CSNK2B splice site mutations in patients cause intellectual disability with or without myoclonic epilepsy

Abstract

De novo mutations are a frequent cause of disorders related to brain development. We report the results from the screening of two patients diagnosed with intellectual disability (ID) using exome sequencing to identify new causative de novo mutations. Exome sequencing was conducted in two patient-parent trios to identify de novo variants. In silico and expression studies were also performed to evaluate the functional consequences of these variants. The two patients presented developmental delay with minor facial dysmorphy. One of them presented pharmacoresistant myoclonic epilepsy. We identified two de novo splice variants (c.175+2T>G; c.367+2T>C) in the CSNK2B gene encoding the β subunit of the Caseine kinase 2 (CK2). CK2 is a ubiquitously expressed kinase that is present in high levels in brain and it appears to be constitutively active. The mRNA transcripts were abnormal and significantly reduced in affected fibroblasts and most likely produced truncated proteins. Taking into account that mutations in CSNK2A1, encoding the α subunit of CK2, were previously identified in patients with neurodevelopmental disorders and dysmorphic features, our study confirmed that the protein kinase CK2 plays a major role in brain, and showed that CSNK2, encoding the β subunit, is a novel ID gene. This study adds knowledge to the increasingly growing list of causative and candidate genes in ID and epilepsy, and highlights CSNK2B as a new gene for neurodevelopmental disorders.

Germline de novo variants in CSNK2B in Chinese patients with epilepsy

“…The variants in black fonts are from this study and the symbol * indicates that there are two cases with the variant. The variants highlighted in red are from recently reported patients with ID/DD and epilepsy 20,21 , the variant highlighted in gold is from recently reported patient with ID 20 , and the variants highlighted in green are from recently reported patient with profound ID and refractory epilepsy 22 .…”

“…CSNK2B splice site mutations has been reported in two patients with ID with or without myoclonic epilepsy 20 . The patient with myoclonic seizures (c.175 + 2 A > G) had refractory epilepsy, which occurred at the age of 18 months, and no remarkable improvement was found after LEV and VPA treatment.…”

“…Casein kinase 2 beta ( CSNK2B ) mutations associated with epilepsy and/or ID/DD have only been reported in five cases 20–22 . Huillard et al .…”

Protein Kinase CK2 Subunits Differentially Perturb the Adhesion and Migration of GN11 Cells: A Model of Immature Migrating Neurons

“…CK2 is expressed and constitutively active in the adult mouse brain, with levels of CK2α’ subunit higher in the cortex and hippocampus and lower in the striatum compared to CK2α [19,20,21]. Interestingly, mutations in CSNK2A1 and CSNK2B have been found in patients affected by neurodevelopmental disorders (NDDs), which combine intellectual disability, autism spectrum disorder, and general developmental delay [22,23,24,25,26]. NDDs are mainly caused by defective patterning and/or migration of neurons, which are essential biological processes for proper brain development [27].…”

Single nucleotide polymorphism rs110861313 in the intergenic region of chromosome 23 is associated with the development of leukosis in the Russian Black Pied cattle

“…Тем не менее у людей, больных Т-клеточным лейкозом взрослых (Adult T cell leukemia/lymphoma) и инфицированных вирусом HTLV-I, была обнаружена повышенная частота соматических мутаций в гене CSNK2B (Ka taoka et al, 2015). Интересно, что мутации в этом ге не у человека ассоциированы с развитием шизофрении Niu et al, 2019), судорожных припадков (Nakashima et al, 2019) и эпилепсии (Poirier et al, 2017;Sakaguchi et al, 2017). В связи с этим представляется перспективным исследовать изменение поведения животных после инфицирования ВЛКРС.…”