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

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Title A dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with aura
Author 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; Tucker, Stephen J; Ebers, George; Rouleau, Guy A
Journal Name Nature Medicine
Year Published 2010
Place of publication United States
Publisher Nature Publishing Group
Abstract 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.
Peer Reviewed Yes
Published Yes
Alternative URI http://dx.doi.org/10.1038/nm.2216
Volume 16
Issue Number 10
Page from 1157
Page to 1160
ISSN 1078-8956
Date Accessioned 2010-12-09
Language en_AU
Research Centre Menzies Health Institute Qld
Faculty Griffith Health Faculty
Subject Medical and Health Sciences
URI http://hdl.handle.net/10072/35661
Publication Type Journal Articles (Refereed Article)
Publication Type Code c1

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