Mice Harboring a Non-FunctionalAllele Fail to Model the Epileptic Phenotype in Patients Carrying Variant.

Abstract

CILK1 (ciliogenesis associated kinase 1)/ICK (intestinal cell kinase) is a highly conserved protein kinase that regulates primary cilia structure and function.mutations cause a wide spectrum of human diseases collectively called ciliopathies. While severalheterozygous variants have been recently linked to juvenile myoclonic epilepsy (JME), it remains unclear whether these mutations cause seizures. Herein, we investigated whether mice harboring either a heterozygous null() mutation or a heterozygous loss-of-functionmutation () have epilepsy. We first evaluated the spontaneous seizure phenotype ofandmice relative to wildtype littermates. We observed no electrographic differences among the three mouse genotypes during prolonged recordings. We also evaluated electrographic and behavioral responses of mice recovering from isoflurane anesthesia, an approach recently used to measure seizure-like activity. Again, we observed no electrographic or behavioral differences in control versusandmice upon isoflurane recovery. These results indicate that mice bearing a non-functional copy offail to produce electrographic patterns resembling those of JME patients with a variantcopy. Our findings argue againsthaploinsufficiency being the mechanism that linksvariants to JME.