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 symptoms1. 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 anaesthesia2. 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.

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Figure 1: Segregation analysis in a large migraine with aura pedigree.
Figure 2: KCNK18 and TRESK expression patterns in mice and humans.
Figure 3: Electrophysiological characterization of the F139WfsX24 TRESK mutant.

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Acknowledgements

We thank the subjects and their families for participating in the study and M.K. Charles, M. Albanese, M. Imbeau, A. Anton, S. Meilleur and F. Fernandez for technical assistance. Funding was kindly provided by Genome Canada, Genome Quebec, Emerillon Therapeutics, the Wellcome Trust and Pfizer. M.Z.C. was supported by the Medical Research Council (UK). J.-F.P. was supported by an industrial postdoctoral fellowship from the Natural Sciences and Engineering Research Council of Canada.

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R.G.L. and M.Z.C. planned the experiments and wrote the manuscript. R.G.L. supervised the PCR, dHPLC and sequence analysis, annotated exon and intron structures and verified all data tables and figures. M.Z.C. provided migraine samples, obtained clinical information, performed the linkage analysis and supervised the protein expression studies. M.-P.D. also performed linkage analysis. J.-F.P. supervised PCR, RT-PCR and screening experiments, did DNA sequence analyses and helped write the manuscript. M.S. supervised and performed dHPLC screening experiments and analyses. N.G. supervised PCR and screening experiments. F.L., K.B. and S.M. performed dHPLC and PCR experiments and provided some sequence analysis. M.M.M. conducted the in situ hybridization experiments. S.R. helped obtain clinical information and linkage analysis. O.A. supervised the protein expression studies. I.A.-E. and S.J.T. performed the electrophysiology and helped write the manuscript. L.R.G., G.E., B.B., J.S. and J.M.P.-M. provided migraine samples and clinical information. G.A.R. supervised all aspects of the project and edited the manuscript.

Corresponding authors

Correspondence to M Zameel Cader or Guy A Rouleau.

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The authors declare no competing financial interests.

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Supplementary Tables 1 and 2 and Supplementary Methods (PDF 106 kb)

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Lafrenière, R., Cader, M., Poulin, JF. et al. A dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with aura. Nat Med 16, 1157–1160 (2010). https://doi.org/10.1038/nm.2216

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