CNNM2, encoding a basolateral protein required for renal Mg(2+) handling, is mutated in dominant hypomagnesemia

Item Type:	Article
Title:	CNNM2, encoding a basolateral protein required for renal Mg(2+) handling, is mutated in dominant hypomagnesemia
Creators Name:	Stuiver, M. and Lainez, S. and Will, C. and Terryn, S. and Guenzel, D. and Debaix, H. and Sommer, K. and Kopplin, K. and Thumfart, J. and Kampik, N.B. and Querfeld, U. and Willnow, T.E. and Nemec, V. and Wagner, C.A. and Hoenderop, J.G. and Devuyst, O. and Knoers, N.V. and Bindels, R.J. and Meij, I.C. and Mueller, D.
Abstract:	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.
Keywords:	Amino Acid Sequence, Amino Acid Substitution, Base Sequence, Cation Transport Proteins, Cyclins, Electrophysiological Phenomena, Dominant Genes, HEK293 Cells, Immunohistochemistry, Kidney, Magnesium, Magnesium Deficiency, Molecular Sequence Data, Mutation, Nephrons, Pedigree, Up-Regulation, Animals, Mice
Source:	American Journal of Human Genetics
ISSN:	0002-9297
Publisher:	Cell Press
Volume:	88
Number:	3
Page Range:	333-343
Date:	11 March 2011
Official Publication:	https://doi.org/10.1016/j.ajhg.2011.02.005
PubMed:	View item in PubMed

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