The laboratory identified EFHC1 as a gene responsible for Juvenile myoclonic epilepsy (JME), the most frequent cause of hereditary grand mal seizures in collaboration with the University of California Los Angeles (UCLA). Most of genes identified for idiopathic epilepsies so far encode ion channels, but the EFHC1 does not and it suggests a new pathological cascade. The identification of EFHC1 as the JME gene should contribute to the understanding of the pathomechanism of epilepsy and to improvement of its therapies.
Background
Epilepsy is one of the most frequent neurological disorders occurring in ~1% of the general population. Epilepsy is characterized by repetitive seizures, and consists of various subtypes. Genetic backgrounds are assumed to exist in the majority of cases and the number of responsible genes may exceed 100. Epilepsy is subcategorized to three groups; 1) idiopathic epilepsy which is generally mild, controllable, and shows only epileptic seizures as disease phenotypes; 2) syndromic epilepsy which shows not only seizures but also additional neurological symptoms like ataxia and mental decline as well as histological abnormalities in the brain; 3) criptogenic epilepsy which is also severe but no histological abnormality in the brain. Idiopathic subtype accounts for the majority of epilepsy. ~20 genes have been so far identified to be responsible for idiopathic epilepsy, and most of those encode ion channels. JME is the most frequent idiopathic epilepsy characterized by myoclonic, tonic-clonic seizures with juvenile onset. Several genes (GABRA1, BED2, ...) have been proposed to be responsible for JME, but mutations in only one family or no coding mutations were described in those genes.
Results
We recruited 44 JME families with informed consents, analyzed by genetic methodologies including linkage analysis and haplotype analysis, and mapped and narrowed the JME region on chromosome 6p12-p11 (EJM1). We identified in the EJM1 region a gene, EFHC1 , which encodes a protein with an EF-hand motif. Mutation analyses revealed five missense mutations in EFHC1 co-segregating with epilepsy or EEG polyspike wave-affected members of six unrelated JME families that did not appear in 382 control individuals. EFHC1 overexpression in mouse hippocampal primary culture neurons induced apoptosis that was significantly lowered by the JME mutations. The 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 co-immunoprecipitated with Cav2.3 C-terminus. In patch-clamp analysis, EFHC1 specifically increased R-type calcium currents that were reversed by JME mutations. These observations strongly favor EFHC1 as the EJM1 gene.
Future perspective
In the definition, idiopathic epilepsy does not have histological abnormalities in the brain. However, several reports described minor histological abnormalities, named "microdysgenesis", that includes increased number of neurons, dystopic neurons (ex. in white matter), etc. With the identification of EFHC1 as the JME gene and its cell-death causing effect, we speculate that EFHC1 may play roles in the brain development and the JME mutations may prevent elimination of unwanted neurons and lead to heperexcitable neural circuit. This is still only a hypothesis and should be further investigated by additional experiments such as those on animal models.
As a whole, this is the identification of the gene responsible for the most frequent epilepsy that suggests a new pathological cascade. It should largely contribute to the understanding of the pathology and to improvements of therapies for epilepsy.
