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

Abstract

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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Acknowledgements

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.

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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). https://doi.org/10.1038/ng.2441

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