Ronald G Lafreniere, M Z Cader, Jean-Francois Poulin, Isabelle Andres-Enguix, Maryse Simoneau, Namrata Gupta, Karine Boisvert, Francois Lafreniere, Shannon McLaughlan, Marie-Pierre Dube, Martin M Marcinkiewicz, Sreeram Ramagopalan, Olaf Ansorge, Bernard Brais, Jorge Sequeiros, Jose M Pereira-Monteiro, Lyn R Griffiths, Stephen J Tucker, George Ebers, and Guy A Rouleau (2010)
A dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with aura.
Nat Med, 16(10):1157-60. *Joint first authors.
Migraine with aura is a common, debilitating, recurrent headache disorder associated with transient and reversible focal neurological symptoms. A role hasbeen 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 migraineby screening the KCNK18 gene in subjects diagnosed with migraine. Here we reporta 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. Functionalcharacterization of this mutation demonstrates that it causes a complete loss ofTRESK function and that the mutant subunit suppresses wild-type channel functionthrough 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.