• Ronald G Lafrenière, M Zameel Cader, Jean-François Poulin, Isabelle Andres-Enguix, Maryse Simoneau, Namrata Gupta, Karine Boisvert, François Lafrenière, Shannon McLaughlan, Marie-Pierre Dubé, Martin M Marcinkiewicz, Sreeram Ramagopalan, Olaf Ansorge, Bernard Brais, Jorge Sequeiros, Jose Maria Pereira-Monteiro, Lyn R Griffiths, Stephen J Tucker, George Ebers, and Guy A Rouleau.
• Centre of Excellence in Neuromics and Department of Medicine, Université de Montréal, Centre Hospitalier de l'Université de Montréal, Research Centre, Notre-Dame Hospital, Montreal, Quebec, Canada.
• Nat. Med. 2010 Oct 1; 16 (10): 1157-60.

AbstractMigraine 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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