2. Academic Validation
  3. Mutations in EFHC1 cause juvenile myoclonic epilepsy

Mutations in EFHC1 cause juvenile myoclonic epilepsy

  • Nat Genet. 2004 Aug;36(8):842-9. doi: 10.1038/ng1393.
Toshimitsu Suzuki 1,  Antonio V Delgado-Escueta,  Kripamoy Aguan,  Maria E Alonso,  Jun Shi,  Yuji Hara,  Motohiro Nishida,  Tomohiro Numata,  Marco T Medina,  Tamaki Takeuchi,  Ryoji Morita,  Dongsheng Bai,  Subramaniam Ganesh,  Yoshihisa Sugimoto,  Johji Inazawa,  Julia N Bailey,  Adriana Ochoa,  Aurelio Jara-Prado,  Astrid Rasmussen,  Jaime Ramos-Peek,  Sergio Cordova,  Francisco Rubio-Donnadieu,  Yushi Inoue,  Makiko Osawa,  Sunao Kaneko,  Hirokazu Oguni,  Yasuo Mori,  Kazuhiro Yamakawa
Affiliations

Affiliation

  • 1 Laboratory for Neurogenetics, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama, 351-0198, Japan.
PMID: 15258581 DOI: 10.1038/ng1393
Abstract

Juvenile myoclonic epilepsy (JME) is the most frequent cause of hereditary grand mal seizures. We previously mapped and narrowed a region associated with JME on chromosome 6p12-p11 (EJM1). Here, we describe a new gene in this region, EFHC1, which encodes a protein with an EF-hand motif. Mutation analyses identified five missense mutations in EFHC1 that cosegregated with epilepsy or EEG polyspike wave in affected members of six unrelated families with JME and did not occur in 382 control individuals. Overexpression of EFHC1 in mouse hippocampal primary culture neurons induced Apoptosis that was significantly lowered by the mutations. Apoptosis was specifically suppressed by SNX-482, an antagonist of R-type voltage-dependent Ca(2+) channel (Ca(v)2.3). EFHC1 and Ca(v)2.3 immunomaterials overlapped in mouse brain, and EFHC1 coimmunoprecipitated with the Ca(v)2.3 C terminus. In patch-clamp analysis, EFHC1 specifically increased R-type Ca(2+) currents that were reversed by the mutations associated with JME.

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