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Transmembrane water-flux through SLC4A11: a route defective in genetic corneal diseases.
- Source :
-
Human molecular genetics [Hum Mol Genet] 2013 Nov 15; Vol. 22 (22), pp. 4579-90. Date of Electronic Publication: 2013 Jun 27. - Publication Year :
- 2013
-
Abstract
- Three genetic corneal dystrophies [congenital hereditary endothelial dystrophy type 2 (CHED2), Harboyan syndrome and Fuchs endothelial corneal dystrophy] arise from mutations of the SLC4a11 gene, which cause blindness from fluid accumulation in the corneal stroma. Selective transmembrane water conductance controls cell size, renal fluid reabsorption and cell division. All known water-channelling proteins belong to the major intrinsic protein family, exemplified by aquaporins (AQPs). Here we identified SLC4A11, a member of the solute carrier family 4 of bicarbonate transporters, as an unexpected addition to known transmembrane water movement facilitators. The rate of osmotic-gradient driven cell-swelling was monitored in Xenopus laevis oocytes and HEK293 cells, expressing human AQP1, NIP5;1 (a water channel protein from plant), hCNT3 (a human nucleoside transporter) and human SLC4A11. hCNT3-expressing cells swelled no faster than control cells, whereas SLC4A11-mediated water permeation at a rate about half that of some AQP proteins. SLC4A11-mediated water movement was: (i) similar to some AQPs in rate; (ii) uncoupled from solute-flux; (iii) inhibited by stilbene disulfonates (classical SLC4 inhibitors); (iv) inactivated in one CHED2 mutant (R125H). Localization of AQP1 and SLC4A11 in human and murine corneal (apical and basolateral, respectively) suggests a cooperative role in mediating trans-endothelial water reabsorption. Slc4a11(-/-) mice manifest corneal oedema and distorted endothelial cells, consistent with loss of a water-flux. Observed water-flux through SLC4A11 extends the repertoire of known water movement pathways and call for a re-examination of explanations for water movement in human tissues.
- Subjects :
- Animals
Aquaporin 1 metabolism
Aquaporins metabolism
Cornea metabolism
Corneal Dystrophies, Hereditary metabolism
Corneal Dystrophies, Hereditary pathology
Corneal Stroma metabolism
Corneal Stroma pathology
HEK293 Cells
Hearing Loss, Sensorineural genetics
Hearing Loss, Sensorineural metabolism
Hearing Loss, Sensorineural pathology
Humans
Membrane Transport Proteins metabolism
Mice
Mice, Knockout
Models, Animal
Oocytes metabolism
Phenotype
SLC4A Proteins genetics
Signal Transduction genetics
Xenopus laevis
Corneal Dystrophies, Hereditary genetics
Corneal Stroma physiopathology
SLC4A Proteins metabolism
Water metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2083
- Volume :
- 22
- Issue :
- 22
- Database :
- MEDLINE
- Journal :
- Human molecular genetics
- Publication Type :
- Academic Journal
- Accession number :
- 23813972
- Full Text :
- https://doi.org/10.1093/hmg/ddt307