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


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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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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Authors and Affiliations



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.

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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).

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