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

Authors

  • M. Stuiver
  • S. Lainez
  • C. Will
  • S. Terryn
  • D. Guenzel
  • H. Debaix
  • K. Sommer
  • K. Kopplin
  • J. Thumfart
  • N.B. Kampik
  • U. Querfeld
  • T.E. Willnow
  • V. Nemec
  • C.A. Wagner
  • J.G. Hoenderop
  • O. Devuyst
  • N.V. Knoers
  • R.J. Bindels
  • I.C. Meij
  • D. Mueller

Journal

  • American Journal of Human Genetics

Citation

  • Am J Hum Genet 88 (3): 333-343

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.


DOI

doi:10.1016/j.ajhg.2011.02.005