2. Academic Validation
  3. A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy

A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy

  • Nat Genet. 2015 Jan;47(1):39-46. doi: 10.1038/ng.3144.
Mikko Muona 1,  Samuel F Berkovic 2,  Leanne M Dibbens 3,  Karen L Oliver 2,  Snezana Maljevic 4,  Marta A Bayly 3,  Tarja Joensuu 5,  Laura Canafoglia 6,  Silvana Franceschetti 6,  Roberto Michelucci 7,  Salla Markkinen 5,  Sarah E Heron 3,  Michael S Hildebrand 2,  Eva Andermann 8,  Frederick Andermann 8,  Antonio Gambardella 9,  Paolo Tinuper 10,  Laura Licchetta 10,  Ingrid E Scheffer 11,  Chiara Criscuolo 12,  Alessandro Filla 12,  Edoardo Ferlazzo 13,  Jamil Ahmad 14,  Adeel Ahmad 15,  Betul Baykan 16,  Edith Said 17,  Meral Topcu 18,  Patrizia Riguzzi 7,  Mary D King 19,  Cigdem Ozkara 20,  Danielle M Andrade 21,  Bernt A Engelsen 22,  Arielle Crespel 23,  Matthias Lindenau 24,  Ebba Lohmann 25,  Veronica Saletti 26,  João Massano 27,  Michael Privitera 28,  Alberto J Espay 29,  Birgit Kauffmann 30,  Michael Duchowny 31,  Rikke S Møller 32,  Rachel Straussberg 33,  Zaid Afawi 34,  Bruria Ben-Zeev 35,  Kaitlin E Samocha 36,  Mark J Daly 37,  Steven Petrou 38,  Holger Lerche 4,  Aarno Palotie 39,  Anna-Elina Lehesjoki 5
Affiliations

Affiliations

  • 1 1] Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland. [2] Folkhälsan Institute of Genetics, Helsinki, Finland. [3] Neuroscience Center, University of Helsinki, Helsinki, Finland. [4] Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.
  • 2 Epilepsy Research Center, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.
  • 3 School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.
  • 4 Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
  • 5 1] Folkhälsan Institute of Genetics, Helsinki, Finland. [2] Neuroscience Center, University of Helsinki, Helsinki, Finland. [3] Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.
  • 6 Department of Neurophysiopathology, C. Besta Foundation Neurological Institute, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Milan, Italy.
  • 7 Neurology Unit, IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy.
  • 8 Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
  • 9 Institute of Neurology, University Magna Graecia, Catanzaro, Italy.
  • 10 1] Neurology Unit, IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy. [2] Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
  • 11 1] Epilepsy Research Center, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia. [2] Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria, Australia. [3] Department of Pediatrics, Royal Children's Hospital, University of Melbourne, Melbourne, Victoria, Australia.
  • 12 Department of Neurosciences, Reproductive Sciences and Odontostomatology, Federico II University, Naples, Italy.
  • 13 1] Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy. [2] Regional Epilepsy Center, Bianchi-Melacrino-Morelli Hospital, Reggio Calabria, Italy.
  • 14 Department of Biotechnology and Informatics, Balochistan University of Information Technology, Engineering and Management Sciences, Quetta, Pakistan.
  • 15 Department of Medicine, Mayo Hospital, Lahore, Pakistan.
  • 16 1] Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey. [2] Epilepsy Center (EPIMER), Istanbul University, Istanbul, Turkey.
  • 17 1] Department of Anatomy and Cell Biology, University of Malta, Msida, Malta. [2] Section of Medical Genetics, Mater dei Hospital, Msida, Malta.
  • 18 Division of Pediatric Neurology, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey.
  • 19 1] Department of Neurology, Temple Street Children's University Hospital, Dublin, Ireland. [2] Academic Centre on Rare Diseases, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
  • 20 Department of Neurology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey.
  • 21 Division of Neurology, Department of Medicine, University of Toronto, Toronto Western Hospital, Krembil Neurosciences Program, Toronto, Ontario, Canada.
  • 22 1] Department of Clinical Medicine, University of Bergen, Bergen, Norway. [2] Department of Neurology, Haukeland University Hospital, Bergen, Norway.
  • 23 Epilepsy Unit, Hôpital Gui de Chauliac, Montpellier, France.
  • 24 Department of Neurology and Epileptology, Epilepsy Center Hamburg-Alsterdorf, Hamburg, Germany.
  • 25 1] Department of Neurology and Epileptology, Epilepsy Center Hamburg-Alsterdorf, Hamburg, Germany. [2] Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. [3] German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
  • 26 Developmental Neurology Unit, C. Besta Foundation Neurological Institute, IRCCS, Milan, Italy.
  • 27 1] Department of Neurology, Centro Hospitalar São João, Porto, Portugal. [2] Department of Clinical Neurosciences and Mental Health, Faculty of Medicine, University of Porto, Porto, Portugal.
  • 28 Epilepsy Center, University of Cincinnati Neuroscience Institute, Cincinnati, Ohio, USA.
  • 29 Gardner Center for Parkinson Disease and Movement Disorders, University of Cincinnati, Cincinnati, Ohio, USA.
  • 30 Klinikum Links der Weser, Bremen, Germany.
  • 31 1] Brain Institute, Miami Children's Hospital, Miami, Florida, USA. [2] Department of Neurology, University of Miami Miller School of Medicine, Miami, Florida, USA.
  • 32 1] Danish Epilepsy Centre, Dianalund, Denmark. [2] Institute of Regional Health Services Research, University of Southern Denmark, Odense, Denmark.
  • 33 1] Neurogenetic Clinic, Child Neurology Institute, Schneider Children's Medical Center of Israel, Petah Tiqvah, Israel. [2] Sackler School of Medicine, Tel-Aviv University, Ramat Aviv, Israel.
  • 34 1] Sackler School of Medicine, Tel-Aviv University, Ramat Aviv, Israel. [2] Zlotowski Center for Neuroscience, Ben-Gurion University, Beer-Sheva, Israel.
  • 35 1] Sackler School of Medicine, Tel-Aviv University, Ramat Aviv, Israel. [2] Pediatric Neurology Unit, Edmond and Lilly Safra Children's Hospital, Sheba Medical Center, Ramat-Gan, Israel.
  • 36 1] Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [3] Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [4] Program in Genetics and Genomics, Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts, USA.
  • 37 1] Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [3] Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [4] Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
  • 38 1] Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria, Australia. [2] Centre for Neural Engineering, University of Melbourne, Melbourne, Victoria, Australia.
  • 39 1] Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland. [2] Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [3] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [4] Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [5] Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK. [6] Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts, USA. [7] Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.
PMID: 25401298 DOI: 10.1038/ng.3144
Abstract

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.

Figures