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

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...

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Bibliographic Details
Published in:Human mutation 2010-11, Vol.31 (11), p.1261-1268
Main Authors: Riazuddin, S. Amer, Vithana, Eranga N., Seet, Li-Fong, Liu, Yangjian, Al-Saif, Amr, Koh, Li Wei, Heng, Yee Meng, Aung, Tin, Meadows, Danielle N., Eghrari, Allen O., Gottsch, John D., Katsanis, Nicholas
Format: Article
Language:English
Subjects:
Adult
Amino Acid Substitution
Anion Transport Proteins - chemistry
Anion Transport Proteins - genetics
Anion Transport Proteins - metabolism
anterior segment
Antiporters - chemistry
Antiporters - genetics
Antiporters - metabolism
Base Sequence
Case-Control Studies
corneal endothelium
DNA - genetics
Female
Fuchs corneal dystrophy
Fuchs' Endothelial Dystrophy - etiology
Fuchs' Endothelial Dystrophy - genetics
Fuchs' Endothelial Dystrophy - metabolism
Genes, Dominant
HEK293 Cells
Heterozygote
Humans
Male
Models, Genetic
Mutagenesis, Site-Directed
Mutant Proteins - chemistry
Mutant Proteins - genetics
Mutant Proteins - metabolism
Mutation, Missense
Pedigree
Protein Processing, Post-Translational
Protein Stability
Recombinant Proteins - chemistry
Recombinant Proteins - genetics
Recombinant Proteins - metabolism
SLC4A11
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Summary: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.
ISSN:1059-7794
1098-1004
1098-1004
DOI:10.1002/humu.21356