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Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy

Nature Genetics volume 44, pages 1188–1190 (2012)Cite this article

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Abstract

We performed genomic mapping of a family with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) and intellectual and psychiatric problems, identifying a disease-associated region on chromosome 9q34.3. Whole-exome sequencing identified a mutation in KCNT1, encoding a sodium-gated potassium channel subunit. KCNT1 mutations were identified in two additional families and a sporadic case with severe ADNFLE and psychiatric features. These findings implicate the sodium-gated potassium channel complex in ADNFLE and, more broadly, in the pathogenesis of focal epilepsies.

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Figure 1: KCNT1 mutations in ADNFLE and sporadic NFLE.

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Acknowledgements

We thank the affected individuals and their families for their participation in this study, and B. Johns and R. Schultz for technical assistance. This work was supported by the National Health and Medical Research Council of Australia (Program Grant 628952 to S.F.B., I.E.S., S.P. and L.M.D., Program Grant 490037 to M.B., Training Fellowship 1016715 to S.E.H., Senior Research Fellowship 1005050 to S.P., Australia Fellowship 466671 to S.F.B., Practitioner Fellowship 1006110 to I.E.S. and Career Development Fellowship 1032603 to L.M.D.). The Florey Institute of Neuroscience and Mental Health is supported by Victorian State government infrastructure funds. K.R.S. is supported by a PhD scholarship funded by the Pratt Foundation. M.B. is supported by Australian Research Council Future Fellowship FT100100764. Work by K.R.S. and M.B. was also supported by Victorian State Government Operational Infrastructure and Australian Government National Health and Medical Research Council Independent Research Institutes Infrastructure Support Scheme (IRIISS) funding. The study was approved by the Human Research Ethics Committees of Austin Health and the University of South Australia. Informed consent was obtained from all participants or their parents or guardians.

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Author notes

  1. Ingrid E Scheffer and Leanne M Dibbens: These authors jointly directed this work.

Authors and Affiliations

  1. Epilepsy Research Program, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia

    Sarah E Heron & Leanne M Dibbens

  2. Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia

    Sarah E Heron & Leanne M Dibbens

  3. Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia

    Katherine R Smith & Melanie Bahlo

  4. Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia

    Katherine R Smith

  5. Department of Mathematics and Statistics, The University of Melbourne, Melbourne, Victoria, Australia

    Melanie Bahlo

  6. Epilepsy Surgery Center, Sleep Medicine Center, Ospedale Niguarda, Milan, Italy

    Lino Nobili

  7. Department of Neurology, Barzilai Medical Center, Ashkelon, School of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel

    Esther Kahana

  8. Department of Medicine, Epilepsy Research Centre, The University of Melbourne, Melbourne, Victoria, Australia

    Laura Licchetta, Karen L Oliver, Samuel F Berkovic & Ingrid E Scheffer

  9. Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel

    Aziz Mazarib

  10. Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv, Israel

    Zaid Afawi

  11. Sieratzki Chair of Neurology, Tel-Aviv University Medical School, Ramat Aviv, Israel

    Amos Korczyn

  12. Department of Neurological Sciences, University of Bologna, Bologna, Italy

    Giuseppe Plazzi

  13. Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia

    Steven Petrou & Ingrid E Scheffer

  14. Department of Anatomy and Neuroscience, The University of Melbourne, Melbourne, Victoria, Australia

    Steven Petrou

  15. Centre for Neural Engineering, The University of Melbourne, Melbourne, Victoria, Australia

    Steven Petrou

  16. Department of Paediatrics, The University of Melbourne, Royal Children's Hospital, Melbourne, Victoria, Australia

    Ingrid E Scheffer

Authors
  1. Sarah E Heron
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  2. Katherine R Smith
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  3. Melanie Bahlo
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  4. Lino Nobili
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  5. Esther Kahana
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  6. Laura Licchetta
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  7. Karen L Oliver
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  8. Aziz Mazarib
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  10. Amos Korczyn
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  11. Giuseppe Plazzi
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  12. Steven Petrou
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  13. Samuel F Berkovic
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  14. Ingrid E Scheffer
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  15. Leanne M Dibbens
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Contributions

S.E.H. analyzed whole-exome sequencing data, and designed and performed the molecular genetic aspects of the project. K.R.S. performed linkage analysis. M.B. supervised linkage analysis. K.L.O. and L.L. collated and analyzed clinical data. G.P., L.N., E.K., A.M., Z.A., A.K. and I.E.S. identified families and provided clinical information. S.P. contributed to discussions on the functional effects of the mutations. L.M.D. designed and oversaw the study. S.E.H., I.E.S., S.F.B. and L.M.D. wrote the manuscript.

Corresponding author

Correspondence to Samuel F Berkovic.

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The authors declare no competing financial interests.

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Supplementary Methods, Supplementary Table 1 and Supplementary Figure 1 (PDF 159 kb)

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Heron, S., Smith, K., Bahlo, M. et al. Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet 44, 1188–1190 (2012). https://doi.org/10.1038/ng.2440

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