A missense mutation in the Kv1.1 voltage-gated potassium channel-encoding gene KCNA1 is linked to human autosomal dominant hypomagnesemiaGlaudemans, B., van der Wijst, J., Scola, R. H., Lorenzoni, P. J., Heister, A., van der Kemp, A. W., Knoers, N. V., Hoenderop, J. G. & Bindels, R. J., Apr-2009, In : The Journal of Clinical Investigation. 119, 4, p. 936-942 7 p.
Research output: Contribution to journal › Article › Academic › peer-review
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.
|Number of pages||7|
|Journal||The Journal of Clinical Investigation|
|Publication status||Published - Apr-2009|
- 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