Asif, Maria, Kaygusuz, Emrah, Shinawi, Marwan, Nickelsen, Anna, Hsieh, Tzung-Chien, Wagle, Prerana, Budde, Birgit S., Hochscherf, Jennifer ORCID: 0000-0002-4412-7391, Abdullah, Uzma, Honing, Stefan, Nienberg, Christian, Lindenblatt, Dirk, Noegel, Angelika A., Altmuller, Janine ORCID: 0000-0003-4372-1521, Thiele, Holger, Motameny, Susanne, Fleischer, Nicole, Segal, Idan, Pais, Lynn, Tinschert, Sigrid, Samra, Nadra Nasser, Savatt, Juliann M., Rudy, Natasha L., De Luca, Chiara, Fortugno, Paola, White, Susan M., Krawitz, Peter, Hurst, Anna C. E., Niefind, Karsten ORCID: 0000-0002-0183-6315, Jose, Joachim ORCID: 0000-0002-0666-2676, Brancati, Francesco, Nurnberg, Peter and Hussain, Muhammad Sajid ORCID: 0000-0002-1353-8809 (2022). De novo variants of CSNK2B cause a new intellectual disability-craniodigital syndrome by disrupting the canonical Wnt signaling pathway. Hum. Genet. Genom. Adv., 3 (3). AMSTERDAM: ELSEVIER. ISSN 2666-2477

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Abstract

CSNK2B encodes for casein kinase II subunit beta (CK2 beta), the regulatory subunit of casein kinase II (CK2), which is known to mediate diverse cellular pathways. Variants in this gene have been recently identified as a cause of Poirier-Bienvenu neurodevelopmental syndrome (POBINDS), but functional evidence is sparse. Here, we report five unrelated individuals: two of them manifesting POBINDS, while three are identified to segregate a new intellectual disability-craniodigital syndrome (IDCS), distinct from POBINDS. The three IDCS individuals carried two different de novo missense variants affecting the same codon of CSNK2B. Both variants, NP_001311.3; p.Asp32His and NP_001311.3; p.Asp32Asn, lead to an upregulation of CSNK2B expression at transcript and protein level, along with global dysregulation of canonical Wnt signaling. We found impaired interaction of the two key players DVL3 and beta-catenin with mutated CK2f3. The variants compromise the kinase activity of CK2 as evident by a marked reduction of phosphorylated beta-catenin and consequent absence of active beta-catenin inside nuclei of the patient-derived lymphoblastoid cell lines (LCLs). In line with these findings, whole-transcriptome profiling of patient-derived LCLs harboring the NP_001311.3; p.Asp32His variant confirmed a marked difference in expression of genes involved in the Wnt signaling pathway. In addition, whole-phosphoproteome analysis of the LCLs of the same subject showed absence of phosphorylation for 313 putative CK2 substrates, enriched in the regulation of nuclear beta-catenin and transcription of the target genes. Our findings suggest that discrete variants in CSNK2B cause dominant-negative perturbation of the canonical Wnt signaling pathway, leading to a new craniodigital syndrome distinguishable from POBINDS.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Asif, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kaygusuz, EmrahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shinawi, MarwanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nickelsen, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hsieh, Tzung-ChienUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wagle, PreranaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Budde, Birgit S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hochscherf, JenniferUNSPECIFIEDorcid.org/0000-0002-4412-7391UNSPECIFIED
Abdullah, UzmaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Honing, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nienberg, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lindenblatt, DirkUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Noegel, Angelika A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmuller, JanineUNSPECIFIEDorcid.org/0000-0003-4372-1521UNSPECIFIED
Thiele, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Motameny, SusanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fleischer, NicoleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Segal, IdanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pais, LynnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tinschert, SigridUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Samra, Nadra NasserUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Savatt, Juliann M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rudy, Natasha L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Luca, ChiaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fortugno, PaolaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
White, Susan M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krawitz, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hurst, Anna C. E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Niefind, KarstenUNSPECIFIEDorcid.org/0000-0002-0183-6315UNSPECIFIED
Jose, JoachimUNSPECIFIEDorcid.org/0000-0002-0666-2676UNSPECIFIED
Brancati, FrancescoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nurnberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hussain, Muhammad SajidUNSPECIFIEDorcid.org/0000-0002-1353-8809UNSPECIFIED
URN: urn:nbn:de:hbz:38-696652
DOI: 10.1016/j.xhgg.2022.100111
Journal or Publication Title: Hum. Genet. Genom. Adv.
Volume: 3
Number: 3
Date: 2022
Publisher: ELSEVIER
Place of Publication: AMSTERDAM
ISSN: 2666-2477
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
PROTEIN-KINASE CK2; TRUNCATING MUTATION; BETA-SUBUNIT; GENE; CK2-BETA; FAMILY; BRAIN; VISUALIZATION; PROTEOMICS; ANOMALIESMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69665

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