A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy

Mikko Muona, Samuel F. Berkovic, Leanne M. Dibbens, Karen L. Oliver, Snezana Maljevic, Marta A. Bayly, Tarja Joensuu, Laura Canafoglia, Silvana Franceschetti, Roberto Michelucci, Salla Markkinen, Sarah E. Heron, Michael S. Hildebrand, Eva Andermann, Frederick Andermann, Antonio Gambardella, Paolo Tinuper, Laura Licchetta, Ingrid E. Scheffer, Chiara CriscuoloAlessandro Filla, Edoardo Ferlazzo, Jamil Ahmad, Adeel Ahmad, Betul Baykan, Edith Said, Meral Topcu, Patrizia Riguzzi, Mary D. King, Cigdem Ozkara, Danielle M. Andrade, Bernt A. Engelsen, Arielle Crespel, Matthias Lindenau, Ebba Lohmann, Veronica Saletti, João Massano, Michael Privitera, Alberto J. Espay, Birgit Kauffmann, Michael Duchowny, Rikke S. Møller, Rachel Straussberg, Zaid Afawi, Bruria Ben-Zeev, Kaitlin E. Samocha, Mark J. Daly, Steven Petrou, Holger Lerche, Aarno Palotie, Anna Elina Lehesjoki

Research output: Contribution to journalArticlepeer-review


Progressive myoclonus epilepsies (PMEs) are a group of rare, inherited disorders manifesting with action myoclonus, tonic-clonic seizures and ataxia. We sequenced the exomes of 84 unrelated individuals with PME of unknown cause and molecularly solved 26 cases (31 %). Remarkably, a recurrent de novo mutation, c. 959G>A (p.Arg320His), in KCNC1 was identified as a new major cause for PME. Eleven unrelated exome-sequenced (13%) and two affected individuals in a secondary cohort (7%) had this mutation. KCNC1 encodes KV3.1, a subunit of the KV3 voltage-gated potassium ion channels, which are major determinants of high-frequency neuronal firing. Functional analysis of the Arg320His mutant channel showed a dominant-negative loss-of-function effect. Ten cases had pathogenic mutations in known PME-associated genes (NEU1, NHLRC1, AFG3L2, EPM2A, CLN6 and SERPINI1). Identification of mutations in PRNP, SACS and TBC1D24 expand their phenotypic spectra to PME. These findings provide insights into the molecular genetic basis of PME and show the role of de novo mutations in this disease entity.

Original languageEnglish
Pages (from-to)39-46
Number of pages8
JournalNature Genetics
Issue number1
Publication statusPublished - Jan 1 2015

ASJC Scopus subject areas

  • Genetics


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