title: De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy.
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.
authors.affiliation: Department of Pediatric Neurology, Centre de Reference Epilepsies Rares, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, France.
authors.forename: Giulia
authors.initials: G
authors.lastname: Barcia
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Fleming
authors.forename: Aline
authors.initials: A
authors.lastname: Deligniere
authors.forename: Valeswara-Rao
authors.initials: VR
authors.lastname: Gazula
authors.forename: Maile R
authors.initials: MR
authors.lastname: Brown
authors.forename: Maeva
authors.initials: M
authors.lastname: Langouet
authors.forename: Haijun
authors.initials: H
authors.lastname: Chen
authors.forename: Jack
authors.initials: J
authors.lastname: Kronengold
authors.forename: Avinash
authors.initials: A
authors.lastname: Abhyankar
authors.forename: Roberta
authors.initials: R
authors.lastname: Cilio
authors.forename: Patrick
authors.initials: P
authors.lastname: Nitschke
authors.forename: Anna
authors.initials: A
authors.lastname: Kaminska
authors.forename: Nathalie
authors.initials: N
authors.lastname: Boddaert
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.forename: Isabelle
authors.initials: I
authors.lastname: Desguerre
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Olivier
authors.initials: O
authors.lastname: Dulac
authors.forename: Leonard K
authors.initials: LK
authors.lastname: Kaczmarek
authors.forename: Laurence
authors.initials: L
authors.lastname: Colleaux
authors.forename: Rima
authors.initials: R
authors.lastname: Nabbout
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004569:Electroencephalography; D004828:Epilepsies, Partial / Q000235:genetics* / Q000503:physiopathology; D059472:Exome; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D014981:Xenopus
chemical_list: D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human; D011493:Protein Kinase C