{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T17:44:28Z","timestamp":1789926268235,"version":"4.0.1"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,6,14]],"date-time":"2022-06-14T00:00:00Z","timestamp":1655164800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81701541"],"award-info":[{"award-number":["81701541"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100019091","name":"Key Research and Development Program of Hunan Province of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100019091","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012476","name":"Fundamental Research Funds for Central Universities of the Central South University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012476","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:p><jats:italic>CSNK2B<\/jats:italic> has recently been identified as the causative gene for Poirier\u2013Bienvenu neurodevelopmental syndrome (POBINDS). POBINDS is a rare neurodevelopmental disorder characterized by early-onset epilepsy, developmental delay, hypotonia, and dysmorphism. Limited by the scarcity of patients, the genotype\u2013phenotype correlations in POBINDS are still unclear. In the present study, we describe the clinical and genetic characteristics of eight individuals with POBINDS, most of whom suffered developmental delay, generalized epilepsy, and hypotonia. Minigene experiments confirmed that two intron variants (c.367+5G&amp;gt;A and c.367+6T&amp;gt;C) resulted in the skipping of exon 5, leading to a premature termination of mRNA transcription. Combining our data with the available literature, the types of POBINDS-causing variants included missense, nonsense, frameshift, and splicing, but the variant types do not reflect the clinical severity. Reduced casein kinase 2 holoenzyme activity may represent a unifying pathogenesis. We also found that individuals with missense variants in the zinc finger domain had manageable seizures (<jats:italic>p<\/jats:italic> = 0.009) and milder intellectual disability (<jats:italic>p<\/jats:italic> = 0.003) than those with missense variants in other domains of <jats:italic>CSNK2B<\/jats:italic>. This is the first study of genotype\u2013phenotype correlations in POBINDS, drawing attention to the pathogenicity of intron variants and expanding the understanding of neurodevelopmental disorders.<\/jats:p>","DOI":"10.3389\/fnins.2022.892768","type":"journal-article","created":{"date-parts":[[2022,6,14]],"date-time":"2022-06-14T10:49:52Z","timestamp":1655203792000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Splicing Interruption by Intron Variants in CSNK2B Causes Poirier\u2013Bienvenu Neurodevelopmental Syndrome: A Focus on Genotype\u2013Phenotype Correlations"],"prefix":"10.3389","volume":"16","author":[{"given":"Wen","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanghua","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shimeng","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Pang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,6,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"20795","DOI":"10.1074\/jbc.M301638200","article-title":"Multiple effects of SERCA2b mutations associated with darier\u2019s disease.","volume":"278","author":"Ahn","year":"2003","journal-title":"J. Biol. Chem."},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3390\/ph10010004","article-title":"Drosophila protein kinase CK2: genetics, regulatory complexity and emerging roles during development.","volume":"10","author":"Bandyopadhyay","year":"2016","journal-title":"Pharmaceuticals"},{"key":"B3","doi-asserted-by":"publisher","first-page":"3619","DOI":"10.1046\/j.1432-1033.2002.03038.x","article-title":"Phosphorylation of calmodulin. Functional implications.","volume":"269","author":"Benaim","year":"2002","journal-title":"Eur. J. Biochem."},{"key":"B4","doi-asserted-by":"publisher","first-page":"2160","DOI":"10.1038\/s41436-021-01250-6","article-title":"High rate of hypomorphic variants as the cause of inherited ataxia and related diseases: study of a cohort of 366 families.","volume":"23","author":"Benkirane","year":"2021","journal-title":"Genet. Med."},{"key":"B5","doi-asserted-by":"publisher","first-page":"10395","DOI":"10.1074\/jbc.270.18.10395","article-title":"Cloning and disruption of CKB1, the gene encoding the 38-kDa beta subunit of Saccharomyces cerevisiae casein kinase II (CKII). Deletion of CKII regulatory subunits elicits a salt-sensitive phenotype.","volume":"270","author":"Bidwai","year":"1995","journal-title":"J. Biol. Chem."},{"key":"B6","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1007\/s11010-005-3117-x","article-title":"Knocking out the regulatory beta subunit of protein kinase CK2 in mice: gene dosage effects in ES cells and embryos.","volume":"274","author":"Blond","year":"2005","journal-title":"Mol. Cell. Biochem."},{"key":"B7","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1042\/0264-6021:3580087","article-title":"Assembly of protein kinase CK2: investigation of complex formation between catalytic and regulatory subunits using a zinc-finger-deficient mutant of CK2beta.","volume":"358","author":"Canton","year":"2001","journal-title":"Biochem. J."},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3390\/ph10010007","article-title":"CK2-An emerging target for neurological and psychiatric disorders.","volume":"10","author":"Castello","year":"2017","journal-title":"Pharmaceuticals"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1062","DOI":"10.1016\/j.omtn.2020.07.037","article-title":"CRISPR start-loss: a novel and practical alternative for gene silencing through base-editing-induced start codon mutations.","volume":"21","author":"Chen","year":"2020","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2021.12.017","article-title":"Modeling dopamine dysfunction in autism spectrum disorder: from invertebrates to vertebrates.","volume":"133","author":"DiCarlo","year":"2022","journal-title":"Neurosci. Biobehav. Rev."},{"key":"B11","doi-asserted-by":"publisher","first-page":"2719","DOI":"10.1242\/dev.132605","article-title":"KRAB zinc finger proteins.","volume":"144","author":"Ecco","year":"2017","journal-title":"Development"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3390\/cells8080940","article-title":"Loss of protein kinase Csnk2b\/CK2\u03b2 at neuromuscular junctions affects morphology and dynamics of aggregated nicotinic acetylcholine receptors, neuromuscular transmission, and synaptic gene expression.","volume":"8","author":"Eiber","year":"2019","journal-title":"Cells"},{"key":"B13","doi-asserted-by":"publisher","first-page":"e103","DOI":"10.1111\/epi.16931","article-title":"CSNK2B: a broad spectrum of neurodevelopmental disability and epilepsy severity.","volume":"62","author":"Ernst","year":"2021","journal-title":"Epilepsia"},{"key":"B14","doi-asserted-by":"publisher","first-page":"5003","DOI":"10.1074\/jbc.275.7.5003","article-title":"The regulatory beta subunit of protein kinase CK2 mediates formation of tetrameric CK2 complexes.","volume":"275","author":"Graham","year":"2000","journal-title":"J. Biol. Chem."},{"key":"B15","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1016\/s0014-5793(99)01553-7","article-title":"Protein kinase CK2: evidence for a protein kinase CK2beta subunit fraction, devoid of the catalytic CK2alpha subunit, in mouse brain and testicles.","volume":"462","author":"Guerra","year":"1999","journal-title":"FEBS Lett."},{"key":"B16","doi-asserted-by":"publisher","first-page":"2737","DOI":"10.1128\/MCB.01566-09","article-title":"Disruption of CK2beta in embryonic neural stem cells compromises proliferation and oligodendrogenesis in the mouse telencephalon.","volume":"30","author":"Huillard","year":"2010","journal-title":"Mol. Cell. Biol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"3195","DOI":"10.1113\/jphysiol.2008.151894","article-title":"Protein kinase CK2 modulates synaptic plasticity by modification of synaptic NMDA receptors in the hippocampus.","volume":"586","author":"Kimura","year":"2008","journal-title":"J. Physiol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1007\/s12031-015-0574-x","article-title":"The effect of miR-132, miR-146a, and miR-155 on MRP8\/TLR4-Induced Astrocyte-Related inflammation.","volume":"57","author":"Kong","year":"2015","journal-title":"J. Mol. Neurosci."},{"key":"B19","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/s0959-440x(00)00167-6","article-title":"Zinc finger proteins: new insights into structural and functional diversity.","volume":"11","author":"Laity","year":"2001","journal-title":"Curr. Opin. Struc. Biol."},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20235951","article-title":"Protein kinase CK2 subunits differentially perturb the adhesion and migration of GN11 cells: a model of immature migrating neurons.","volume":"20","author":"Lettieri","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-53484-9","article-title":"Germline de novo variants in CSNK2B in Chinese patients with epilepsy.","volume":"9","author":"Li","year":"2019","journal-title":"Sci. Rep."},{"key":"B22","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1136\/jnnp-2013-306483","article-title":"Autosomal-recessive cerebellar ataxia caused by a novel ADCK3 mutation that elongates the protein: clinical, genetic and biochemical characterisation.","volume":"85","author":"Liu","year":"2014","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1160","DOI":"10.1523\/JNEUROSCI.21-04-01160.2001","article-title":"Casein kinase 2 determines the voltage dependence of the Kv3.1 channel in auditory neurons and transfected cells.","volume":"21","author":"Macica","year":"2001","journal-title":"J. Neurosci."},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2000-1-4-reviews0004","article-title":"An overview of the potassium channel family.","volume":"1","author":"Miller","year":"2000","journal-title":"Genome Biol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1038\/s10038-018-0559-z","article-title":"Identification of de novo CSNK2A1 and CSNK2B variants in cases of global developmental delay with seizures.","volume":"64","author":"Nakashima","year":"2019","journal-title":"J. Hum. Genet."},{"key":"B26","doi-asserted-by":"publisher","first-page":"5320","DOI":"10.1093\/emboj\/20.19.5320","article-title":"Crystal structure of human protein kinase CK2: insights into basic properties of the CK2 holoenzyme.","volume":"20","author":"Niefind","year":"2001","journal-title":"EMBO J."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1196","DOI":"10.1111\/cns.12860","article-title":"Novel West syndrome candidate genes in a Chinese cohort.","volume":"24","author":"Peng","year":"2018","journal-title":"CNS Neurosci. Ther."},{"key":"B28","doi-asserted-by":"publisher","first-page":"932","DOI":"10.1002\/humu.23270","article-title":"CSNK2B splice site mutations in patients cause intellectual disability with or without myoclonic epilepsy.","volume":"38","author":"Poirier","year":"2017","journal-title":"Hum. Mutat."},{"key":"B29","doi-asserted-by":"publisher","first-page":"14096","DOI":"10.1073\/pnas.0906857106","article-title":"CK2 negatively regulates Galphas signaling.","volume":"106","author":"Rebholz","year":"2009","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B30","doi-asserted-by":"crossref","first-page":"18192","DOI":"10.1016\/S0021-9258(17)32434-1","article-title":"Cloning and disruption of CKB2, the gene encoding the 32-kDa regulatory beta\u2019-subunit of Saccharomyces cerevisiae casein kinase II.","volume":"269","author":"Reed","year":"1994","journal-title":"J. Biol. Chem."},{"key":"B31","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"B32","doi-asserted-by":"publisher","first-page":"12324","DOI":"10.1021\/bi0011431","article-title":"Cooperative modulation of protein kinase CK2 by separate domains of its regulatory beta-subunit.","volume":"39","author":"Sarno","year":"2000","journal-title":"Biochemistry"},{"key":"B33","doi-asserted-by":"publisher","first-page":"594","DOI":"10.1038\/nsmb.2301","article-title":"Translation drives mRNA quality control.","volume":"19","author":"Shoemaker","year":"2012","journal-title":"Nat. Struct. Mol. Biol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"542","DOI":"10.1016\/j.bbrc.2004.07.158","article-title":"Protein kinase CK2 in postsynaptic densities: phosphorylation of PSD-95\/SAP90 and NMDA receptor regulation.","volume":"322","author":"Soto","year":"2004","journal-title":"Biochem. Bioph. Res. Commun."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1030","DOI":"10.1002\/humu.23798","article-title":"MetaDome: pathogenicity analysis of genetic variants through aggregation of homologous human protein domains.","volume":"40","author":"Wiel","year":"2019","journal-title":"Hum. Mutat."},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-03247-3","article-title":"Comprehensive integrative analyses identify GLT8D1 and CSNK2B as schizophrenia risk genes.","volume":"9","author":"Yang","year":"2018","journal-title":"Nat. Commun."},{"key":"B37","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1007\/s10048-021-00649","article-title":"Clinical and genetic analysis of six Chinese children with Poirier-Bienvenu neurodevelopmental syndrome caused by CSNK2B mutation.","volume":"22","author":"Yang","year":"2021","journal-title":"Neurogenetics"}],"container-title":["Frontiers in Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2022.892768\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,14]],"date-time":"2022-06-14T10:49:58Z","timestamp":1655203798000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2022.892768\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,14]]},"references-count":37,"alternative-id":["10.3389\/fnins.2022.892768"],"URL":"https:\/\/doi.org\/10.3389\/fnins.2022.892768","relation":{},"ISSN":["1662-453X"],"issn-type":[{"value":"1662-453X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,14]]},"article-number":"892768"}}