Two rare de novo missense variants in the CSNK2A1 gene have been identified in ASD probands from simplex families from the Simons Simplex Collection (Iossifov et al., 2014) and the ASD: Genomes to Outcome Study cohort (Yuen et al., 2017). Heterozygous variants in the CSNK2A1 gene are also responsible for Okur-Chung neurodevelopmental syndrome (OMIM 617062), an autosomal dominant disorder characterized by delayed psychomotor development, intellectual disability with poor speech, behavioral abnormalities, cortical malformations in some patients, and variable dysmorphic facial features; autistic features and/or stereotypy has been reported in a subset of affected individuals (Okur et al., 2016; Trinh et al., 2017; Chiu et al., 2018; Owen et al., 2018, Martinez-Monseny et al., 2020).
Molecular Function
Casein kinase II is a serine/threonine protein kinase that phosphorylates acidic proteins such as casein. It is involved in various cellular processes, including cell cycle control, apoptosis, and circadian rhythm. The kinase exists as a tetramer and is composed of an alpha, an alpha-prime, and two beta subunits. The alpha subunits contain the catalytic activity while the beta subunits undergo autophosphorylation. The protein encoded by this gene represents the alpha subunit.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
The contribution of de novo coding mutations to autism spectrum disorder
Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings
Phenotypic and genetic analysis of children with unexplained neurodevelopmental delay and neurodevelopmental comorbidities in a Chinese cohort using trio-based whole-exome sequencing
Missense mutation in the activation segment of the kinase CK2 models Okur-Chung neurodevelopmental disorder and alters the hippocampal glutamatergic synapse
The homozygous mutant Csnk2a1 mouse model with a missense mutation found in humans (K198R) shows embryonic lethality, while the heterozygote shows incomplete penetrance in the lethality phenotype, with surviving animals developing a smaller size. Heterozygous mutants show enlarged cerebral ventricles, decrease thickness of the corpus callosum and increased density of synapses in the hippocampus. The heterozygote mutants show deficiencies in hippocampus-dependent behaviors, including fear conditioning memory and spatial memory, and hippocampal long-term depression. The heterozygous mutants show no social phenotype but an increase in repetitive behaviors.
References
Type
Title
Author, Year
Primary
Missense mutation in the activation segment of the kinase CK2 models Okur-Chung neurodevelopmental disorder and alters the hippocampal glutamatergic synapse
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Homozygous knockin mice carry two alleles with a K198R missense mutation in the Csnk2a1 gene (MGI:6383802).
Allele Type: ASD mutation
Strain of Origin: Not specified
Genetic Background: C57BL/6J
ES Cell Line: Not applicable
Mutant ES Cell Line: Model Source: Jackson Laboratory
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Heterozygous knockin mice carry one allele with a K198R missense mutation in the Csnk2a1 gene (MGI:6383802).
Allele Type: ASD mutation
Strain of Origin: Not specified
Genetic Background: C57BL/6J
ES Cell Line: Not applicable
Mutant ES Cell Line: Model Source: Jackson Laboratory
Cardiovascular development and function: embryonic1
Decreased
Description: Homozygous mutant mice show edematous heart defects, the blood was not circulating, and the resorption of the yolk sac had started. At E11.5, homozygotes were non-viable, and 50% showed a failure to close the cranium.
Description: Heterozygous mice display enhanced stereotypies (rearings) which were assessed for 1 h during the dark active cycle (3â??4 am) cycle, with a similar result obtained during the light cycle.
Description: The thickness of the postsynaptic density is not changed, but postsynaptic density disc diameter was enhanced in heterozygous animals.
Exp Paradigm: hippocampus
Description: There is normal induction and expression of long-term potentiation (LTP) in the hippocampal slices prepared from wildtype mice, but an attenuation of LTP in slices from heterozygous mice.
Exp Paradigm: theta bust stimulation
Cardiovascular development and function: embryonic1
Decreased
Description: At E11.5, half of heterozygous embryos were viable and resembled wildtype, and others exhibited heart defects, were developmentally delayed and resembled homozygotes at E10.5.
Description: Male and female heterozygous mice weighed 16.07% and 17.6% less, respectively, at 14 weeks of age, a difference that increases with age for males reaching nearly 33.9% at 16 months.
Mortality/lethality: life span: incomplete penetrance1
Decreased
Description: During aging, no difference was observed between sexes of the same genotypes, however heterozygous mice have significantly enhanced mortality rate.
Cued or contextual fear conditioning: memory of context2
Decreased
Description: Heterozygous mice showed reduced fear expression 24 h after training, suggesting an impairment in contextual fear memory compared with wildtype mice.
Description: Mass spectrometric analysis of striatal tissue revealed 13017 unique phosphopeptides (p-peptides), out of which 394 were significantly altered by a factor of 1.5 or more between genotypes. 163 were present at higher levels in wildtype striatum, while 231 peptides were enriched in heterozygous mice.
Exp Paradigm: striatum
Description: Heterozygous mutant mice show a significant decrease in phosphorylation of the CK2 site, Ser97. Heterozygote mice show a trend towards elevated phosphorylation of Ser473 AKT, a PDK1 substrate and an indicator of the activation state of AKT.
