Mice Harboring a Non-Functional CILK1/ICK Allele Fail to Model the Epileptic Phenotype in Patients Carrying Variant CILK1/ICK.

Kathryn A Salvati,Zheng Fu,Ashley J Mason,Mark P Beenhakker,Casey D Gailey,Eric J Wang

doi:10.3390/ijms22168875

Abstract

CILK1 (ciliogenesis associated kinase 1)/ICK (intestinal cell kinase) is a highly conserved protein kinase that regulates primary cilia structure and function. CILK1 mutations cause a wide spectrum of human diseases collectively called ciliopathies. While several CILK1 heterozygous 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 Cilk1 (Cilk1+/−) mutation or a heterozygous loss-of-function Cilk1 mutation (Cilk1R272Q/+) have epilepsy. We first evaluated the spontaneous seizure phenotype of Cilk1+/− and Cilk1R272Q/+ mice 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 versus Cilk1+/− and Cilk1R272Q/+ mice upon isoflurane recovery. These results indicate that mice bearing a non-functional copy of Cilk1 fail to produce electrographic patterns resembling those of JME patients with a variant CILK1 copy. Our findings argue against CILK1 haploinsufficiency being the mechanism that links CILK1 variants to JME.

Highlights

The primary cilium is a single solitary microtubule-based protrusion on the apical surface of most vertebrate cells that senses and transduces environmental and hormonal signals to regulate diverse cellular processes [1]
Ciliogenesis-associated kinase 1 (CILK1) variants associate with both juvenile myoclonic epilepsy (JME) [11] (Figure 1A, red) and human ciliopathies [4,5,6] (Figure 1A, purple)
Recent evidence calls into question the association between CILK1 variants and JME [13]

Summary

Introduction

The primary cilium is a single solitary microtubule-based protrusion on the apical surface of most vertebrate cells that senses and transduces environmental and hormonal signals to regulate diverse cellular processes [1]. Ciliogenesis-associated kinase 1 (CILK1), formerly known as intestinal cell kinase (ICK), is a highly conserved serine/threonine kinase that negatively regulates cilia length and ciliogenesis [3]. Cells from heterozygous Cilk null mice grow normal cilia and the mice develop normally [7,8], indicating that at least one wildtype copy of the gene is sufficient for normal cilia growth. These results support the general conclusion that CILK1 mutations causing exuberant cilia growth result in ciliopathy, whereas CILK1 mutations preserving normal cilia growth are associated with normal development

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Discussion

Conclusion