De novo variants of CSNK2B cause a new intellectual disability-craniodigital syndrome by disrupting the canonical Wnt signaling pathway
Year: 2022
Type: article
Study design: Case Report
Abstract: CSNK2B encodes for casein kinase II subunit beta (CK2β), 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 β-catenin with mutated CK2β. The variants compromise the kinase activity of CK2 as evident by a marked reduction of phosphorylated β-catenin and consequent absence of active β-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 β-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.
Authors: Maria Asif, Emrah Kaygusuz, Marwan Shinawi, Anna Nickelsen, Tzung-Chien Hsieh, Prerana Wagle, Birgit S. Budde, Jennifer Hochscherf, Uzma Abdullah, Stefan Höning, Christian Nienberg, Dirk Lindenblatt, Angelika A. Noegel, Janine Altmüller, Holger Thiele, Susanne Motameny, Nicole Fleischer, Idan Segal, Lynn Pais, Sigrid Tinschert, Nadra Nasser Samra, Juliann M. Savatt, Natasha L. Rudy, Chiara De Luca, Paola Fortugno, Susan M. White, Peter Krawitz, Anna C.E. Hurst, Karsten Niefind, Joachim Jose, Francesco Brancati, Peter Nürnberg, Muhammad Sajid Hussain
Institutions: University of Cologne, University Hospital Cologne, Bilecik Şeyh Edebali Üniversitesi, Washington University in St. Louis, University of Münster, University of Bonn, University Hospital Bonn, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, Pir Mehr Ali Shah Arid Agriculture University, Max Delbrück Center, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Rebecca Sieff Hospital, Broad Institute, Innsbruck Medical University, Bar-Ilan University, Geisinger Health System, University of Alabama at Birmingham, University of L'Aquila, IRCCS San Raffaele Roma, The University of Melbourne, Victorian Clinical Genetics Services, Murdoch Children's Research Institute
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,300
Funders: Children's Hospital Foundation, Broad Institute, Murdoch Children's Research Institute, Royal Children's Hospital Foundation, Deutsche Forschungsgemeinschaft, Universität zu Köln, Center for Molecular Medicine Cologne, University of Cologne, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Eye Institute, Eunice Kennedy Shriver National Institute of Child Health and Human Development
OpenAlex ID: W4223967714