A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy (vol 47, pg 39, 2015)

被引:237
作者
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, Joao
Privitera, Michael
Espay, Alberto J.
Kauffmann, Birgit
Duchowny, Michael
Moller, Rikke S.
Straussberg, Rachel
Afawi, Zaid
Ben-Zeev, Bruria
Samocha, Kaitlin E.
Daly, Mark J.
Petrou, Steven
Lerche, Holger
Palotie, Aarno
机构
[1] Institute for Molecular Medicine Finland, University of Helsinki, Helsinki
[2] Folkhälsan Institute of Genetics, Helsinki
[3] Neuroscience Center, University of Helsinki, Helsinki
[4] Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki
[5] Epilepsy Research Center, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC
[6] School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA
[7] Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen
[8] Department of Neurophysiopathology, C. Besta Foundation Neurological Institute, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Milan
[9] Neurology Unit, IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna
[10] Montreal Neurological Institute, McGill University, Montreal, QC
[11] Institute of Neurology, University Magna Graecia, Catanzaro
[12] Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna
[13] Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC
[14] Department of Pediatrics, Royal Children's Hospital, University of Melbourne, Melbourne, VIC
[15] Department of Neurosciences, Reproductive Sciences and Odontostomatology, Federico II University, Naples
[16] Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro
[17] Regional Epilepsy Center, Bianchi-Melacrino-Morelli Hospital, Reggio Calabria
[18] Department of Biotechnology and Informatics, Balochistan University of Information Technology, Engineering and Management Sciences, Quetta
[19] Department of Medicine, Mayo Hospital, Lahore
[20] Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul
[21] Epilepsy Center (EPIMER), Istanbul University, Istanbul
[22] Department of Anatomy and Cell Biology, University of Malta, Msida
[23] Section of Medical Genetics, Mater dei Hospital, Msida
[24] Division of Pediatric Neurology, Department of Pediatrics, Hacettepe University, Faculty of Medicine, Ankara
[25] Department of Neurology, Temple Street Children's University Hospital, Dublin
[26] Academic Centre on Rare Diseases, School of Medicine and Medical Science, University College Dublin, Dublin
[27] Department of Neurology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul
[28] Division of Neurology, Department of Medicine, University of Toronto, Toronto Western Hospital, Krembil Neurosciences Program, Toronto, ON
[29] Department of Clinical Medicine, University of Bergen, Bergen
[30] Department of Neurology, Haukeland University Hospital, Bergen
[31] Epilepsy Unit, Hôpital Gui de Chauliac, Montpellier
[32] Department of Neurology and Epileptology, Epilepsy Center Hamburg-Alsterdorf, Hamburg
[33] Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen
[34] German Center for Neurodegenerative Diseases (DZNE), Tübingen
[35] Developmental Neurology Unit, C. Besta Foundation Neurological Institute, IRCCS, Milan
[36] Department of Neurology, Centro Hospitalar São João, Porto
[37] Department of Clinical Neurosciences and Mental Health, Faculty of Medicine, University of Porto, Porto
[38] Epilepsy Center, University of Cincinnati, Neuroscience Institute, Cincinnati, OH
[39] Gardner Center for Parkinson Disease and Movement Disorders, University of Cincinnati, Cincinnati, OH
[40] Klinikum Links der Weser, Bremen
[41] Brain Institute, Miami Children's Hospital, Miami, FL
[42] Department of Neurology, University of Miami Miller, School of Medicine, Miami, FL
[43] Danish Epilepsy Centre, Dianalund
[44] Institute of Regional Health Services Research, University of Southern Denmark, Odense
[45] Neurogenetic Clinic, Child Neurology Institute, Schneider Children's Medical Center of Israel, Petah Tiqvah
[46] Sackler School of Medicine, Tel-Aviv University, Ramat Aviv
[47] Zlotowski Center for Neuroscience, Ben-Gurion University, Beer-Sheva
[48] Pediatric Neurology Unit, Edmond and Lilly Safra Children's Hospital, Sheba Medical Center, Ramat-Gan
[49] Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA
[50] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA
基金
澳大利亚国家健康与医学研究理事会; 芬兰科学院; 英国医学研究理事会; 英国惠康基金;
关键词
D O I
10.1038/ng.3144
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Progressive myoclonus epilepsies (PMEs) are a group of rare, inherited disorders manifesting with action myoclonus, tonicclonic 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 K(V)3.1, a subunit of the K(V)3 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.
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页码:39 / +
页数:1
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[1]   A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy (vol 47, pg 39, 2015) [J].
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, Joao ;
Privitera, Michael ;
Espay, Alberto J. ;
Kauffmann, Birgit ;
Duchowny, Michael ;
Moller, Rikke S. ;
Straussberg, Rachel ;
Afawi, Zaid ;
Ben-Zeev, Bruria ;
Samocha, Kaitlin E. ;
Daly, Mark J. ;
Petrou, Steven ;
Lerche, Holger ;
Palotie, Aarno .
NATURE GENETICS, 2015, 47 (01) :39-+