| Literature DB >> 25401298 |
Mikko Muona1, Samuel F Berkovic2, Leanne M Dibbens3, Karen L Oliver2, Snezana Maljevic4, Marta A Bayly3, Tarja Joensuu5, Laura Canafoglia6, Silvana Franceschetti6, Roberto Michelucci7, Salla Markkinen5, Sarah E Heron3, Michael S Hildebrand2, Eva Andermann8, Frederick Andermann8, Antonio Gambardella9, Paolo Tinuper10, Laura Licchetta10, Ingrid E Scheffer11, Chiara Criscuolo12, Alessandro Filla12, Edoardo Ferlazzo13, Jamil Ahmad14, Adeel Ahmad15, Betul Baykan16, Edith Said17, Meral Topcu18, Patrizia Riguzzi7, Mary D King19, Cigdem Ozkara20, Danielle M Andrade21, Bernt A Engelsen22, Arielle Crespel23, Matthias Lindenau24, Ebba Lohmann25, Veronica Saletti26, João Massano27, Michael Privitera28, Alberto J Espay29, Birgit Kauffmann30, Michael Duchowny31, Rikke S Møller32, Rachel Straussberg33, Zaid Afawi34, Bruria Ben-Zeev35, Kaitlin E Samocha36, Mark J Daly37, Steven Petrou38, Holger Lerche4, Aarno Palotie39, Anna-Elina Lehesjoki5.
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.Entities:
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Year: 2014 PMID： 25401298 PMCID： PMC4281260 DOI： 10.1038/ng.3144
Source DB: PubMed Journal: Nat Genet ISSN： 1061-4036 Impact factor: 38.330