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

2014-11-17

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

Journal Article

10.1038/ng.3144

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.

link

Nature Genetics 2014; 47(1): 39-46

Nature genetics