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R125H, W240S, C386R, and V507I SLC4A11 mutations associated with corneal endothelial dystrophy affect the transporter function but not trafficking in PS120 cells.
- Source :
-
Experimental eye research [Exp Eye Res] 2019 Mar; Vol. 180, pp. 86-91. Date of Electronic Publication: 2018 Dec 14. - Publication Year :
- 2019
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Abstract
- SLC4A11 mutations are associated with Fuchs' endothelial corneal dystrophy (FECD), congenital hereditary endothelial dystrophy (CHED) and Harboyan syndrome (endothelial dystrophy with auditory deficiency). Mice with genetically ablated Slc4a11 recapitulate CHED, exhibiting significant corneal edema and altered endothelial morphology. We recently demonstrated that SLC4A11 functions as an NH <subscript>3</subscript> sensitive, electrogenic H <superscript>+</superscript> transporter. Here, we investigated the properties of five clinically relevant SLC4A11 mutants: R125H, W240S, C386R, V507I and N693A, relative to wild type, expressed in a PS120 fibroblast cell line. The effect of these mutations on the NH <subscript>4</subscript> Cl-dependent transporter activity was investigated by intracellular pH and electrophysiology measurements. Relative to plasma membrane expression of NaK ATPase, there were no significant differences in plasma membrane SLC4A11 expression among each mutant and wild type. All mutants revealed a marked decrease in acidification in response to NH <subscript>4</subscript> Cl when compared to wild type, indicating a decreased H <superscript>+</superscript> permeability in mutants. All mutants exhibited significantly reduced H <superscript>+</superscript> currents at negative holding potentials as compared to wild type. Uniquely, the C386R and W240S mutants exhibited a different inward current profile upon NH <subscript>4</subscript> Cl challenges, suggesting an altered transport mode. Thus, our data suggest that these SLC4A11 mutants, rather than having impaired protein trafficking, show altered H <superscript>+</superscript> flux properties.<br /> (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Subjects :
- Ammonium Chloride metabolism
Animals
Anion Transport Proteins genetics
Cell Line
Corneal Dystrophies, Hereditary metabolism
Cricetinae
Fibroblasts metabolism
Humans
Hydrogen-Ion Concentration
Mutagenesis, Site-Directed
Patch-Clamp Techniques
Transfection
Anion Transport Proteins metabolism
Antiporters genetics
Cell Membrane metabolism
Corneal Dystrophies, Hereditary genetics
Point Mutation
Protein Transport physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1096-0007
- Volume :
- 180
- Database :
- MEDLINE
- Journal :
- Experimental eye research
- Publication Type :
- Academic Journal
- Accession number :
- 30557570
- Full Text :
- https://doi.org/10.1016/j.exer.2018.12.003