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

• Published in: Nature medicine Vol. 16; no. 10; pp. 1157 - 1160
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2010; Nature Publishing Group
• Subjects: 631/208/737; 631/45/269/1151; 692/699/375/226/1654; Anesthesia; Animals; Biomedical and Life Sciences; Biomedicine; Cancer Research; Gene expression; Gene mutations; Genetic aspects; Genetic Linkage; Genetics; Humans; Identification and classification; Infectious Diseases; letter; Metabolic Diseases; Mice; Migraine; Migraine with Aura - genetics; Molecular Medicine; Mutation; Neurology; Neurosciences; Pain; Physiological aspects; Polymorphism, Single Nucleotide; Potassium; Potassium channels; Potassium Channels - genetics; Potassium Channels - physiology; Properties; United Kingdom
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/nm.2216

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.