A dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with aura

Lafrenière, Ronald G, Cader, M Zameel, Poulin, Jean-François, Andres-Enguix, Isabelle, Simoneau, Maryse, Gupta, Namrata, Boisvert, Karine, Lafrenière, François, McLaughlan, Shannon, Dubé, Marie-Pierre, Marcinkiewicz, Martin M, Ramagopalan, Sreeram, Ansorge, Olaf, Brais, Bernard, Sequeiros, Jorge, Pereira-Monteiro, Jose Maria, Griffiths, Lyn R., Tucker, Stephen J., Ebers, George, & Rouleau, Guy A. (2010) A dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with aura. Nature Medicine, 16(10), pp. 1157-1160.

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Abstract

Migraine with aura is a common, debilitating, recurrent headache disorder associated with transient and reversible focal neurological symptoms. 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. 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.

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ID Code: 62586
Item Type: Journal Article
Refereed: Yes
DOI: 10.1038/nm.2216
ISSN: 1546-170X
Divisions: Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2010 Nature Publishing Group
Deposited On: 17 Sep 2013 03:35
Last Modified: 31 Oct 2013 02:38

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