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

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          Abstract

          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.

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          Author and article information

          Journal
          Nat Genet
          Nature genetics
          Springer Science and Business Media LLC
          1546-1718
          1061-4036
          Nov 2012
          : 44
          : 11
          Affiliations
          [1 ] Department of Pediatric Neurology, Centre de Reference Epilepsies Rares, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, France.
          Article
          ng.2441 NIHMS476852
          10.1038/ng.2441
          3687547
          23086397
          8a1077e5-486e-406a-86b5-dd73c7ffe5d8
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