To shed light into their functions, we studied EFHC1, an evolutionarily conserved protein required for motile cilia function and linked to a common form of inherited epilepsy in humans, juvenile myoclonic epilepsy (JME).We demonstrate that <i>C. elegans</i> EFHC-1 functions within specialized non-motile mechanosensory cilia, where it regulates neuronal activation and dopamine signaling.
We reanalyzed 54 EFHC1 variants associated with epilepsy from 17 cohorts based on National Human Genome Research Institute (NHGRI) and American College of Medical Genetics and Genomics (ACMG) guidelines for interpretation of sequence variants.
Public databases also show that the EFHC1P77T-R221H JME haplotype is present in unphenotyped West African ancestry populations, and we show that it can be found at appreciable frequency in healthy individuals with no family history of epilepsy.
Interestingly, the EJM1 region includes the Transporter associated with antigen processing 1 (TAP-1) gene encoding the TAP-1, and previous studies have reported associations between HLA-II polymorphisms and different types of epilepsy.
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.
Multipoint linkage analysis with use of microsatellite markers from the chromosomal region 6p25-q13 in 29 German families of JME patients provided significant evidence that an epilepsy locus (EJM1) close to the HLA locus confers susceptibility to "idiopathic" generalized seizures (Zmax = 3.27 at theta max = 0.033 centromeric to the HLA-DQ locus), assuming an autosomal dominant mode of inheritance with 70% penetrance.
We report here evidence that at least one form of epilepsy that is similar to JME--pure, adolescent-onset grand mal epilepsy in which the seizures occur at any time during waking--is not linked to the EJM-1 locus.
Our results demonstrate that (1) the genetic susceptibility to idiopathic absence epilepsies and broader spectra of IGEs is heterogeneous, (2) the gene effect of EJM1 depends on the familial genetic background, and (3) EJM1 confers genetic susceptibility to idiopathic absence epilepsies and broader spectra of IGEs in the presence of family members with JME.