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

Nature genetics | Nov 29, 2012

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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Associated grants

  • Agency: NIDCD NIH HHS, Id: DC01919
  • Agency: NICHD NIH HHS, Id: R01 HD067517
  • Agency: NINDS NIH HHS, Id: NS073943
  • Agency: NCRR NIH HHS, Id: 5UL1RR024143
  • Agency: NINDS NIH HHS, Id: R21 NS073943
  • Agency: NCRR NIH HHS, Id: UL1 RR024143
  • Agency: NICHD NIH HHS, Id: HD067517
  • Agency: NIDCD NIH HHS, Id: R01 DC001919

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