title: SLC4A11 mutations in Fuchs endothelial corneal dystrophy.
abstract: The endothelial (posterior) corneal dystrophies, which result from primary endothelial dysfunction, include Fuchs endothelial corneal dystrophy (FECD), posterior polymorphous corneal dystrophy (PPCD) and congenital hereditary endothelial dystrophy (CHED). Mutations in SLC4A11 gene have been recently identified in patients with recessive CHED (CHED2). In this study, we show that heterozygous mutations in the SLC4A11 gene also cause late-onset FECD. Four heterozygous mutations [three missense mutations (E399K, G709E and T754M) and one deletion mutation (c.99-100delTC)] absent in ethnically matched controls were identified in a screen of 89 FECD patients. Missense mutations involved amino acid residues showing high interspecies conservation, indicating that mutations at these sites would be deleterious. Accordingly, immunoblot analysis, biochemical assay of cell surface localization and confocal immunolocalization showed that missense proteins encoded by the mutants were defective in localization to the cell surface. Our data suggests that SLC4A11 haploinsufficiency and gradual accumulation of the aberrant misfolded protein may play a role in FECD pathology and that reduced levels of SLC4A11 influence the long-term viability of the neural crest derived corneal endothelial cells.
authors.affiliation: Singapore Eye Research Institute, 11 Third Hospital Avenue, Singapore 168751, Singapore. evithana@yahoo.co.uk
authors.forename: Eranga N
authors.initials: EN
authors.lastname: Vithana
authors.forename: Patricio E
authors.initials: PE
authors.lastname: Morgan
authors.forename: Vedam
authors.initials: V
authors.lastname: Ramprasad
authors.forename: Donald T H
authors.initials: DT
authors.lastname: Tan
authors.forename: Victor H K
authors.initials: VH
authors.lastname: Yong
authors.forename: Divya
authors.initials: D
authors.lastname: Venkataraman
authors.forename: Anandalakshmi
authors.initials: A
authors.lastname: Venkatraman
authors.forename: Gary H F
authors.initials: GH
authors.lastname: Yam
authors.forename: Soumittra
authors.initials: S
authors.lastname: Nagasamy
authors.forename: Ricky W K
authors.initials: RW
authors.lastname: Law
authors.forename: Rama
authors.initials: R
authors.lastname: Rajagopal
authors.forename: Chi P
authors.initials: CP
authors.lastname: Pang
authors.forename: Govindsamy
authors.initials: G
authors.lastname: Kumaramanickevel
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Casey
authors.forename: Tin
authors.initials: T
authors.lastname: Aung
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D027321:Anion Transport Proteins / Q000235:genetics*; D017920:Antiporters / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D015331:Cohort Studies; D017124:Conserved Sequence; D005260:Female; D016368:Frameshift Mutation; D005642:Fuchs' Endothelial Dystrophy / Q000175:diagnosis / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D017353:Gene Deletion; D005820:Genetic Testing; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D017386:Sequence Homology, Amino Acid; D013223:Statistics as Topic
chemical_list: D027321:Anion Transport Proteins; D017920:Antiporters; C425809:SLC4A11 protein, human