A missense mutation in the Kv1.1 voltage-gated potassium channel–encoding gene KCNA1 is linked to human autosomal dominant hypomagnesemia
Bob Glaudemans, … , Joost G. Hoenderop, René J. Bindels
Bob Glaudemans, … , Joost G. Hoenderop, René J. Bindels
Published March 23, 2009
Citation Information: J Clin Invest. 2009;119(4):936-942. https://doi.org/10.1172/JCI36948.
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Research Article

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

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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Figure 1

Heterozygous KCNA1 A763G mutation causes isolated hypomagnesemia.

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Heterozygous KCNA1 A763G mutation causes isolated hypomagnesemia. (A...
(A) Pedigree with 5 generations (I–V) of a Brazilian family with autosomal dominant hypomagnesemia. Affected family members are indicated in black; males and females are indicated by squares and circles, respectively. A diagonal line indicates that the individual is deceased. Numbers in red indicate individuals included in the Sequence Tagged Site (STS) mapping. (B) 10K SNP array–based haplotyping analysis was performed that showed linkage to a 14.3-cM region between SNP rs717596 and rs252028 on the short arm of chromosome 12. This region was confirmed and narrowed down with STS markers to a 11.6-cM region between markers D12S1626 and D12S1623 containing 31 genes, including KCNA1. (C) KCNA1 encodes the voltage-gated potassium channel Kv1.1. Mutation analysis of KCNA1 revealed a heterozygous A763G missense mutation in affected individual III-1 that results in a N255D amino acid substitution (underlined). (D) Multiple alignment analysis shows conservation of the N255 amino acid (red bar) among species and Kv1 family members. Mutated amino acids in other families with the Kv1.1 genotype are indicated by dark blue dots (17, 19, 21, 22). Blue and black letters represent conserved and nonconserved amino acids, respectively. (E) Schematic representation of the Kv1.1 channel, which consists of a voltage sensor in transmembrane segment S4 and a pore-forming region (S5 and S6). Localization of the newly identified N255D mutation is denoted by the red dot, while other nearby mutations are indicated by dark blue dots.