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Nat Genet January 1, 2015; 47 (1): 39-46.
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A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy.

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

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.

PubMed ID: 25401298
PMC ID: PMC4281260
Article link: Nat Genet

Species referenced: Xenopus
Genes referenced: afg3l2 cln6 cstb epm2a ids kcnc1 kcnc3 neu1 nhlrc1 prnp sacs serpini1
GO keywords: voltage-gated potassium channel activity

Disease Ontology terms: progressive myoclonus epilepsy

Article Images: [+] show captions
References [+] :
Abecasis, An integrated map of genetic variation from 1,092 human genomes. 2012, Pubmed