De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy


Malignant migrating partial seizures of infancy (MMPSI) is a rare epileptic encephalopathy of infancy that combines pharmacoresistant seizures with developmental delay1. We performed exome sequencing in three probands with MMPSI and identified de novo gain-of-function mutations affecting the C-terminal domain of the KCNT1 potassium channel. We sequenced KCNT1 in 9 additional individuals with MMPSI and identified mutations in 4 of them, in total identifying mutations in 6 out of 12 unrelated affected individuals. Functional studies showed that the mutations led to constitutive activation of the channel, mimicking the effects of phosphorylation of the C-terminal domain by protein kinase C. In addition to regulating ion flux, KCNT1 has a non-conducting function, as its C terminus interacts with cytoplasmic proteins involved in developmental signaling pathways. These results provide a focus for future diagnostic approaches and research for this devastating condition.

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Figure 1: MMPSI-associated mutations increase the amplitude of Kcnt1-generated currents.
Figure 2: MMPSI-associated mutations mimic and occlude the effects of phosphorylation of rat Kcnt1 at Ser407.
Figure 3: Mutations affecting rat Kcnt1 do not alter sodium ion sensitivity but suppress channel subconductance states.

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  1. 1

    Coppola, G., Plouin, P., Chiron, C., Robain, O. & Dulac, O. Migrating partial seizures in infancy: a malignant disorder with developmental arrest. Epilepsia 36, 1017–1024 (1995).

    CAS  Article  Google Scholar 

  2. 2

    Coppola, G. et al. Mutational scanning of potassium, sodium and chloride ion channels in malignant migrating partial seizures in infancy. Brain Dev. 28, 76–79 (2006).

    Article  Google Scholar 

  3. 3

    Gérard, F., Kaminska, A., Plouin, P., Echenne, B. & Dulac, O. Focal seizures versus focal epilepsy in infancy: a challenging distinction. Epileptic Disord. 1, 135–139 (1999).

    PubMed  Google Scholar 

  4. 4

    Okuda, K. et al. Successful control with bromide of two patients with malignant migrating partial seizures in infancy. Brain Dev. 22, 56–59 (2000).

    CAS  Article  Google Scholar 

  5. 5

    Wilmshurst, J.M., Appleton, D.B. & Grattan-Smith, P.J. Migrating partial seizures in infancy: two new cases. J. Child Neurol. 15, 717–722 (2000).

    CAS  Article  Google Scholar 

  6. 6

    Veneselli, E., Perrone, M.V., Di Rocco, M., Gaggero, R. & Biancheri, R. Malignant migrating partial seizures in infancy. Epilepsy Res. 46, 27–32 (2001).

    CAS  Article  Google Scholar 

  7. 7

    Gross-Tsur, V., Ben-Zeev, B. & Shalev, R.S. Malignant migrating partial seizures in infancy. Pediatr. Neurol. 31, 287–290 (2004).

    Article  Google Scholar 

  8. 8

    Marsh, E., Melamed, S.E., Barron, T. & Clancy, R.R. Migrating partial seizures in infancy: expanding the phenotype of a rare seizure syndrome. Epilepsia 46, 568–572 (2005).

    Article  Google Scholar 

  9. 9

    Hmaimess, G., Kadhim, H., Nassogne, M.C., Bonnier, C. & van Rijckevorsel, K. Levetiracetam in a neonate with malignant migrating partial seizures. Pediatr. Neurol. 34, 55–59 (2006).

    Article  Google Scholar 

  10. 10

    Zamponi, N., Rychlicki, F., Corpaci, L., Cesaroni, E. & Trignani, R. Vagus nerve stimulation (VNS) is effective in treating catastrophic 1 epilepsy in very young children. Neurosurg. Rev. 31, 291–297 (2008).

    Article  Google Scholar 

  11. 11

    Caraballo, R.H. et al. Migrating focal seizures in infancy: analysis of the electroclinical patterns in 17 patients. J. Child Neurol. 23, 497–506 (2008).

    Article  Google Scholar 

  12. 12

    Lee, E.H., Yum, M.S., Jeong, M.H., Lee, K.Y. & Ko, T.S. A case of malignant migrating partial seizures in infancy as a continuum of infantile epileptic encephalopathy. Brain Dev. 34, 768–772 (2012).

    Article  Google Scholar 

  13. 13

    Gilhuis, H.J., Schieving, J. & Zwarts, M.J. Malignant migrating partial seizures in a 4-month-old boy. Epileptic Disord. 13, 185–187 (2011).

    PubMed  Google Scholar 

  14. 14

    Djuric, M., Kravljanac, R., Kovacevic, G. & Martic, J. The efficacy of bromides, stiripentol and levetiracetam in two patients with malignant migrating partial seizures in infancy. Epileptic Disord. 13, 22–26 (2011).

    PubMed  Google Scholar 

  15. 15

    Carranza Rojo, D. et al. De novo SCN1A mutations in migrating partial seizures of infancy. Neurology 77, 380–383 (2011).

    CAS  Article  Google Scholar 

  16. 16

    Freilich, E.R. et al. Novel SCN1A mutation in a proband with malignant migrating partial seizures of infancy. Arch. Neurol. 68, 665–671 (2011).

    Article  Google Scholar 

  17. 17

    Vendrame, M. et al. Treatment of malignant migrating partial epilepsy of infancy with rufinamide: report of five cases. Epileptic Disord. 13, 18–21 (2011).

    PubMed  Google Scholar 

  18. 18

    Nabbout, R. & Dulac, O. Epileptic syndromes in infancy and childhood. Curr. Opin. Neurol. 21, 161–166 (2008).

    Article  Google Scholar 

  19. 19

    Poduri, A. & Lowenstein, D. Epilepsy genetics—past, present, and future. Curr. Opin. Genet. Dev. 21, 325–332 (2011).

    CAS  Article  Google Scholar 

  20. 20

    Yuan, A. et al. The sodium-activated potassium channel is encoded by a member of the Slo gene family. Neuron 37, 765–773 (2003).

    CAS  Article  Google Scholar 

  21. 21

    Bhattacharjee, A. & Kaczmarek, L.K. For K+ channels, Na+ is the new Ca 2 + . Trends Neurosci. 28, 422–428 (2005).

    CAS  Article  Google Scholar 

  22. 22

    Brown, M.R. et al. Amino-termini isoforms of the Slack K+ channel, regulated by alternative promoters, differentially modulate rhythmic firing and adaptation. J. Physiol. (Lond.) 586, 5161–5179 (2008).

    CAS  Article  Google Scholar 

  23. 23

    Ruffin, V.A. et al. The sodium-activated potassium channel Slack is modulated by hypercapnia and acidosis. Neuroscience 151, 410–418 (2008).

    CAS  Article  Google Scholar 

  24. 24

    Brown, M.R. et al. Fragile X mental retardation protein controls gating of the sodium-activated potassium channel Slack. Nat. Neurosci. 13, 819–821 (2010).

    CAS  Article  Google Scholar 

  25. 25

    Chen, H. et al. The N-terminal domain of Slack determines the formation and trafficking of Slick/Slack heteromeric sodium-activated potassium channels. J. Neurosci. 29, 5654–5665 (2009).

    CAS  Article  Google Scholar 

  26. 26

    Santi, C.M. et al. Opposite regulation of Slick and Slack K+ channels by neuromodulators. J. Neurosci. 26, 5059–5068 (2006).

    CAS  Article  Google Scholar 

  27. 27

    Joiner, W.J. et al. Formation of intermediate-conductance calcium-activated potassium channels by interaction of Slack and Slo subunits. Nat. Neurosci. 1, 462–469 (1998).

    CAS  Article  Google Scholar 

  28. 28

    Yang, B., Desai, R. & Kaczmarek, L.K. Slack and Slick KNa channels regulate the accuracy of timing of auditory neurons. J. Neurosci. 27, 2617–2627 (2007).

    CAS  Article  Google Scholar 

  29. 29

    Nabbout, R. et al. Spectrum of SCN1A mutations in severe myoclonic epilepsy of infancy. Neurology 60, 1961–1967 (2003).

    CAS  Article  Google Scholar 

  30. 30

    Steinlein, O.K., Conrad, C. & Weidner, B. Benign familial neonatal convulsions: always benign? Epilepsy Res. 73, 245–249 (2007).

    CAS  Article  Google Scholar 

  31. 31

    Weckhuysen, S. et al. KCNQ2 encephalopathy: emerging phenotype of a neonatal epileptic encephalopathy. Ann. Neurol. 71, 15–25 (2012).

    CAS  Article  Google Scholar 

  32. 32

    Wei, A.D.v. et al. International Union of Pharmacology. LII. Nomenclature and molecular relationships of calcium-activated potassium channels. Pharmacol. Rev. 57, 463–472 (2005).

    CAS  Article  Google Scholar 

  33. 33

    Du, W. et al. Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder. Nat. Genet. 37, 733–738 (2005).

    CAS  Article  Google Scholar 

  34. 34

    Kaczmarek, L.K. Non-conducting functions of voltage-gated ion channels. Nat. Rev. Neurosci. 7, 761–771 (2006).

    CAS  Article  Google Scholar 

  35. 35

    Fleming, M.R. & Kaczmarek, L.K. Use of optical biosensors to detect modulation of Slack potassium channels by G protein–coupled receptors. J. Recept. Signal Transduct. Res. 29, 173–181 (2009).

    CAS  Article  Google Scholar 

  36. 36

    O'Roak, B.J. et al. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat. Genet. 43, 585–589 (2011).

    CAS  Article  Google Scholar 

  37. 37

    Hamdan, F.F. et al. Intellectual disability without epilepsy associated with STXBP1 disruption. Eur. J. Hum. Genet. 19, 607–609 (2011).

    CAS  Article  Google Scholar 

  38. 38

    Friocourt, G. & Parnavelas, J.G. Mutations in ARX result in several defects involving GABAergic neurons. Front Cell Neurosci. 4, 4 (2010).

    PubMed  PubMed Central  Google Scholar 

  39. 39

    Bolton, P.F., Park, R.J., Higgins, J.N., Griffiths, P.D. & Pickles, A. Neuro-epileptic determinants of autism spectrum disorders in tuberous sclerosis complex. Brain 125, 1247–1255 (2002).

    Article  Google Scholar 

  40. 40

    Byun, M. et al. Whole-exome sequencing–based discovery of STIM1 deficiency in a child with fatal classic Kaposi sarcoma. J. Exp. Med. 207, 2307–2312 (2010).

    CAS  Article  Google Scholar 

  41. 41

    Bolze, A. et al. Whole-exome-sequencing–based discovery of human FADD deficiency. Am. J. Hum. Genet. 87, 873–881 (2010).

    CAS  Article  Google Scholar 

  42. 42

    Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009).

    CAS  Article  Google Scholar 

  43. 43

    McKenna, A. et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20, 1297–1303 (2010).

    CAS  Article  Google Scholar 

  44. 44

    Li, H. et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009).

    Article  Google Scholar 

  45. 45

    Chen, W., Han, Y., Chen, Y. & Astumian, D. Electric field–induced functional reductions in the K+ channels mainly resulted from supramembrane potential–mediated electroconformational changes. Biophys. J. 75, 196–206 (1998).

    CAS  Article  Google Scholar 

  46. 46

    Brewer, G.J., Torricelli, J.R., Evege, E.K. & Price, P.J. Optimized survival of hippocampal-neurons in B27-supplemented Neurobasal, a new serum-free medium combination. J. Neurosci. Res. 35, 567–576 (1993).

    CAS  Article  Google Scholar 

  47. 47

    Bhattacharjee, A., Gan, L. & Kaczmarek, L.K. Localization of the Slack potassium channel in the rat central nervous system. J. Comp. Neurol. 454, 241–254 (2002).

    CAS  Article  Google Scholar 

  48. 48

    Lobner, D. Saturation of neuroprotective effects of adenosine in cortical culture. Neuroreport 13, 2075–2078 (2002).

    CAS  Article  Google Scholar 

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We are grateful to the affected individuals and their families for their participation in the study. The team of L.C. was supported in part by the Centre National de la Recherche Scientifique and the French National Research Agency (ANR-08-MNP-010). Work by the team of L.K.K. is supported by the US National Institutes of Health (NIH) grants HD067517, DC01919 and NS073943 and a grant from the FRAXA foundation. The Laboratory of Human Genetics of Infectious Diseases is supported in part by grants from the St. Giles Foundation, the Rockefeller University Center for Clinical and Translational Science grant 5UL1RR024143 and the Rockefeller University.

Author information




R.N. designed the study. G.B. and L.C. designed and performed the genetics experiments and wrote the sections related to sequence analysis. J.-L.C. and A.A. performed the exome study and wrote the section related to exome sequencing. P.N. developed the web interface allowing exome data analysis. G.B. and L.C. analyzed the exome data. M.L. contributed to genetic experiments. L.K.K. supervised electrophysiological experiments. M.R.F. and L.K.K. designed the electrophysiology experiments, coordinated the analysis of recordings and wrote the sections related to electrophysiology. M.R.F. performed macroscopic current electrophysiology recordings, and J.K. carried out the single-channel recordings. J.K., M.R.B. and H.C. participated in the design and analysis of the electrophysiological data. V.-R.G. performed immunohistochemistry and wrote the related section. R.N., O.D., I.D., A.D., A.K. and R.C. recruited and evaluated the study subjects. N.B. performed and analyzed brain imaging. O.D. and A.M. participated in revising the manuscript. R.N. and L.C. supervised G.B. and wrote and revised the manuscript.

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Correspondence to Rima Nabbout.

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Barcia, G., Fleming, M., Deligniere, A. et al. De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy. Nat Genet 44, 1255–1259 (2012).

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