11 in 192 sporadic and small nuclear late-onset FCD families and found seven heterozygous missense novel variations that were absent from ethnically matched controls. Familial data available for one of these mutations showed segregation under a dominant model in a three-generational family. In silico analyses suggested that most of these substitutions are intolerant, whereas biochemical studies of the mutant protein indicated that these alleles impact the localization and/or posttranslational modification of the protein. These results suggest that heterozygous mutations in SLC4A11 are modest contributors to the pathogenesis of adult FCD, suggesting a causality continuum between FCD and CHED. Taken together with a recent model between FCD and yet another early onset corneal dystrophy, PPCD, our data suggest a shared pathomechanism and genetic overlap across several corneal dystrophies.

Association of TCF4 and CLU polymorphisms with Fuchs’ endothelial dystrophy and implication of CLU and TGFBI proteins in the disease process

“…16,17 The SLC4A11 (solute carrier family 4, sodium borate transporter, member 11) mutations cause sporadic and familial late-onset FED. 8,18 Mutations identified in the COL8A2, ZEB1 and SLC4A11 genes account for a small number of FED cases. Furthermore, four chromosomal loci are associated with late-onset FED, but the causative genes remain to be identified.…”

Involvement of ZEB1 and Snail1 in excessive production of extracellular matrix in Fuchs endothelial corneal dystrophy

“…Late-onset classic FECD can either be familial or sporadic, with an onset typically occurring after the age of 40 years. Although mutations in the zinc-finger E-box binding homeobox 1 (ZEB1) gene 6,7 and the solute carrier family 4 member 11 (SLC4A11) gene 8,9 have been reported as causative of late-onset FECD, these mutations were only rarely observed in the patient population. On the other hand, Baratz et al 10 reported that a genome-wide association study (GWAS) revealed a highly significant association between single nucleotide polymorphisms in transcription factor 4 genes (TCF4) in classic late-onset FECD.…”

Detailed Assessment of Renal Function in a Proband with Harboyan Syndrome Caused by a Novel Homozygous <b><i>SLC4A11 </i></b>Nonsense Mutation

“…Mutations within SLC4A11 have been associated in humans with the development of both recessive and dominant corneal endothelial dystrophies [3,4,5,17] as well as recessive Harboyan syndrome presenting as congenital hereditary endothelial dystrophy with sensorineural deafness [2]. …”

“…In addition, heterozygous missense SLC4A11 mutations have been identified in a subset of patients with dominantly inherited late-onset Fuchs' endothelial corneal dystrophy (FECD4, OMIM No. 613268) [4,5]. …”