Alternative titles; symbols
HGNC Approved Gene Symbol: CSNK2B
Cytogenetic location: 6p21.33 Genomic coordinates (GRCh38): 6:31,666,080-31,670,067 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p21.33 | Poirier-Bienvenu neurodevelopmental syndrome | 618732 | Autosomal dominant | 3 |
The CSNK2B gene encodes a regulatory subunit of casein kinase II (CK2), a highly conserved ubiquitous enzyme consisting of subunits alpha (CSNK2A1; 115440), alpha-prime (CSNK2A2; 115442), and beta. It is present in high levels in the brain and appears to be constitutively active. Animal models suggest that CK2 may play a role in dopamine signaling (summary by Poirier et al., 2017; Yang et al., 2018).
CK2 is a ubiquitous serine/threonine kinase, localized in both the cytoplasm and the nucleus. Jakobi et al. (1989) prepared subunit beta from human placenta and determined the amino acid sequence of a protease digestion peptide. The deduced nucleotide sequence was used for the synthesis of a mixture of 20-mers as a hybridization probe to screen a lambda-gt10 HeLa cell cDNA library for clones encoding the beta subunit. The beta subunit presumably serves regulatory functions. Heller-Harrison et al. (1989) found evidence of a single gene. They described a cDNA of 2.57 kb containing 96 bp of 5-prime untranslated sequence, 645 bp of open reading frame, and 1,832 bp of 3-prime untranslated sequence.
Li et al. (2019) noted that the CSNK2B gene is highly expressed in the developing prefrontal cortex, with lesser expression in childhood and adulthood.
Voss et al. (1991) analyzed the structure of the gene encoding human casein kinase II subunit beta and Boldyreff and Issinger (1995) determined the structure of the mouse counterpart. The latter is composed of 7 exons contained within 7,874 bp. The lengths of the mouse coding exons correspond exactly to the lengths of the exons in the human CK2B gene. Both genes contain a first untranslated exon. Despite common features, a striking difference concerned the human CK2A subunit binding domain at position -170 to -239 of the human gene. This domain has no counterpart in the mouse gene.
By hybridization to spot-blotting filters of flow-sorted human chromosomes followed by in situ hybridization, Yang-Feng et al. (1990) mapped the CSNK2B gene to 6p21.1.
Albertella et al. (1996) characterized the genes in the central 1,100-kb class III region of the major histocompatibility complex. One of the genes found in this region was identified as CSNK2B. This would suggest that CSNK2B is located in the 6p21.3 region rather than the 6p21.1 region.
Sarno et al. (2000) reported that a C-terminally truncated form of CK2-beta lacking residues 170 to 215 could not stably associate with the catalytic CK2 subunits. This CK2-beta mutant retained its central homodimerization domain and still existed as a dimer. However, the mutant was defective in a number of other properties mediated by elements still present in its N-terminal half, notably downregulation of catalytic activity, autophosphorylation, and responsiveness to polycationic effectors. All these functions were restored by simultaneous addition of a synthetic peptide reproducing the CK2-beta deleted region, which was able to associate with the catalytic subunits and to stimulate catalytic activity. This peptide includes a segment that shares similarity with a region of cyclin A (see 604036) involved in activation of CDK2 (116953), and Sarno et al. (2000) found that a peptide reproducing this sequence (residues 181 to 203) interacted with the CK2-alpha subunit and stimulated its catalytic activity. This smaller peptide also partially restored the ability of truncated CK2-beta to autophosphorylate. Sarno et al. (2000) concluded that residues 181 to 203 are essential for the regulatory properties of CK2-beta.
Phosphorylation of the human p53 protein (191170) at ser392 is responsive to ultraviolet (UV) but not gamma irradiation. Keller et al. (2001) identified and purified a mammalian UV-activated protein kinase complex that phosphorylates ser392 in vitro. This kinase complex contains CK2 and the chromatin transcriptional elongation factor FACT, a heterodimer of SPT16 (605012) and SSRP1 (604328). In vitro studies showed that FACT alters the specificity of CK2 in the complex such that it selectively phosphorylates p53 over other substrates, including casein. In addition, phosphorylation by the kinase complex was found to enhance p53 activity. These results provided a potential mechanism for p53 activation by UV irradiation.
Doray et al. (2002) demonstrated that the Golgi-localized, gamma-ear-containing adenosine diphosphate ribosylation factor-binding proteins (GGA1, 606004 and GGA3, 606006) and the coat protein adaptor protein-1 (AP-1) complex (see AP1G2, 603534) colocalize in clathrin-coated buds of the trans-Golgi networks of mouse L cells and human HeLa cells. Binding studies revealed a direct interaction between the hinge domains of the GGAs and the gamma-ear domain of AP-1. Further, AP-1 contained bound casein kinase-2 that phosphorylated GGA1 and GGA3, thereby causing autoinhibition. Doray et al. (2002) demonstrated that this autoinhibition could induce the directed transfer of mannose 6-phosphate receptors (see 154540) from the GGAs to AP-1. Mannose 6-phosphate receptors that were defective in binding to GGAs were poorly incorporated into adaptor protein complex containing clathrin coated vesicles. Thus, Doray et al. (2002) concluded that GGAs and the AP-1 complex interact to package mannose 6-phosphate receptors into AP-1-containing coated vesicles.
Rodriguez et al. (2008) stated that, in addition to cytoplasm, nuclei, and other organelles, CK2 localizes to the external side of the cell membrane, where it acts as an ectokinase and phosphorylates extracellular proteins and external domains of proteins. By mutation analysis, they showed that an N-terminal region of Xenopus Ck2-beta containing 2 phenylalanines and an acidic cluster was necessary but not sufficient to allow Ck2-alpha to function as an ectokinase in transfected HEK293 cells.
In vitro cellular studies by Yang et al. (2018) showed that knockdown of the Csnk2b gene in mouse embryonic neural stem cells increased proliferation, impaired cell differentiation, and reduced the dendritic length and branch points compared to controls. Knockdown of Csnk2b also altered synaptic transmission compared to controls. The authors suggested that variation in the CSNK2B gene may contribute to the risk of schizophrenia (SCZD; see 181500), which is believed to be a disorder related to altered neurodevelopment.
Excessive erythrocytosis is a major hallmark of chronic mountain sickness (CMS; see 616182), or Monge disease, a clinical syndrome caused by years of exposure to high-altitude hypoxia. Using RNA-sequencing analysis, Azad et al. (2023) identified HIKER (LINC02228; 620525) as a differentially expressed long noncoding RNA in individuals with CMS compared with non-CMS controls under hypoxic conditions. HIKER was upregulated in CMS cells, but not in non-CMS cells. HIKER regulated erythropoiesis in CMS individuals under hypoxia via the downstream factor CSNK2B. Further analysis confirmed that CSNK2B was an erythropoietic regulator in CMS and non-CMS cells under hypoxia and showed that CSNK2B regulated erythropoiesis at high altitude partially through GATA1 (305371). Furthermore, csnk2b knockdown induced severe hemoglobinization defects in zebrafish embryos, confirming an evolutionarily conserved role of CSNK2B in erythropoiesis.
In 2 unrelated patients with Poirier-Bienvenu neurodevelopmental syndrome (POBINDS; 618732), Poirier et al. (2017) identified de novo heterozygous splice site mutations in the CSNK2B gene (115441.0001 and 115441.0002). The mutations, which were found by trio-based whole-exome sequencing and confirmed by Sanger sequencing, were not found in the 1000 Genomes Project and ExAC databases. Analysis of patient cells showed decreased mRNA levels compared to controls, and RT-PCR showed that the mutations resulted in exon skipping and premature termination, consistent with haploinsufficiency and a loss of function. However, the authors noted that the mutations may induce the production of an aberrant truncated protein. Poirier et al. (2017) postulated that the mutations may cause abnormal dopamine signaling.
In a 21-month-old Japanese boy with POBINDS, Sakaguchi et al. (2017) identified a de novo heterozygous frameshift mutation in the CSNK2B gene (115441.0003). The mutation was found by trio-based whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in haploinsufficiency.
In a 15-year-old Malaysian girl (patient 3) with POBINDS, Nakashima et al. (2019) identified a de novo heterozygous frameshift mutation in the CSNK2B gene (115441.0004). The mutation, which was found by trio-based whole-exome sequencing and confirmed by Sanger sequencing, was classified as pathogenic according to ACMG guidelines. Transfection of the mutation into HEK293 cells showed that the mutant protein was expressed, but was unable to bind with CSNK2A1 (115440), which may induce instability of the CK2 holoenzyme.
In 9 unrelated patients with POBINDS, Li et al. (2019) identified de novo heterozygous mutations in the CSNK2B gene (see, e.g., 115441.0005-115441.0007). The mutations, which were found by trio-based whole-exome sequencing of a cohort of 816 probands with epilepsy, were confirmed by Sanger sequencing. The mutations occurred throughout the gene and comprised 4 missense variants, 3 frameshifts, and 1 splice site mutation. None of the variants were found in the 1000 Genomes Project or gnomAD databases; all were predicted to be pathogenic (8) or likely pathogenic (1) by ACMG criteria, but only 4 had predictive evidence of 'very strong' pathogenicity. Functional studies of the variants and studies of patient cells were not performed. Five variants occurred in the zinc-binding domain, suggesting a hotspot; all of these patients responded to antiepileptic treatment. However, patients with missense mutations could have a severe phenotype and those with frameshift mutations could have a mild phenotype, precluding establishment of a definitive genotype/phenotype correlation.
Blond et al. (2005) found that complete knockout of the Csnk2b gene in mice was embryonic lethal. Heterozygous knockout mice did not exhibit any abnormalities, although the number of heterozygous offspring was lower than expected, suggesting that some heterozygous mice do not survive.
Huillard et al. (2010) found that mice with Ck2b deletion in neural stem/progenitor cells (NSCs) of developing brain were born at the expected mendelian ratio, but they did not feed and died shortly after birth. Loss of Ck2b in embryonic NSCs compromised forebrain NSC proliferation and impaired NSC differentiation to develop oligodendrocyte precursor cells (OPCs), resulting in defects in telencephalon development in brain. In vitro analyses identified Olig2 (606386), a critical modulator of OPC development, as a Ck2b-dependent substrate. Ck2b interacted directly with the bHLH domain of Olig2, and Ck2 phosphorylated Olig2 on its serine/threonine-rich (STR) domain. The phosphorylated STR domain was involved in the oligodendroglial function of Olig2.
In a 10-year-old boy (patient 1) with Poirier-Bienvenu neurodevelopmental syndrome (POBINDS; 618732), Poirier et al. (2017) identified a de novo heterozygous T-to-C transition (c.367+2T-C, NM_001320.5) affecting a splice site in intron 5 of the CSNK2B gene. The mutation, which was found by trio-based whole-exome sequencing and confirmed by Sanger sequencing, was not found in the 1000 Genomes Project or ExAC database. Analysis of patient cells showed decreased mRNA levels compared to controls, and RT-PCR showed that the mutation resulted in the skipping of exon 5 and premature termination (Leu98AlafsTer11), consistent with haploinsufficiency and a loss of function. However, the authors noted that the mutation may induce the production of an aberrant truncated protein.
Li et al. (2019) noted that this mutation affects the zinc-binding domain and that the patient reported by Poirier et al. (2017) did not have seizures.
In a 19-year-old man (patient 2) with Poirier-Bienvenu neurodevelopmental syndrome (POBINDS; 618732), Poirier et al. (2017) identified a de novo heterozygous T-to-G transversion (c.175+2T-G, NM_001320.5) affecting a splice site in intron 3 of the CSNK2B gene. The mutation, which was found by trio-based whole-exome sequencing and confirmed by Sanger sequencing, was not found in the 1000 Genomes Project or ExAC databases. Analysis of patient cells showed decreased mRNA levels compared to controls, and RT-PCR showed that the mutation resulted in the skipping of exon 3 and caused premature termination (Val25MetfsTer13), consistent with haploinsufficiency and a loss of function. However, the authors noted that the mutation may induce the production of an aberrant truncated protein.
In a 21-month-old Japanese boy with Poirier-Bienvenu neurodevelopmental syndrome (POBINDS; 618732), Sakaguchi et al. (2017) identified a de novo heterozygous 1-bp duplication (c.108dup, NM_001320.6) in exon 3 of the CSNK2B gene, predicted to result in a frameshift and premature termination (Thr37Tyrfs). The mutation was found by trio-based whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed.
In a 15-year-old Malaysian girl (patient 3) with Poirier-Bienvenu neurodevelopmental syndrome (POBINDS; 618732), Nakashima et al. (2019) identified a de novo heterozygous 2-bp insertion (c.533_534insGT, NM_001320.5) in the CSNK2B gene, resulting in a frameshift and premature termination (Pro179TyrfsTer49). The mutation, which was found by trio-based whole-exome sequencing and confirmed by Sanger sequencing, was classified as pathogenic according to ACMG guidelines. Transfection of the mutation into HEK293 cells showed that the mutant protein was expressed, but was unable to bind with CSNK2A1 (115440), which may induce instability of the CK2 holoenzyme.
In a 3-year-old Chinese girl (P2) with Poirier-Bienvenu neurodevelopmental syndrome (POBINDS; 618732), Li et al. (2019) identified a de novo heterozygous 1-bp insertion (c.620_621insC, NM_001320) in exon 7 of the CSNK2B gene, predicted to result in a frameshift and premature termination (Phe207PhefsTer39). The mutation, which was found by trio-based whole-exome sequencing and confirmed by Sanger sequencing, was not found in several public databases, including gnomAD. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in haploinsufficiency and was classified as strongly pathogenic according to ACMG guidelines.
This variant, formerly designated POIRIER-BIENVENU NEURODEVELOPMENTAL SYNDROME, has been reclassified because the numbering of the variant in the article by Li et al. (2019) does not correspond with the cited reference sequence.
In a 2-year-old Chinese boy (P5) with Poirier-Bienvenu neurodevelopmental syndrome (POBINDS; 618732), Li et al. (2019) identified a de novo heterozygous 1-bp deletion (c.264delC, NM_001320) in exon 4 of the CSNK2B gene, predicted to result in a frameshift and premature termination (Ile88IlefsTer46). The mutation, which was found by trio-based whole-exome sequencing and confirmed by Sanger sequencing, was not found in several public databases, including gnomAD. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in haploinsufficiency and was classified as strongly pathogenic according to ACMG guidelines.
In a 6-month-old Chinese girl (P9) with Poirier-Bienvenu neurodevelopmental syndrome (POBINDS; 618732), Li et al. (2019) identified a de novo heterozygous A-to-G transition in intron 5 of the CSNK2B gene (c.368-2A-G), predicted to result in a splice site alteration. The mutation, which was found by trio-based whole-exome sequencing and confirmed by Sanger sequencing, was not found in several public databases, including gnomAD. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in haploinsufficiency and was classified as strongly pathogenic according to ACMG guidelines. The mutation affected the zinc-binding domain, and the patient had controlled seizures and mildly impaired development.
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