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| Item Type: | Article |
|---|---|
| Title: | De novo variants of CSNK2B cause a new intellectual disability-craniodigital syndrome by disrupting the canonical Wnt signaling pathway |
| Creators Name: | Asif, M. and Kaygusuz, E. and Shinawi, M. and Nickelsen, A. and Hsieh, T.C. and Wagle, P. and Budde, B. and Hochscherf, J. and Abdullah, U. and Höning, S. and Nienberg, C. and Lindenblatt, D. and Noegel, A.A. and Altmüller, J. and Thiele, H. and Motameny, S. and Fleischer, N. and Segal, I. and Pais, L. and Tinschert, S. and Samra, N.G. and Savatt, J.M. and Rudy, N.L. and De Luca, C. and Fortugno, P. and White, S.M. and Krawitz, P. and Hurst, A.C.E. and Niefind, K. and Jose, J. and Brancati, F. and Nürnberg, P. and Hussain, M.S. |
| Abstract: | CSNK2B encodes for casein kinase II subunit beta (CK2b), 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 b-catenin with mutated CK2b. The variants compromise the kinase activity of CK2 as evident by a marked reduction of phosphorylated b-catenin and consequent absence of active b-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 b-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. |
| Source: | Human Genetics and Genomics Advances |
| ISSN: | 2666-2477 |
| Publisher: | Cell Press |
| Volume: | 3 |
| Number: | 3 |
| Page Range: | 100111 |
| Date: | 14 July 2022 |
| Official Publication: | https://doi.org/10.1016/j.xhgg.2022.100111 |
| PubMed: | View item in PubMed |
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