TY - JOUR
T1 - A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy
AU - Muona, Mikko
AU - Berkovic, Samuel F.
AU - Dibbens, Leanne M.
AU - Oliver, Karen L.
AU - Maljevic, Snezana
AU - Bayly, Marta A.
AU - Joensuu, Tarja
AU - Canafoglia, Laura
AU - Franceschetti, Silvana
AU - Michelucci, Roberto
AU - Markkinen, Salla
AU - Heron, Sarah E.
AU - Hildebrand, Michael S.
AU - Andermann, Eva
AU - Andermann, Frederick
AU - Gambardella, Antonio
AU - Tinuper, Paolo
AU - Licchetta, Laura
AU - Scheffer, Ingrid E.
AU - Criscuolo, Chiara
AU - Filla, Alessandro
AU - Ferlazzo, Edoardo
AU - Ahmad, Jamil
AU - Ahmad, Adeel
AU - Baykan, Betul
AU - Said, Edith
AU - Topcu, Meral
AU - Riguzzi, Patrizia
AU - King, Mary D.
AU - Ozkara, Cigdem
AU - Andrade, Danielle M.
AU - Engelsen, Bernt A.
AU - Crespel, Arielle
AU - Lindenau, Matthias
AU - Lohmann, Ebba
AU - Saletti, Veronica
AU - Massano, João
AU - Privitera, Michael
AU - Espay, Alberto J.
AU - Kauffmann, Birgit
AU - Duchowny, Michael
AU - Møller, Rikke S.
AU - Straussberg, Rachel
AU - Afawi, Zaid
AU - Ben-Zeev, Bruria
AU - Samocha, Kaitlin E.
AU - Daly, Mark J.
AU - Petrou, Steven
AU - Lerche, Holger
AU - Palotie, Aarno
AU - Lehesjoki, Anna Elina
N1 - Funding Information:
We thank the patients and family members who contributed samples for the purpose of this study. We also thank the following for patient referrals: K. Joost, K. Carvalho, C. Marques Lourenco, P. Cossette, A. Covanis, A. Parmeggiani, P. Van Bogaert, S. Mole, A. Sierra Marcos, M. Carreno and S.S. Rich. We thank P. Hakala, E. Hämäläinen, B. Johns, R. Schulz, J. Damiano, H. Löffler and N. Jezutkovic for sample logistics and technical assistance in the laboratory, C. Scott and J. Durham (Wellcome Trust Sanger Institute) for exome sequence processing, P. Gormley, B. Winsvold and P. Palta for assistance in exome data analysis, and A. Farooq Bazai for support. CSC–IT Center for Science, Ltd., is acknowledged for the allocation of computational resources. This study was supported by the Folkhälsan Research Foundation (A.-E.L.), Academy of Finland grant 141549 (A.-E.L.), Wellcome Trust grants 089062 and 098051 (A.P.), European Commission Framework Programme 7 (FP7) project 201413 ENGAGE (A.P.), project 242167 SynSys (A.P.), Health-2010 projects 261433 BioSHare (A.P.) and project 261123 gEUVADIS (A.P.), Academy of Finland grants 251704 and 263401 (A.P.), the Sigrid Juselius Foundation (A.P.), US NIH grant RFA-HL-12-007 (A.P.), the Emil Aaltonen Foundation (M.M.), Epilepsiatutkimussäätiö (M.M.), University of Helsinki Funds (M.M.), the Doctoral Programme in Biomedicine (M.M.), National Health and Medical Research Council (NHMRC) of Australia program grant 628952 (S.F.B., L.M.D. and I.E.S.), NHMRC Career Development Fellowship 1032603 (L.M.D.), NHMRC Early Career Fellowship 1016715 (S.E.H.), the German Network for Rare Diseases of the Federal Ministry of Education and Research (BMBF), IonNeurONet 01GM1105A (S. Maljevic and H.L.), the EuroEPINOMICS program of the European Science Foundation, German Research Foundation (DFG) grant Le1030/11-1 (H.L. and S. Maljevic), NHMRC program grant 400121 (S.P.) and NMHRC fellowship 1005050 (S.P.). The Florey Institute of Neuroscience and Mental Health (S.P.) is supported by government infrastructure funds from the state of Victoria.
PY - 2015/1/1
Y1 - 2015/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84930946843&partnerID=8YFLogxK
U2 - 10.1038/ng.3144
DO - 10.1038/ng.3144
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C2 - 25401298
AN - SCOPUS:84930946843
SN - 1061-4036
VL - 47
SP - 39
EP - 46
JO - Nature Genetics
JF - Nature Genetics
IS - 1
ER -