Myoclonin1 haploinsufficiency in motile ciliated cells partially recapitulates epileptic features of Efhc1-deficient mice in adult age.

Mutations in the EFHC1 (EF-hand domain containing 1) gene, which encodes myoclonin1, a homolog of the Chlamydomonas axonemal protein Rib72, have been identified in patients with epilepsies including juvenile myoclonic epilepsy (JME). Myoclonin1 is expressed in choroid plexus epithelial cells during fetal development and in motile cilia of ependymal cells lining brain ventricles as well as in tracheal cilia and sperm flagella during postnatal stages. We previously reported that systemic Efhc1 deficiency in mice causes spontaneous myoclonus, increased susceptibility to the chemoconvulsant pentylenetetrazol (PTZ), and enlargement of brain ventricles. In the present study, we show that mice with selective deletion of myoclonin1 in choroid plexus and ependymal cells, generated by crossing newly developed floxed-Efhc1 mice with FoxJ1 (forkhead box J1)-Cre driver mice, exhibit increased susceptibility to PTZ-induced seizures in adult heterozygous mutants and enlarged brain ventricles in homozygous mutants, while neither heterozygous nor homozygous mutants display spontaneous myoclonus. These findings suggest that myoclonin1 haploinsufficiency in cells bearing motile cilia partially reproduces the epileptic phenotypes observed in mice with systemic Efhc1 deficiency and contributes to the pathophysiology of epilepsies associated with EFHC1 mutations.