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

作者：Lafreniere Ronald G; Cader M Zameel; Poulin Jean Francois; Andres Enguix Isabelle; Simoneau Maryse; Gupta Namrata; Boisvert Karine; Lafreniere Francois; McLaughlan Shannon; Dube 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^*

来源：Nature Medicine, 2010, 16(10): 1157-U1501.

DOI：10.1038/nm.2216

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.

• 出版日期2010-10