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 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.


  1. 1

    Lipton, R.B., Stewart, W.F., Diamond, S., Diamond, M.L. & Reed, M. Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache 41, 646–657 (2001).

    CAS  Article  Google Scholar 

  2. 2

    Huang, D.Y., Yu, B.W. & Fan, Q.W. Roles of TRESK, a novel two-pore domain K+ channel, in pain pathway and general anesthesia. Neurosci. Bull. 24, 166–172 (2008).

    CAS  Article  Google Scholar 

  3. 3

    Bolay, H. et al. Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nat. Med. 8, 136–142 (2002).

    CAS  Article  Google Scholar 

  4. 4

    Zhang, X. et al. Activation of meningeal nociceptors by cortical spreading depression: implications for migraine with aura. J. Neurosci. 30, 8807–8814 (2010).

    CAS  Article  Google Scholar 

  5. 5

    Iadecola, C. From CSD to headache: a long and winding road. Nat. Med. 8, 110–112 (2002).

    CAS  Article  Google Scholar 

  6. 6

    De Fusco, M. et al. Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump α2 subunit associated with familial hemiplegic migraine type 2. Nat. Genet. 33, 192–196 (2003).

    CAS  Article  Google Scholar 

  7. 7

    Dichgans, M. et al. Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine. Lancet 366, 371–377 (2005).

    CAS  Article  Google Scholar 

  8. 8

    Ophoff, R.A. et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 87, 543–552 (1996).

    CAS  Article  Google Scholar 

  9. 9

    de Vries, B., Frants, R.R., Ferrari, M.D. & van den Maagdenberg, A.M. Molecular genetics of migraine. Hum. Genet. 126, 115–132 (2009).

    Article  Google Scholar 

  10. 10

    Ramagopalan, S.V., Ramscar, N.E. & Cader, M.Z. Molecular mechanisms of migraine? J. Neurol. 254, 1629–1635 (2007).

    CAS  Article  Google Scholar 

  11. 11

    Enyedi, P. & Czirjak, G. Molecular background of leak K+ currents: two-pore domain potassium channels. Physiol. Rev. 90, 559–605 (2010).

    CAS  Article  Google Scholar 

  12. 12

    Czirják, G., Toth, Z.E. & Enyedi, P. The two-pore domain K+ channel, TRESK, is activated by the cytoplasmic calcium signal through calcineurin. J. Biol. Chem. 279, 18550–18558 (2004).

    Article  Google Scholar 

  13. 13

    Mathie, A. Neuronal two-pore-domain potassium channels and their regulation by G protein–coupled receptors. J. Physiol. (Lond.) 578, 377–385 (2007).

    CAS  Article  Google Scholar 

  14. 14

    Smith, H.S. Calcineurin as a nociceptor modulator. Pain Physician 12, E309–E318 (2009).

    PubMed  Google Scholar 

  15. 15

    Czirják, G. & Enyedi, P. Targeting of calcineurin to an NFAT-like docking site is required for the calcium-dependent activation of the background K+ channel, TRESK. J. Biol. Chem. 281, 14677–14682 (2006).

    Article  Google Scholar 

  16. 16

    Liu, C., Au, J.D., Zou, H.L., Cotten, J.F. & Yost, C.S. Potent activation of the human tandem pore domain K channel TRESK with clinical concentrations of volatile anesthetics. Anesth. Analg. 99, 1715–1722 (2004).

    CAS  Article  Google Scholar 

  17. 17

    Piper, R.D. & Lambert, G.A. Inhalational anesthetics inhibit spreading depression: relevance to migraine. Cephalalgia 16, 87–92 (1996).

    CAS  Article  Google Scholar 

  18. 18

    Cader, Z.M. et al. Significant linkage to migraine with aura on chromosome 11q24. Hum. Mol. Genet. 12, 2511–2517 (2003).

    CAS  Article  Google Scholar 

  19. 19

    Abecasis, G.R., Cherny, S.S., Cookson, W.O. & Cardon, L.R. Merlin—rapid analysis of dense genetic maps using sparse gene flow trees. Nat. Genet. 30, 97–101 (2002).

    CAS  Article  Google Scholar 

  20. 20

    Sano, Y. et al. A novel two-pore domain K+ channel, TRESK, is localized in the spinal cord. J. Biol. Chem. 278, 27406–27412 (2003).

    CAS  Article  Google Scholar 

  21. 21

    Yoo, S. et al. Regional expression of the anesthetic-activated potassium channel TRESK in the rat nervous system. Neurosci. Lett. 465, 79–84 (2009).

    CAS  Article  Google Scholar 

  22. 22

    Dobler, T. et al. TRESK two-pore-domain K+ channels constitute a significant component of background potassium currents in murine dorsal root ganglion neurones. J. Physiol. (Lond.) 585, 867–879 (2007).

    CAS  Article  Google Scholar 

  23. 23

    Wuttke, T.V. et al. Peripheral nerve hyperexcitability due to dominant-negative KCNQ2 mutations. Neurology 69, 2045–2053 (2007).

    CAS  Article  Google Scholar 

  24. 24

    Zerr, P., Adelman, J.P. & Maylie, J. Episodic ataxia mutations in Kv1.1 alter potassium channel function by dominant negative effects or haploinsufficiency. J. Neurosci. 18, 2842–2848 (1998).

    CAS  Article  Google Scholar 

  25. 25

    London, B. et al. Long QT and ventricular arrhythmias in transgenic mice expressing the N terminus and first transmembrane segment of a voltage-gated potassium channel. Proc. Natl. Acad. Sci. USA 95, 2926–2931 (1998).

    CAS  Article  Google Scholar 

  26. 26

    Barel, O. et al. Maternally inherited Birk Barel mental retardation dysmorphism syndrome caused by a mutation in the genomically imprinted potassium channel KCNK9. Am. J. Hum. Genet. 83, 193–199 (2008).

    CAS  Article  Google Scholar 

  27. 27

    Ferrari, U. et al. Calcineurin inhibitor–induced headache: clinical characteristics and possible mechanisms. Headache 45, 211–214 (2005).

    Article  Google Scholar 

  28. 28

    Lemos, C. et al. Familial clustering of migraine: further evidence from a Portuguese study. Headache 49, 404–411 (2009).

    Article  Google Scholar 

  29. 29

    Colson, N.J., Lea, R.A., Quinlan, S., MacMillan, J. & Griffiths, L.R. Investigation of hormone receptor genes in migraine. Neurogenetics 6, 17–23 (2005).

    CAS  Article  Google Scholar 

  30. 30

    The International Classification of Headache Disorders. 2nd edition. Cephalalgia 24 Suppl 1, 9–160 (2004).

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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.

Author information




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.

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Correspondence to M Zameel Cader or Guy A Rouleau.

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The authors declare no competing financial interests.

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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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