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A dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with aura
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A dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with aura
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Journal Article
A dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with aura
2010
Overview
Migraine headaches are a debilitating condition that affect many individuals. Now, Guy Rouleau and his colleagues link loss-of-function mutations in a potassium channel protein with a particular migraine syndrome in humans.
Migraine with aura is a common, debilitating, recurrent headache disorder associated with transient and reversible focal neurological symptoms
1
. A role has been suggested for the two-pore domain (K2P) potassium channel, TWIK-related spinal cord potassium channel (TRESK, encoded by
KCNK18
), in pain pathways and general anaesthesia
2
. We therefore examined whether TRESK is involved in migraine by screening the
KCNK18
gene in subjects diagnosed with migraine. Here we report a frameshift mutation, F139WfsX24, which segregates perfectly with typical migraine with aura in a large pedigree. We also identified prominent TRESK expression in migraine-salient areas such as the trigeminal ganglion. Functional characterization of this mutation demonstrates that it causes a complete loss of TRESK function and that the mutant subunit suppresses wild-type channel function through a dominant-negative effect, thus explaining the dominant penetrance of this allele. These results therefore support a role for TRESK in the pathogenesis of typical migraine with aura and further support the role of this channel as a potential therapeutic target.
Publisher
Nature Publishing Group US,Nature Publishing Group
