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XB-ART-48098
Hum Mol Genet November 15, 2013; 22 (22): 4579-90.

Transmembrane water-flux through SLC4A11: a route defective in genetic corneal diseases.

Vilas GL , Loganathan SK , Liu J , Riau AK , Young JD , Mehta JS , Vithana EN , Casey JR .


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.

PubMed ID: 23813972
PMC ID: PMC3889808
Article link: Hum Mol Genet
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: aqp1 nps slc4a1 slc4a11
GO keywords: cellular water homeostasis [+]

Disease Ontology terms: congenital hereditary endothelial dystrophy of cornea [+]
OMIMs: CORNEAL DYSTROPHY AND PERCEPTIVE DEAFNESS; CDPD [+]

Article Images: [+] show captions
References [+] :
Agre, Aquaporin water channels--from atomic structure to clinical medicine. 2002, Pubmed