Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/12478
Title: A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy.
Austin Authors: Muona, Mikko;Berkovic, Samuel F ;Dibbens, Leanne M;Oliver, Karen L;Maljevic, Snezana;Bayly, Marta A;Joensuu, Tarja;Canafoglia, Laura;Franceschetti, Silvana;Michelucci, Roberto;Markkinen, Salla;Heron, Sarah E;Hildebrand, Michael S ;Andermann, Eva;Andermann, Frederick;Gambardella, Antonio;Tinuper, Paolo;Licchetta, Laura;Scheffer, Ingrid E ;Criscuolo, Chiara;Filla, Alessandro;Ferlazzo, Edoardo;Ahmad, Jamil;Ahmad, Adeel;Baykan, Betul;Said, Edith;Topcu, Meral;Riguzzi, Patrizia;King, Mary D;Ozkara, Cigdem;Andrade, Danielle M;Engelsen, Bernt A;Crespel, Arielle;Lindenau, Matthias;Lohmann, Ebba;Saletti, Veronica;Massano, João;Privitera, Michael;Espay, Alberto J;Kauffmann, Birgit;Duchowny, Michael;Møller, Rikke S;Straussberg, Rachel;Afawi, Zaid;Ben-Zeev, Bruria;Samocha, Kaitlin E;Daly, Mark J;Petrou, Steven;Lerche, Holger;Palotie, Aarno;Lehesjoki, Anna-Elina
Affiliation: Epilepsy Research Center, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Epilepsy Center, University of Cincinnati Neuroscience Institute, Cincinnati, Ohio, USA
Gardner Center for Parkinson Disease and Movement Disorders, University of Cincinnati, Cincinnati, Ohio, USA
Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia
Division of Neurology, Department of Medicine, University of Toronto, Toronto Western Hospital, Krembil Neurosciences Program, Toronto, Ontario, Canada
Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA
Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.
Brain Institute, Miami Children's Hospital, Miami, Florida, USA
Epilepsy Research Center, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
Danish Epilepsy Centre, Dianalund, Denmark.
Department of Neurology, Centro Hospitalar São João, Porto, Portugal.
Neurogenetic Clinic, Child Neurology Institute, Schneider Children's Medical Center of Israel, Petah Tiqvah, Israel.
Neurology Unit, IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy.
Department of Clinical Medicine, University of Bergen, Bergen, Norway.
Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy.
Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
Department of Anatomy and Cell Biology, University of Malta, Msida, Malta.
Department of Neurology, Temple Street Children's University Hospital, Dublin, Ireland.
Department of Neurology and Epileptology, Epilepsy Center Hamburg-Alsterdorf, Hamburg, Germany.
Program in Genetics and Genomics, Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts, USA
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK
Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts, USA
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA
Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria, Australia
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
Department of Neurology, University of Miami Miller School of Medicine, Miami, Florida, USA
Centre for Neural Engineering, University of Melbourne, Melbourne, Victoria, Australia
Institute of Regional Health Services Research, University of Southern Denmark, Odense, Denmark.
Department of Clinical Neurosciences and Mental Health, Faculty of Medicine, University of Porto, Porto, Portugal.
Sackler School of Medicine, Tel-Aviv University, Ramat Aviv, Israel.
Zlotowski Center for Neuroscience, Ben-Gurion University, Beer-Sheva, Israel.
Pediatric Neurology Unit, Edmond and Lilly Safra Children's Hospital, Sheba Medical Center, Ramat-Gan, Israel.
Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
Department of Neurology, Haukeland University Hospital, Bergen, Norway.
Regional Epilepsy Center, Bianchi-Melacrino-Morelli Hospital, Reggio Calabria, Italy.
Epilepsy Center (EPIMER), Istanbul University, Istanbul, Turkey.
Section of Medical Genetics, Mater dei Hospital, Msida, Malta.
Academic Centre on Rare Diseases, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA
Department of Pediatrics, Royal Children's Hospital, University of Melbourne, Melbourne, Victoria, Australia
Folkhälsan Institute of Genetics, Helsinki, Finland.
Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
Neuroscience Center, University of Helsinki, Helsinki, Finland.
Department of Neurophysiopathology, C. Besta Foundation Neurological Institute, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Milan, Italy.
Institute of Neurology, University Magna Graecia, Catanzaro, Italy.
Department of Neurosciences, Reproductive Sciences and Odontostomatology, Federico II University, Naples, Italy.
Department of Biotechnology and Informatics, Balochistan University of Information Technology, Engineering and Management Sciences, Quetta, Pakistan.
Department of Medicine, Mayo Hospital, Lahore, Pakistan.
Division of Pediatric Neurology, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey.
Neurology Unit, IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy.
Department of Neurology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey.
Epilepsy Unit, Hôpital Gui de Chauliac, Montpellier, France.
Department of Neurology and Epileptology, Epilepsy Center Hamburg-Alsterdorf, Hamburg, Germany.
Developmental Neurology Unit, C. Besta Foundation Neurological Institute, IRCCS, Milan, Italy.
Klinikum Links der Weser, Bremen, Germany.
Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Issue Date: 17-Nov-2014
Publication information: Nature Genetics 2014; 47(1): 39-46
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.
Gov't Doc #: 25401298
URI: http://ahro.austin.org.au/austinjspui/handle/1/12478
DOI: 10.1038/ng.3144
URL: https://pubmed.ncbi.nlm.nih.gov/25401298
Type: Journal Article
Subjects: Amino Acid Sequence
Amino Acid Substitution
Animals
Base Sequence
Carrier Proteins.genetics
Conserved Sequence
Exome
Female
Genes, Dominant
Heat-Shock Proteins.genetics
Humans
Male
Molecular Sequence Data
Mutation, Missense
Myoclonic Epilepsies, Progressive.genetics
Pedigree
Point Mutation
Prions.genetics
Protein Conformation
Sequence Alignment
Sequence Homology, Amino Acid
Shaw Potassium Channels.genetics.physiology
Species Specificity
Appears in Collections:Journal articles

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