title: Missense mutations in the sodium borate cotransporter SLC4A11 cause late-onset Fuchs corneal dystrophy.
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.
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: S Amer
authors.initials: SA
authors.lastname: Riazuddin
authors.forename: Eranga N
authors.initials: EN
authors.lastname: Vithana
authors.forename: Li-Fong
authors.initials: LF
authors.lastname: Seet
authors.forename: Yangjian
authors.initials: Y
authors.lastname: Liu
authors.forename: Amr
authors.initials: A
authors.lastname: Al-Saif
authors.forename: Li Wei
authors.initials: LW
authors.lastname: Koh
authors.forename: Yee Meng
authors.initials: YM
authors.lastname: Heng
authors.forename: Tin
authors.initials: T
authors.lastname: Aung
authors.forename: Danielle N
authors.initials: DN
authors.lastname: Meadows
authors.forename: Allen O
authors.initials: AO
authors.lastname: Eghrari
authors.forename: John D
authors.initials: JD
authors.lastname: Gottsch
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D027321:Anion Transport Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017920:Antiporters / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D016022:Case-Control Studies; D004247:DNA / Q000235:genetics; D005260:Female; D005642:Fuchs' Endothelial Dystrophy / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D005799:Genes, Dominant; D057809:HEK293 Cells; D006579:Heterozygote; D006801:Humans; D008297:Male; D008957:Models, Genetic; D016297:Mutagenesis, Site-Directed; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D010375:Pedigree; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D027321:Anion Transport Proteins; D017920:Antiporters; D050505:Mutant Proteins; D011994:Recombinant Proteins; C425809:SLC4A11 protein, human; D004247:DNA