Mutations in EFHC1 cause juvenile myoclonic epilepsy

Nat Genet. 2004 Aug;36(8):842-9. doi: 10.1038/ng1393. Epub 2004 Jul 18.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Calcium-Binding Proteins / genetics
  • Cells, Cultured
  • Humans
  • Mice
  • Molecular Sequence Data
  • Mutation, Missense
  • Myoclonic Epilepsy, Juvenile / genetics*
  • Pedigree


  • Calcium-Binding Proteins
  • EFHC1 protein, human

Associated data

  • GENBANK/AK001328
  • GENBANK/AK006489
  • GENBANK/AL122084
  • GENBANK/AV595456
  • GENBANK/AW344780
  • GENBANK/AY608689
  • GENBANK/BE666117