A missense mutation in the Kv1.1 voltage-gated potassium channel-encoding gene KCNA1 is linked to human autosomal dominant hypomagnesemia

J Clin Invest. 2009 Apr;119(4):936-42. doi: 10.1172/JCI36948. Epub 2009 Mar 23.

Abstract

Primary hypomagnesemia is a heterogeneous group of disorders characterized by renal or intestinal magnesium (Mg2+) wasting, resulting in tetany, cardiac arrhythmias, and seizures. The kidney plays an essential role in maintaining blood Mg2+ levels, with a prominent function for the Mg2+-transporting channel transient receptor potential cation channel, subfamily M, member 6 (TRPM6) in the distal convoluted tubule (DCT). In the DCT, Mg2+ reabsorption is an active transport process primarily driven by the negative potential across the luminal membrane. Here, we studied a family with isolated autosomal dominant hypomagnesemia and used a positional cloning approach to identify an N255D mutation in KCNA1, a gene encoding the voltage-gated potassium (K+) channel Kv1.1. Kv1.1 was found to be expressed in the kidney, where it colocalized with TRPM6 along the luminal membrane of the DCT. Upon overexpression in a human kidney cell line, patch clamp analysis revealed that the KCNA1 N255D mutation resulted in a nonfunctional channel, with a dominant negative effect on wild-type Kv1.1 channel function. These data suggest that Kv1.1 is a renal K+ channel that establishes a favorable luminal membrane potential in DCT cells to control TRPM6-mediated Mg2+ reabsorption.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Base Sequence
  • Brazil
  • Cell Line
  • Chromosome Mapping
  • DNA Mutational Analysis
  • Female
  • Genes, Dominant
  • Humans
  • Kidney / metabolism
  • Kv1.1 Potassium Channel / chemistry
  • Kv1.1 Potassium Channel / genetics*
  • Kv1.1 Potassium Channel / metabolism
  • Magnesium Deficiency / genetics*
  • Magnesium Deficiency / metabolism
  • Male
  • Models, Biological
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation, Missense*
  • Pedigree
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Sequence Homology, Amino Acid
  • TRPM Cation Channels / metabolism
  • Transfection

Substances

  • KCNA1 protein, human
  • Recombinant Proteins
  • TRPM Cation Channels
  • TRPM6 protein, human
  • Kv1.1 Potassium Channel