Germline de novo variants in CSNK2B in Chinese patients with epilepsy

Abstract

CSNK2B, which encodes the beta subunit of casein kinase II (CK2), plays an important role in neuron morphology and synaptic transmission. Variants in CSNK2B associated with epilepsy and/or intellectual disability (ID)/developmental delay (DD) have been reported in five cases only. Among the 816 probands suspected hereditary epilepsy whose initial report of trio-based whole exome sequencing (WES) were negative, 10 de novo pathogenic or likely pathogenic variants of CSNK2B in nine probands were identified after reanalysis of their raw Trio-WES data. Six of the nine epileptic patients had ID/DD. The age of seizure onset of these nine patients with CSNK2B variants ranged from 2–12 months. Eight patients had age of seizure onset of less than 6 months. The epilepsy of most probands (8/9) was generalized tonic-clonic seizure and clustered (6/9). Most patients had normal electroencephalogram (5/9) and brain magnetic resonance image (7/9) results. Most patients (7/9) had easy-to-control seizures. Levetiracetam was the most commonly used drug in seizure-free patients (5/7). The variants detected in five patients (5/9, 55.6%) were located in the zinc-binding domain. In summary, our research provided evidence that variants in CSNK2B are associated with epilepsy with or without ID/DD. CSNK2B-related epilepsy is relatively easy to be controlled. The zinc-binding domain appears to be the hotspot region for mutation.

CSNK2B: A broad spectrum of neurodevelopmental disability and epilepsy severity

“…13 The p.Cys137Arg variant disrupts a zinc binding site, the same residue affected in two previously reported individuals (p.Cys137Gly, p.Cys137Phe). 7 Thus, in silico analyses suggest that missense variants in this cohort disrupt CK2β functional domains.…”

“…All 34 reported variants are shown (bold = recurrent variants; #previously reported). Note p.Glu5Ter and p.Arg86Cys were reported in the same individual in Li et al 7 (B) Neurodevelopmental phenotypes across all reported CSNK2B patients (n = 39), males (n = 25), and females (n = 14). Blue = no delays to date, yellow = mild or not otherwise specified, red = moderate to profound.…”

Protein kinase CK2: a potential therapeutic target for diverse human diseases

“…This is a newly defined neurologic disorder, mainly characterized by early-onset seizures and/or intellectual disability/development delay, recently described as an autosomal dominant inherited disease, caused by heterozygous mutation in the CSNK2B gene. 247 – 250 In the last 3 years, 14 CSNK2B de novo variants associated with POBINDS were found with trio WES and they were classified as deleterious (CADD scores) and pathogenic (ACMG guidelines). 247 , 250 The CSNK2B mutations associated with POBINDS were localized in different part of the gene, some of them generating a truncated form of CK2β, others inducing single amino acid changes in functional protein domains.…”

“… 247 – 250 In the last 3 years, 14 CSNK2B de novo variants associated with POBINDS were found with trio WES and they were classified as deleterious (CADD scores) and pathogenic (ACMG guidelines). 247 , 250 The CSNK2B mutations associated with POBINDS were localized in different part of the gene, some of them generating a truncated form of CK2β, others inducing single amino acid changes in functional protein domains. A CSNK2B haploinsufficiency emerged in some patients, but the functional role of the CSNK2B variants remains still unknown.…”

Okur-Chung Neurodevelopmental Syndrome-linked CK2α mutations have reduced kinase activity

“…This includes CK2α deletion and splicing mutants that yield no or severely truncated protein, that may also have a major impact in the developing and maturing brain. In addition to CK2α mutations, two splicing variants for CK2β have been published and symptoms of the carriers overlap with OCNDS, however, these cases are not categorized as OCNDS and have, as a major characteristic, a high frequency of epilepsy (Poirier et al 2017) which, to a much more minor extent, is also a symptom of OCNDS (Li et al 2019;Nakashima et al 2019). These splicing variants yield significantly truncated CK2β proteins, are expected to affect substrate specificity of the CK2 holoenzyme via altered targeting of CK2α to specific substrates.…”