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

Bob Glaudemans, Jenny van der Wijst, Rosana H Scola, Paulo J Lorenzoni, Angelien Heister, Annemiete W van der Kemp, Nine V Knoers, Joost G Hoenderop, René J Bindels

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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.

Original languageEnglish
Pages (from-to)936-942
Number of pages7
JournalThe Journal of Clinical Investigation
Issue number4
Publication statusPublished - Apr-2009
Externally publishedYes


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

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