A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy

• Type: Article in International Scientific Journal
• Date: 2015

Authors

Muona, M (Author) Other; Berkovic, SF (Author) Other; Dibbens, LM (Author) Other; Oliver, KL (Author) Other; Maljevic, S (Author) Other; Bayly, MA (Author) Other; Joensuu, T (Author) Other; Canafoglia, L (Author) Other; Franceschetti, S (Author) Other; Michelucci, R (Author) Other; Markkinen, S (Author) Other; Heron, SE (Author) Other; Hildebrand, MS (Author) Other; Andermann, E (Author) Other; Andermann, F (Author) Other; Gambardella, A (Author) Other; Tinuper, P (Author) Other; Licchetta, L (Author) Other; Scheffer, IE (Author) Other; Criscuolo, C (Author) Other; Filla, A (Author) Other; Ferlazzo, E (Author) Other; Ahmad, J (Author) Other; Ahmad, A (Author) Other; Baykan, B (Author) Other; Said, E (Author) Other; Topcu, M (Author) Other; Riguzzi, P (Author) Other; King, MD (Author) Other; Ozkara, C (Author) Other; Andrade, DM (Author) Other; Engelsen, BA (Author) Other; Crespel, A (Author) Other; Lindenau, M (Author) Other; Lohmann, E (Author) Other; Saletti, V (Author) Other; João Massano (Author) FMUP; Privitera, M (Author) Other; Espay, AJ (Author) Other; Kauffmann, B (Author) Other; Duchowny, M (Author) Other; Moller, RS (Author) Other; Straussberg, R (Author) Other; Afawi, Z (Author) Other; Ben Zeev, B (Author) Other; Samocha, KE (Author) Other; Daly, MJ (Author) Other; Petrou, S (Author) Other; Lerche, H (Author) Other; Palotie, A (Author) Other; Lehesjoki, AE (Author) Other

Journal

Title: Nature Genetics

Vol. 47

Pages: 39-+

ISSN: 1061-4036

Publisher: Springer Nature

Indexing

ISI Web of Knowledge - 181 Citations

Scopus - 188 Citations

Other information

Authenticus ID: P-00A-3Q4

DOI: 10.1038/ng.3144

Abstract (EN): 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 11