Mutations in EFHC1 cause juvenile myoclonic epilepsy.
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.
Suzuki
Toshimitsu
T
Laboratory for Neurogenetics, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama, 351-0198, Japan.
Delgado-Escueta
Antonio V
AV
Aguan
Kripamoy
K
Alonso
Maria E
ME
Shi
Jun
J
Hara
Yuji
Y
Nishida
Motohiro
M
Numata
Tomohiro
T
Medina
Marco T
MT
Takeuchi
Tamaki
T
Morita
Ryoji
R
Bai
Dongsheng
D
Ganesh
Subramaniam
S
Sugimoto
Yoshihisa
Y
Inazawa
Johji
J
Bailey
Julia N
JN
Ochoa
Adriana
A
Jara-Prado
Aurelio
A
Rasmussen
Astrid
A
Ramos-Peek
Jaime
J
Cordova
Sergio
S
Rubio-Donnadieu
Francisco
F
Inoue
Yushi
Y
Osawa
Makiko
M
Kaneko
Sunao
S
Oguni
Hirokazu
H
Mori
Yasuo
Y
Yamakawa
Kazuhiro
K
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
D002135:Calcium-Binding Proteins; C489648:EFHC1 protein, human