Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-47687
Stuiver, M; Lainez, S; Will, C; Terryn, S; Günzel, D; Debaix, H; Sommer, K; Kopplin, K; Thumfart, J; Kampik, N B; Querfeld, U; Willnow, T E; Nemec, V; Wagner, C A; Hoenderop, J G; Devuyst, O; Knoers, N V; Bindels, R J; Meij, I C; Müller, D (2011). CNNM2, encoding a basolateral protein required for renal Mg(2+)handling, is mutated in dominant hypomagnesemia. American Journal of Human Genetics, 88(3):333-343.
Familial hypomagnesemia is a rare human disorder caused by renal or intestinal magnesium (Mg(2+)) wasting, which may lead to symptoms of Mg(2+) depletion such as tetany, seizures, and cardiac arrhythmias. Our knowledge of the physiology of Mg(2+) (re)absorption, particularly the luminal uptake of Mg(2+) along the nephron, has benefitted from positional cloning approaches in families with Mg(2+) reabsorption disorders; however, basolateral Mg(2+) transport and its regulation are still poorly understood. Here, by using a candidate screening approach, we identified CNNM2 as a gene involved in renal Mg(2+) handling in patients of two unrelated families with unexplained dominant hypomagnesemia. In the kidney, CNNM2 was predominantly found along the basolateral membrane of distal tubular segments involved in Mg(2+) reabsorption. The basolateral localization of endogenous and recombinant CNNM2 was confirmed in epithelial kidney cell lines. Electrophysiological analysis showed that CNNM2 mediated Mg(2+)-sensitive Na(+) currents that were significantly diminished in mutant protein and were blocked by increased extracellular Mg(2+) concentrations. Our data support the findings of a recent genome-wide association study showing the CNNM2 locus to be associated with serum Mg(2+) concentrations. The mutations found in CNNM2, its observed sensitivity to extracellular Mg(2+), and its basolateral localization signify a critical role for CNNM2 in epithelial Mg(2+) transport.
|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > Institute of Physiology|
07 Faculty of Science > Institute of Physiology
04 Faculty of Medicine > Center for Integrative Human Physiology
|DDC:||570 Life sciences; biology|
610 Medicine & health
|Deposited On:||22 Mar 2011 14:38|
|Last Modified:||23 Nov 2012 13:22|
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