title: Biosynthetic and functional defects in newly identified SLC4A11 mutants and absence of COL8A2 mutations in Fuchs endothelial corneal dystrophy.
abstract: Late-onset Fuchs endothelial corneal dystrophy (FECD) shows genetic heterogeneity. Identification of SLC4A11 as a candidate gene for congenital hereditary endothelial dystrophy with similar corneal endothelial defects as FECD and reduced mRNA expression of SLC4A11 in the endothelium of FECD cases suggested that this gene may also be involved in pathogenesis of FECD. Mutations in SLC4A11 give rise to SLC4A11 protein marked by retention in the endoplasmic reticulum as a result of mis-folding. We screened 45 sporadic late-onset, 4 early-onset FECD patients and an early-onset autosomal dominant FECD family. We identified three previously unreported missense mutations: c.719G>C (p.W240S), c.1519G>A (p.V507I) and c.1304C>T (p.T434I) in unrelated individuals. These SLC4A11 mutants, expressed in HEK293 cells, had defects in either their cell surface expression or functional activity (rate of osmotically driven water flux). SLC4A11 mutations contribute to 11% (5/45) of sporadic late-onset FECD in the cohort studied. COL8A2, which causes some cases of early-onset FECD, was also screened in this cohort. No mutations were identified in COL8A2, in neither the late-onset cohort nor the early-onset family, suggesting genetic heterogeneity in this FECD family.
authors.affiliation: SNONGC Department of Genetics and Molecular Biology, Vision Research Foundation, Chennai, India.
authors.forename: Nagasamy
authors.initials: N
authors.lastname: Soumittra
authors.affiliation: Membrane Protein Disease Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Sampath K
authors.initials: SK
authors.lastname: Loganathan
authors.affiliation: SNONGC Department of Genetics and Molecular Biology, Vision Research Foundation, Chennai, India.
authors.forename: Dharanija
authors.initials: D
authors.lastname: Madhavan
authors.affiliation: SNONGC Department of Genetics and Molecular Biology, Vision Research Foundation, Chennai, India.
authors.forename: Vedam L
authors.initials: VL
authors.lastname: Ramprasad
authors.affiliation: SNONGC Department of Genetics and Molecular Biology, Vision Research Foundation, Chennai, India.
authors.forename: Tharigopala
authors.initials: T
authors.lastname: Arokiasamy
authors.affiliation: SNONGC Department of Genetics and Molecular Biology, Vision Research Foundation, Chennai, India.
authors.forename: Sundaram
authors.initials: S
authors.lastname: Sumathi
authors.affiliation: SNONGC Department of Genetics and Molecular Biology, Vision Research Foundation, Chennai, India.
authors.forename: Thirumalai
authors.initials: T
authors.lastname: Karthiyayini
authors.affiliation: Cornea Services, Medical Research Foundation, Sankara Nethralaya, Chennai, India.
authors.forename: Sudhir R
authors.initials: SR
authors.lastname: Rachapalli
authors.affiliation: SNONGC Department of Genetics and Molecular Biology, Vision Research Foundation, Chennai, India.
authors.forename: Govindasamy
authors.initials: G
authors.lastname: Kumaramanickavel
authors.affiliation: Membrane Protein Disease Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Casey
authors.affiliation: Cornea Services, Medical Research Foundation, Sankara Nethralaya, Chennai, India.
authors.forename: Rama
authors.initials: R
authors.lastname: Rajagopal
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D027321:Anion Transport Proteins / Q000235:genetics* / Q000378:metabolism; D017920:Antiporters / Q000235:genetics* / Q000378:metabolism; D015331:Cohort Studies; D024102:Collagen Type VIII / Q000235:genetics* / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D005642:Fuchs' Endothelial Dystrophy / Q000235:genetics*; D018740:Genetic Heterogeneity; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D021381:Protein Transport; D055815:Young Adult
chemical_list: D027321:Anion Transport Proteins; D017920:Antiporters; C443712:COL8A2 protein, human; D024102:Collagen Type VIII; C425809:SLC4A11 protein, human