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

Nat Genet. 2012 Nov;44(11):1255-9. doi: 10.1038/ng.2441. Epub 2012 Oct 21.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Electroencephalography
  • Epilepsies, Partial / genetics*
  • Epilepsies, Partial / physiopathology
  • Exome
  • Humans
  • Infant
  • Infant, Newborn
  • Intermediate-Conductance Calcium-Activated Potassium Channels* / genetics
  • Intermediate-Conductance Calcium-Activated Potassium Channels* / metabolism
  • Mice
  • Mutation
  • Neurons* / cytology
  • Neurons* / metabolism
  • Phosphorylation
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism
  • Rats
  • Signal Transduction
  • Xenopus

Substances

  • Intermediate-Conductance Calcium-Activated Potassium Channels
  • KCNN4 protein, human
  • Protein Kinase C