Missense mutations in the sodium borate co-transporter SLC4A11 cause late onset Fuchs corneal dystrophy
Homozygous mutations in the sodium-bicarbonate transporter 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,...
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Published in | Human mutation Vol. 31; no. 11; pp. 1261 - 1268 |
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Main Authors | , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
14.10.2010
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Online Access | Get full text |
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Summary: | Homozygous mutations in the sodium-bicarbonate transporter
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, while biochemical studies of the mutant protein indicated that these alleles impact the localization and/or post-translational modification of the protein. These results suggest that heterozygous 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. |
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ISSN: | 1059-7794 1098-1004 |
DOI: | 10.1002/humu.21356 |