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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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.
The authors declare no competing financial interests.
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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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