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Oligomerization of SLC4A11 protein and the severity of FECD and CHED2 corneal dystrophies caused by SLC4A11 mutations
Author(s) -
Vilas Gonzalo L.,
Loganathan Sampath K.,
Quon Anita,
Sundaresan Periasamy,
Vithana Eranga N.,
Casey Joseph
Publication year - 2012
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21655
Subject(s) - missense mutation , mutant , biology , mutant protein , microbiology and biotechnology , hek 293 cells , mutation , genetics , gene
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. Hum Mutat 33:419–428, 2012. © 2011 Wiley Periodicals, Inc.