Abstract
Infantile spasms syndrome (ISS) is an early-onset epileptic encephalopathy characterized by uncontrollable seizures, severe electroencephalogram abnormalities, as well as delayed cognitive and behavioral development. Independent studies have shown that a variety of genes are involved in ISS and genetic factors play a critical role in its pathogenesis. Here we report two de novo mutations in the casein kinase 1 isoform alpha (CSNK1A1) gene which underlie severe epilepsy with similar clinical presentation in two patients. The identified variants are one missense mutation c.646G > C (p.Ala216Pro, Mut) in NM_001025105.3 and one deletion c.599_604delACATAC (p.His200_Ile201del, Del). In vitro analyses indicated that the Mut causes significant decreases in both mRNA and protein expression, while the Del demonstrated no significant impact on gene expression level. However, co-immunoprecipitation studies have shown that both mutations lead to reduced interactions between CSNK1A1 and β-catenin, resulting in excessive intracellular β-catenin and aberrant expression of several downstream genes. Compared with the wild type (WT), the EdU positive rates in cells transfected with Mut plasmid or Del plasmid were both elevated. Wnt/β-catenin signaling pathway is crucial to neurogenesis. An abnormal rise in β-catenin level has been utilized to generate genetic models for ISS. Our results not only elucidate the role of a novel candidate gene CSNK1A1 in the pathology of ISS, but also provide further evidence for the findings that mediating Wnt/β-catenin signaling is a potential mechanism causing ISS.