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 (Mg 2+ ) wasting, resulting in tetany, cardiac arrhythmias, and seizures. The kidney plays an essential role in maintaining blood Mg 2+ levels, with a prominent function for the Mg 2+ -transporting channel transient receptor potential cation channel, subfamily M, member 6 (TRPM6) in the distal convoluted tubule (DCT). In the DCT, Mg 2+ 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 Mg 2+ reabsorption.

The renal channelopathies

“…A mutation in KCNA1, encoding Kv1.1, results in a non-functional channel, and has been identified in a family with autosomal dominant hypomagnesaemia. 85,86 Interestingly, other mutations in the same protein cause the neurological syndrome of Episodic Ataxia type 1 -these patients are not reported to be hypomagnesaemic. 87 …”

Distal Convoluted Tubule

“…This autosomal dominant form of hypomagnesemia was attributed to a mutation in the Shaker-related voltage-gated K 1 channel Kv1.1 (116). This channel is exclusively expressed at the apical membrane of the early and late DCTs and secretes K 1 into the tubular lumen.…”

“…Although this hypothesis is provocative, the pathophysiology may not be so simple: as discussed above in the section on ROMK gating, such a change in the luminal membrane potential would be expected to markedly enhance ROMK-mediated K 1 secretion and cause hypokalemia, which is not observed in the disorder. Perhaps compensatory changes in ROMK, BK, or even ENaC expression in more downstream nephron segments, where Kv1.1 is not expressed (such as the CNT and CCD) (116), mitigate potassium losses, although to date, this hypothesis has not been tested.…”

The voltage-gated K+ channel subunit Kv1.1 links kidney and brain

“…5). This provocative hypothesis is consistent with their data, which show that cells transfected with wild-type Kv1.1 display a transmembrane voltage near -50 mV, whereas cells transfected with mutant Kv1.1 do not.…”

“…The DCT is now recognized as important not only for Mg 2+ balance, but also for the control of Na + , K + , and Ca 2+ levels (4). In this issue of the JCI, Glaudemans and colleagues report that missense mutations in K + voltage-gated channel, Shaker-related subfamily, member 1 (KCNA1), which encodes voltage-gated K + channel subtype 1.1 (Kv1.1) expressed by DCT cells, causes autosomal dominant hypomagnesemia in humans (5). Surprisingly, other mutations in the same gene cause episodic ataxia type 1 (EA1) (6), a neurological syndrome in which hypomagnesemia has not been reported.…”