CNNM2, encoding a basolateral protein required for renal Mg2+ handling, is mutated in dominant hypomagnesemia

Am J Hum Genet. 2011 Mar 11;88(3):333-43. doi: 10.1016/j.ajhg.2011.02.005.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution / genetics
  • Animals
  • Base Sequence
  • Cation Transport Proteins / chemistry
  • Cation Transport Proteins / genetics*
  • Cyclins / chemistry
  • Cyclins / genetics*
  • Electrophysiological Phenomena / drug effects
  • Female
  • Genes, Dominant / genetics*
  • HEK293 Cells
  • Humans
  • Immunohistochemistry
  • Kidney / drug effects
  • Kidney / metabolism*
  • Kidney / pathology
  • Magnesium / metabolism*
  • Magnesium / pharmacology
  • Magnesium Deficiency / genetics*
  • Magnesium Deficiency / pathology
  • Male
  • Mice
  • Molecular Sequence Data
  • Mutation / genetics*
  • Nephrons / drug effects
  • Nephrons / metabolism
  • Nephrons / pathology
  • Pedigree
  • Up-Regulation / drug effects

Substances

  • CNNM2 protein, human
  • Cation Transport Proteins
  • Cyclins
  • Magnesium