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Mutations in EFHC1 cause juvenile myoclonic epilepsy
Authors:Suzuki Toshimitsu  Delgado-Escueta Antonio V  Aguan Kripamoy  Alonso Maria E  Shi Jun  Hara Yuji  Nishida Motohiro  Numata Tomohiro  Medina Marco T  Takeuchi Tamaki  Morita Ryoji  Bai Dongsheng  Ganesh Subramaniam  Sugimoto Yoshihisa  Inazawa Johji  Bailey Julia N  Ochoa Adriana  Jara-Prado Aurelio  Rasmussen Astrid  Ramos-Peek Jaime  Cordova Sergio  Rubio-Donnadieu Francisco  Inoue Yushi  Osawa Makiko  Kaneko Sunao  Oguni Hirokazu  Mori Yasuo  Yamakawa Kazuhiro
Institution:Laboratory for Neurogenetics, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama, 351-0198, Japan.
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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