A dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with aura.
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.
Lafrenière
Ronald G
RG
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.
Cader
M Zameel
MZ
Poulin
Jean-François
JF
Andres-Enguix
Isabelle
I
Simoneau
Maryse
M
Gupta
Namrata
N
Boisvert
Karine
K
Lafrenière
François
F
McLaughlan
Shannon
S
Dubé
Marie-Pierre
MP
Marcinkiewicz
Martin M
MM
Ramagopalan
Sreeram
S
Ansorge
Olaf
O
Brais
Bernard
B
Sequeiros
Jorge
J
Pereira-Monteiro
Jose Maria
JM
Griffiths
Lyn R
LR
Tucker
Stephen J
SJ
Ebers
George
G
Rouleau
Guy A
GA
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
D015221:Potassium Channels; C476574:KCNK18 protein, human; C486498:Kcnk18 protein, mouse