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

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Item Type:	Article
Title:	CNNM2, encoding a basolateral protein required for renal Mg(2+) handling, is mutated in dominant hypomagnesemia
Creators Name:	Stuiver, M., Lainez, S., Will, C., Terryn, S., Guenzel, 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. 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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