講演情報
[O29-4]若年ミオクロニーてんかん原因遺伝子EFHC1の脳室壁上衣細胞での欠損は全身欠損マウスのてんかん症状を再現する
○山川 和弘, 鈴木 俊光 (名古屋市立大学 大学院医学研究科 脳神経科学研究所 神経発達症遺伝学分野)
We previously reported EFHC1 (EF-hand domain containing 1) (Suzuki et al., Nat Genet 36:842-9, 2004) and ICK (Intestinal Cell Kinase, but later renamed as CILK1 for CILiogenesis associated Kinase 1) (Bailey et al., N Eng J Med 378:1018-28, 2018) as genes for juvenile myoclonic epilepsy. Both myoclonin1 encoded by EFHC1 and CILK1 proteins are densely expressed in ependymal cells which have motile cilia and line the wall of brain ventricles (Suzuki et al., Sci Rep 10:22076, 2020), and therefore a common pathological cascade through ependymal cells has been suspected. We also reported that Efhc1 systemic deficiency in mice caused spontaneous myoclonus, an increased seizure susceptibility to chemoconvulsant pentylenetetrazol (PTZ), and enlargement of brain ventricles (Suzuki et al., Hum Mol Genet 18: 1099-1109, 2009). Here we investigated physiological consequences of selective myoclonin1 deletion in ciliated cells using floxed (flanked by loxP sites) Efhc1 and forkhead box J1 promoter Cre (FoxJ1-Cre) driver mice in which Cre recombinase is expressed in cells that committed to ciliated cell lineage, such as choroid plexus and ependymal cells in brain. We show that minimal selective myoclonin1 deletion in these cells using the Cre driver mice causes an increase of seizure susceptibility to PTZ and enlarged brain ventricles, similar to those of systemic Efhc1 knock-out mice. Taken together, our results indicate that functional impairment of ciliated cells with myoclonin1 haploinsufficiency contributes to the pathology of epilepsies caused by EFHC1 pathogenic variants.