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 3 probands with MMPSI and identified de novo gain-of-function mutations in the C-terminal domain of the KCNT1 potassium channel. We sequenced KCNT1 in 9 additional patients with MMPSI and identified mutations in 4 of them, in total identifying mutations in 6 out of 12 unrelated patients. 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 target for future diagnostic approaches and research in this devastating condition.
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