1. De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy
- Author
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Maile R. Brown, Roberta Cilio, Matthew R. Fleming, Laurence Colleaux, Giulia Barcia, Aline Deligniere, Isabelle Desguerre, Leonard K. Kaczmarek, Nathalie Boddaert, Avinash Abhyankar, Maéva Langouët, Patrick Nitschké, Anna Kaminska, Valeswara-Rao Gazula, Rima Nabbout, Jean-Laurent Casanova, Jack Kronengold, Haijun Chen, Olivier Dulac, Arnold Munnich, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Épilepsie de l'enfant et plasticité cérébrale (Inserm U663), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), Service de neurologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Bio-informatic, New York Genome Center, Service d'informatique médicale et biostatistiques [CHU Necker], Service de radiologie pédiatrique [CHU Necker], St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], and The Rockefeller University
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Proband ,Genetics ,0303 health sciences ,medicine.medical_specialty ,Biology ,Potassium channel ,Article ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,Cytoplasm ,Internal medicine ,medicine ,Phosphorylation ,Signal transduction ,Protein kinase A ,030217 neurology & neurosurgery ,Function (biology) ,Exome sequencing ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology - 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.
- Published
- 2012
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