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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 Article has an altmetric score of 4

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

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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 2

Immunohistochemical analysis of Kv1.1 in kidney.

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Immunohistochemical analysis of Kv1.1 in kidney.
(A) Staining for Kv1.1 ...
(A) Staining for Kv1.1 (green) and TRPM6 (red) of mouse serial kidney sections (right panels: overview of a cortical region; left panels: magnified images of immunopositive tubules). The asterisks indicate the same distal tubules on serial sections intensively stained for Kv1.1 and TRPM6. (B) Mouse kidney sections were costained for Kv1.1 (green) and calbindin D28K (red) (lower panels: immunopositive tubules; upper panel: merged differential interference contrast [DIC] image). (C) Costaining of Kv1.1 (green) and AQP2 (red) in mouse kidney sections (lower panels: immunopositive tubules; upper panel: merged DIC image). G, glomerulus; 28K, calbindin D28K. Scale bars: 50 μm (A, left panels), 80 μm (A, right panels; C, bottom panels), 20 μm (B, top panel), 40 μm (B, bottom panels; C, top panel).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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