西亚试剂：A dominant-negative mutation in the TRESK potassium channel

A dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with aura
Ronald G Lafrenière1,2,13, M Zameel Cader3,4,13, Jean-Fran?ois Poulin2, Isabelle Andres-Enguix5, Maryse Simoneau2, Namrata Gupta2, Karine Boisvert2, Fran?ois Lafrenière2, Shannon McLaughlan2, Marie-Pierre Dubé6, Martin M Marcinkiewicz7, Sreeram Ramagopalan8, Olaf Ansorge9, Bernard Brais1, Jorge Sequeiros10, Jose Maria Pereira-Monteiro11, Lyn R Griffiths12, Stephen J Tucker5, George Ebers8 & Guy A Rouleau1,2

Migraine with aura is a common, debilitating, recurrent headache disorder associated with transient and reversible focal neurological symptoms1. 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 anaesthesia2. 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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