title: Mutations in EFHC1 cause juvenile myoclonic epilepsy.
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.
authors.affiliation: Laboratory for Neurogenetics, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama, 351-0198, Japan.
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Suzuki
authors.forename: Antonio V
authors.initials: AV
authors.lastname: Delgado-Escueta
authors.forename: Kripamoy
authors.initials: K
authors.lastname: Aguan
authors.forename: Maria E
authors.initials: ME
authors.lastname: Alonso
authors.forename: Jun
authors.initials: J
authors.lastname: Shi
authors.forename: Yuji
authors.initials: Y
authors.lastname: Hara
authors.forename: Motohiro
authors.initials: M
authors.lastname: Nishida
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Numata
authors.forename: Marco T
authors.initials: MT
authors.lastname: Medina
authors.forename: Tamaki
authors.initials: T
authors.lastname: Takeuchi
authors.forename: Ryoji
authors.initials: R
authors.lastname: Morita
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Bai
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Ganesh
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Sugimoto
authors.forename: Johji
authors.initials: J
authors.lastname: Inazawa
authors.forename: Julia N
authors.initials: JN
authors.lastname: Bailey
authors.forename: Adriana
authors.initials: A
authors.lastname: Ochoa
authors.forename: Aurelio
authors.initials: A
authors.lastname: Jara-Prado
authors.forename: Astrid
authors.initials: A
authors.lastname: Rasmussen
authors.forename: Jaime
authors.initials: J
authors.lastname: Ramos-Peek
authors.forename: Sergio
authors.initials: S
authors.lastname: Cordova
authors.forename: Francisco
authors.initials: F
authors.lastname: Rubio-Donnadieu
authors.forename: Yushi
authors.initials: Y
authors.lastname: Inoue
authors.forename: Makiko
authors.initials: M
authors.lastname: Osawa
authors.forename: Sunao
authors.initials: S
authors.lastname: Kaneko
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Oguni
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Mori
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yamakawa
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000235:genetics; D002478:Cells, Cultured; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D020190:Myoclonic Epilepsy, Juvenile / Q000235:genetics*; D010375:Pedigree
chemical_list: D002135:Calcium-Binding Proteins; C489648:EFHC1 protein, human