A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy

• Published in: Nature genetics Vol. 47; no. 1; pp. 39 - 46
• Main 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
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.01.2015; Nature Publishing Group
• Subjects: 45/23; 64/114; 692/308/2056; 9/26; Agriculture; Amino Acid Sequence; Amino Acid Substitution; Animal Genetics and Genomics; Animals; Base Sequence; Biomedicine; Cancer Research; Carrier Proteins - genetics; Conserved Sequence; Data analysis; Deoxyribonucleic acid; Disease; DNA; Exome; Female; Gene Function; Gene mutations; Genes, Dominant; Genetic aspects; Genetic testing; Grants; GTPase-Activating Proteins; Health aspects; Heat-Shock Proteins - genetics; Human Genetics; Humans; Male; Membrane Proteins; Mitochondrial DNA; Molecular Sequence Data; Mutation; Mutation, Missense; Myoclonic Epilepsies, Progressive - genetics; Myoclonic epilepsy; Nerve Tissue Proteins; Parents & parenting; Pedigree; Point Mutation; Prion Proteins; Prions - genetics; Protein Conformation; Risk factors; Sequence Alignment; Sequence Homology, Amino Acid; Shaw Potassium Channels - genetics; Shaw Potassium Channels - physiology; Species Specificity; Australia; Germany; Finland
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.3144

Anna-Elina Lehesjoki and colleagues report exome sequencing of 84 cases of progressive myoclonus epilepsy (PME) and targeted resequencing of an additional 28 cases. They identify de novo mutations in KCNC1 in 13 cases and mutations in genes not previously associated with PME, including PRNP , SACS and TBC1D24 , in additional cases. 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 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.