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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: | https://ahro.austin.org.au/austinjspui/handle/1/12478 | DOI: | 10.1038/ng.3144 | Journal: | Nature genetics | 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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