Nature Genetics
36, 842 - 849 (2004)
Published online: 18 July 2004; | doi:10.1038/ng1393
Mutations in EFHC1 cause juvenile myoclonic epilepsyToshimitsu Suzuki1, 2, 12, Antonio V Delgado-Escueta3, Kripamoy Aguan1, 12, Maria E Alonso4, Jun Shi1, Yuji Hara5, 6, Motohiro Nishida5, 6, Tomohiro Numata5, Marco T Medina3, 7, Tamaki Takeuchi1, Ryoji Morita1, Dongsheng Bai3, Subramaniam Ganesh1, Yoshihisa Sugimoto1, Johji Inazawa2, Julia N Bailey3, 8, Adriana Ochoa4, Aurelio Jara-Prado4, Astrid Rasmussen4, Jaime Ramos-Peek4, Sergio Cordova4, Francisco Rubio-Donnadieu4, Yushi Inoue9, Makiko Osawa10, Sunao Kaneko11, Hirokazu Oguni10, Yasuo Mori5, 6
& Kazuhiro Yamakawa11
Laboratory for Neurogenetics, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama, 351-0198, Japan. 2
Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan. 3
Epilepsy Genetics/Genomics Laboratories, Comprehensive Epilepsy Program, David Geffen School of Medicine at UCLA and VA GLAHS-West Los Angeles, Room 3405 (127B), Building 500, West Los Angeles DVA Medical Center, 11301 Wilshire Boulevard, Los Angeles, California 90073, USA. 4
National Institute of Neurology and Neurosurgery, Mexico City, Mexico. 5
Center for Integrative Bioscience, The Graduate University for Advanced Studies, Okazaki, Japan. 6
Graduate School of Engineering, Kyoto University, Kyoto, Japan. 7
National Autonomous University, Tegucigalpa, Honduras. 8
Neuropsychiatric Institute, David Geffen School of Medicine at UCLA, Los Angeles, California, USA. 9
National Epilepsy Center, Shizuoka Medical Institute of Neurological Disorders, Shizuoka, Japan. 10
Department of Pediatrics, Tokyo Women's Medical University, Tokyo, Japan. 11
Department of Neuropsychiatry, School of Medicine, Hirosaki University, Aomori, Japan. 12
These authors contributed equally to this work.
Correspondence should be addressed to Antonio V Delgado-Escueta escueta@ucla.edu or Kazuhiro Yamakawa yamakawa@brain.riken.go.jpJuvenile myoclonic epilepsy (JME) is the most frequent cause of hereditary grand mal seizures1,
2. We previously mapped and narrowed a region associated with JME on chromosome 6p12−p11 (EJM1)3,
4,
5. 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 Ca2+ channel (Cav2.3). EFHC1 and Cav2.3 immunomaterials overlapped in mouse brain, and EFHC1 coimmunoprecipitated with the Cav2.3 C terminus. In patch-clamp analysis, EFHC1 specifically increased R-type Ca2+ currents that were reversed by the mutations associated with JME.
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