title: A dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with aura.
abstract: Migraine with aura is a common, debilitating, recurrent headache disorder associated with transient and reversible focal neurological symptoms. 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. 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.
authors.affiliation: Centre of Excellence in Neuromics and Department of Medicine, Université de Montréal, Centre Hospitalier de l'Université de Montréal, Research Centre, Notre-Dame Hospital, Montreal, Quebec, Canada.
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Lafrenière
authors.forename: M Zameel
authors.initials: MZ
authors.lastname: Cader
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Poulin
authors.forename: Isabelle
authors.initials: I
authors.lastname: Andres-Enguix
authors.forename: Maryse
authors.initials: M
authors.lastname: Simoneau
authors.forename: Namrata
authors.initials: N
authors.lastname: Gupta
authors.forename: Karine
authors.initials: K
authors.lastname: Boisvert
authors.forename: François
authors.initials: F
authors.lastname: Lafrenière
authors.forename: Shannon
authors.initials: S
authors.lastname: McLaughlan
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Dubé
authors.forename: Martin M
authors.initials: MM
authors.lastname: Marcinkiewicz
authors.forename: Sreeram
authors.initials: S
authors.lastname: Ramagopalan
authors.forename: Olaf
authors.initials: O
authors.lastname: Ansorge
authors.forename: Bernard
authors.initials: B
authors.lastname: Brais
authors.forename: Jorge
authors.initials: J
authors.lastname: Sequeiros
authors.forename: Jose Maria
authors.initials: JM
authors.lastname: Pereira-Monteiro
authors.forename: Lyn R
authors.initials: LR
authors.lastname: Griffiths
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Tucker
authors.forename: George
authors.initials: G
authors.lastname: Ebers
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
mesh_terms: D000818:Animals; D008040:Genetic Linkage; D006801:Humans; D051379:Mice; D020325:Migraine with Aura / Q000235:genetics*; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D015221:Potassium Channels / Q000235:genetics* / Q000502:physiology
chemical_list: D015221:Potassium Channels; C476574:KCNK18 protein, human; C486498:Kcnk18 protein, mouse