A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy.
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.
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.
Mikko
0000000209496650
M
Muona
Epilepsy Research Center, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.
Samuel F
SF
Berkovic
School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.
Leanne M
LM
Dibbens
Epilepsy Research Center, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.
Karen L
KL
Oliver
Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Snezana
S
Maljevic
School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.
Marta A
MA
Bayly
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.
Tarja
T
Joensuu
Department of Neurophysiopathology, C. Besta Foundation Neurological Institute, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Milan, Italy.
Laura
L
Canafoglia
Department of Neurophysiopathology, C. Besta Foundation Neurological Institute, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Milan, Italy.
Silvana
S
Franceschetti
Neurology Unit, IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy.
Roberto
R
Michelucci
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.
Salla
S
Markkinen
School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.
Sarah E
SE
Heron
Epilepsy Research Center, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.
Michael S
MS
Hildebrand
Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
Eva
E
Andermann
Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
Frederick
F
Andermann
Institute of Neurology, University Magna Graecia, Catanzaro, Italy.
Antonio
A
Gambardella
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.
Paolo
P
Tinuper
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.
Laura
L
Licchetta
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.
Ingrid E
IE
Scheffer
Department of Neurosciences, Reproductive Sciences and Odontostomatology, Federico II University, Naples, Italy.
Chiara
C
Criscuolo
Department of Neurosciences, Reproductive Sciences and Odontostomatology, Federico II University, Naples, Italy.
Alessandro
A
Filla
1] Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy. [2] Regional Epilepsy Center, Bianchi-Melacrino-Morelli Hospital, Reggio Calabria, Italy.
Edoardo
E
Ferlazzo
Department of Biotechnology and Informatics, Balochistan University of Information Technology, Engineering and Management Sciences, Quetta, Pakistan.
Jamil
0000000203204020
J
Ahmad
Department of Medicine, Mayo Hospital, Lahore, Pakistan.
Adeel
A
Ahmad
1] Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey. [2] Epilepsy Center (EPIMER), Istanbul University, Istanbul, Turkey.
Betul
B
Baykan
1] Department of Anatomy and Cell Biology, University of Malta, Msida, Malta. [2] Section of Medical Genetics, Mater dei Hospital, Msida, Malta.
Edith
E
Said
Division of Pediatric Neurology, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey.
Meral
M
Topcu
Neurology Unit, IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy.
Patrizia
P
Riguzzi
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.
Mary D
MD
King
Department of Neurology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey.
Cigdem
C
Ozkara
Division of Neurology, Department of Medicine, University of Toronto, Toronto Western Hospital, Krembil Neurosciences Program, Toronto, Ontario, Canada.
Danielle M
DM
Andrade
1] Department of Clinical Medicine, University of Bergen, Bergen, Norway. [2] Department of Neurology, Haukeland University Hospital, Bergen, Norway.
Bernt A
BA
Engelsen
Epilepsy Unit, Hôpital Gui de Chauliac, Montpellier, France.
Arielle
A
Crespel
Department of Neurology and Epileptology, Epilepsy Center Hamburg-Alsterdorf, Hamburg, Germany.
Matthias
M
Lindenau
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.
Ebba
E
Lohmann
Developmental Neurology Unit, C. Besta Foundation Neurological Institute, IRCCS, Milan, Italy.
Veronica
V
Saletti
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.
João
0000000257917149
J
Massano
Epilepsy Center, University of Cincinnati Neuroscience Institute, Cincinnati, Ohio, USA.
Michael
M
Privitera
Gardner Center for Parkinson Disease and Movement Disorders, University of Cincinnati, Cincinnati, Ohio, USA.
Alberto J
AJ
Espay
Klinikum Links der Weser, Bremen, Germany.
Birgit
B
Kauffmann
1] Brain Institute, Miami Children's Hospital, Miami, Florida, USA. [2] Department of Neurology, University of Miami Miller School of Medicine, Miami, Florida, USA.
Michael
M
Duchowny
1] Danish Epilepsy Centre, Dianalund, Denmark. [2] Institute of Regional Health Services Research, University of Southern Denmark, Odense, Denmark.
Rikke S
RS
Møller
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.
Rachel
R
Straussberg
1] Sackler School of Medicine, Tel-Aviv University, Ramat Aviv, Israel. [2] Zlotowski Center for Neuroscience, Ben-Gurion University, Beer-Sheva, Israel.
Zaid
Z
Afawi
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.
Bruria
B
Ben-Zeev
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.
Kaitlin E
KE
Samocha
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.
Mark J
MJ
Daly
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.
Steven
S
Petrou
Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Holger
H
Lerche
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.
Aarno
A
Palotie
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.
Anna-Elina
AE
Lehesjoki
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics; D017124:Conserved Sequence; D059472:Exome; D005260:Female; D020690:GTPase-Activating Proteins; D005799:Genes, Dominant; D006360:Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D020191:Myoclonic Epilepsies, Progressive / Q000235:genetics*; D009419:Nerve Tissue Proteins; D010375:Pedigree; D017354:Point Mutation; D000072002:Prion Proteins; D011328:Prions / Q000235:genetics; D011487:Protein Conformation; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D051670:Shaw Potassium Channels / Q000235:genetics* / Q000502:physiology; D013045:Species Specificity
D002352:Carrier Proteins; D020690:GTPase-Activating Proteins; D006360:Heat-Shock Proteins; C489597:KCNC1 protein, human; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C512656:PRNP protein, human; D000072002:Prion Proteins; D011328:Prions; C404403:SACS protein, human; D051670:Shaw Potassium Channels; C552551:TBC1D24 protein, human