title: Oligomerization of SLC4A11 protein and the severity of FECD and CHED2 corneal dystrophies caused by SLC4A11 mutations.
abstract: Mutations in the SLC4A11 gene, which encodes a plasma membrane borate transporter, cause recessive congenital hereditary endothelial corneal dystrophy type 2 (CHED2), corneal dystrophy and perceptive deafness (Harboyan syndrome), and dominant late-onset Fuchs endothelial corneal dystrophy (FECD). We analyzed missense SLC4A11 mutations identified in FECD and CHED2 patients and expressed in transfected HEK 293 cells. Chemical cross-linking and migration in nondenaturing gels showed that SLC4A11 exists as a dimer. Furthermore, co-immunoprecipitation of epitope-tagged proteins revealed heteromeric interactions between wild-type (WT) and mutant SLC4A11 proteins. When expressed alone, FECD- and CHED2-causing mutant SLC4A11 proteins are primarily retained intracellularly. Co-expression with WT SLC4A11 partially rescued the cell surface trafficking of CHED2 mutants, but not FECD mutants. CHED2 alleles of SLC4A11 did not affect cell surface processing of WT SLC4A11. In contrast, FECD mutants reduced WT cell surface processing efficiency, consistent with dominant inheritance of FECD. The reduction in movement of WT protein to the cell surface caused by FECD SLC4A11 helps to explain the dominant inheritance of this disorder. Similarly, the failure of CHED2 mutant SLC4A11 to affect the processing of WT protein, explains the lack of symptoms found in CHED2 carriers and the recessive inheritance of the disorder.
authors.affiliation: Membrane Protein Disease Research Group, Department of Physiology, School of Molecular and Systems Medicine, University of Alberta, Edmonton, Canada.
authors.forename: Gonzalo L
authors.initials: GL
authors.lastname: Vilas
authors.forename: Sampath K
authors.initials: SK
authors.lastname: Loganathan
authors.forename: Anita
authors.initials: A
authors.lastname: Quon
authors.forename: Periasamy
authors.initials: P
authors.lastname: Sundaresan
authors.forename: Eranga N
authors.initials: EN
authors.lastname: Vithana
authors.forename: Joseph
authors.initials: J
authors.lastname: Casey
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D000818:Animals; D027321:Anion Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D017920:Antiporters / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D003317:Corneal Dystrophies, Hereditary; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004285:Dogs; D005642:Fuchs' Endothelial Dystrophy / Q000235:genetics* / Q000378:metabolism*; D015870:Gene Expression; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D009154:Mutation; D055503:Protein Multimerization / Q000187:drug effects; D013388:Succinimides / Q000494:pharmacology
chemical_list: D027321:Anion Transport Proteins; D017920:Antiporters; D003432:Cross-Linking Reagents; C425809:SLC4A11 protein, human; D013388:Succinimides; C035759:3,3'-dithiobis(sulfosuccinimidyl propionate)