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

Nature Medicine volume 16, pages 1157–1160 (2010)Cite this article

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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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Author notes

  1. Ronald G Lafrenière and M Zameel Cader: These authors contributed equally to this work.

Authors and Affiliations

  1. 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

    Ronald G Lafrenière, Bernard Brais & Guy A Rouleau

  2. Emerillon Therapeutics, Montreal, Quebec, Canada

    Ronald G Lafrenière, Jean-François Poulin, Maryse Simoneau, Namrata Gupta, Karine Boisvert, François Lafrenière, Shannon McLaughlan & Guy A Rouleau

  3. Department of Physiology, Medical Research Council Functional Genomics Unit, Anatomy and Genetics, University of Oxford, Oxford, UK

    M Zameel Cader

  4. Department of Clinical Neurology, John Radcliffe Hospital, Oxford, UK

    M Zameel Cader

  5. Department of Physics, Clarendon Laboratory, University of Oxford, Oxford, UK

    Isabelle Andres-Enguix & Stephen J Tucker

  6. Faculty of Medicine, Université de Montréal, Montreal Heart Institute, Montreal, Quebec, Canada

    Marie-Pierre Dubé

  7. Cytochem, Montreal, Quebec, Canada

    Martin M Marcinkiewicz

  8. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK

    Sreeram Ramagopalan & George Ebers

  9. Department of Neuropathology, University of Oxford, Oxford, UK

    Olaf Ansorge

  10. UnIGENe, Institute for Molecular and Cell Biology, University of Porto, Porto, Portugal

    Jorge Sequeiros

  11. Hospital Santo António, Porto, Portugal

    Jose Maria Pereira-Monteiro

  12. Genomics Research Centre, Griffith Health Institute, Griffith University, Gold Coast, Queensland, Australia

    Lyn R Griffiths

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  1. Ronald G Lafrenière
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Contributions

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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