A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy.

Nat Genet
Authors
Keywords
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.

Year of Publication
2015
Journal
Nat Genet
Volume
47
Issue
1
Pages
39-46
Date Published
2015 Jan
ISSN
1546-1718
URL
DOI
10.1038/ng.3144
PubMed ID
25401298
PubMed Central ID
PMC4281260
Links
Grant list
089062 / Wellcome Trust / United Kingdom
098051 / Wellcome Trust / United Kingdom