title: A missense mutation in the Kv1.1 voltage-gated potassium channel-encoding gene KCNA1 is linked to human autosomal dominant hypomagnesemia.
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.
authors.affiliation: Department of Physiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Bob
authors.initials: B
authors.lastname: Glaudemans
authors.forename: Jenny
authors.initials: J
authors.lastname: van der Wijst
authors.forename: Rosana H
authors.initials: RH
authors.lastname: Scola
authors.forename: Paulo J
authors.initials: PJ
authors.lastname: Lorenzoni
authors.forename: Angelien
authors.initials: A
authors.lastname: Heister
authors.forename: Annemiete W
authors.initials: AW
authors.lastname: van der Kemp
authors.forename: Nine V
authors.initials: NV
authors.lastname: Knoers
authors.forename: Joost G
authors.initials: JG
authors.lastname: Hoenderop
authors.forename: René J
authors.initials: RJ
authors.lastname: Bindels
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D001938:Brazil; D002460:Cell Line; D002874:Chromosome Mapping; D004252:DNA Mutational Analysis; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D007668:Kidney / Q000378:metabolism; D051662:Kv1.1 Potassium Channel / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008275:Magnesium Deficiency / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D050053:TRPM Cation Channels / Q000378:metabolism; D014162:Transfection
chemical_list: C496946:KCNA1 protein, human; D011994:Recombinant Proteins; D050053:TRPM Cation Channels; C459082:TRPM6 protein, human; D051662:Kv1.1 Potassium Channel