Malignant migrating partial seizures of infancy (MMPSI) is a rare epileptic encephalopathy of infancy that combines pharmacoresistant seizures with developmental delay. 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.
Pubmed ID: 23086397 RIS Download
Mesh terms: Animals | Cells, Cultured | Electroencephalography | Epilepsies, Partial | Exome | Humans | Infant | Infant, Newborn | Intermediate-Conductance Calcium-Activated Potassium Channels | Mice | Mutation | Neurons | Phosphorylation | Protein Kinase C | Rats | Signal Transduction | Xenopus
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