De novo variants of CSNK2B cause a new intellectual disability-craniodigital syndrome by disrupting the canonical Wnt signaling pathway

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; Italian Undiagnosed Diseases Network; Paola Fortugno; Susan M White; Peter Krawitz; Anna C E Hurst; Karsten Niefind; Joachim Jose; Francesco Brancati; Peter Nürnberg; Muhammad Sajid Hussain

doi:10.1016/j.xhgg.2022.100111

De novo variants of CSNK2B cause a new intellectual disability-craniodigital syndrome by disrupting the canonical Wnt signaling pathway

HGG Adv. 2022 Apr 18;3(3):100111. doi: 10.1016/j.xhgg.2022.100111. eCollection 2022 Jul 14.

Authors

Maria Asif^{1

2

3}, Emrah Kaygusuz^{2

4}, Marwan Shinawi⁵, Anna Nickelsen⁶, Tzung-Chien Hsieh⁷, Prerana Wagle⁸, Birgit S Budde¹, Jennifer Hochscherf⁹, Uzma Abdullah¹⁰, Stefan Höning², Christian Nienberg⁶, Dirk Lindenblatt⁹, Angelika A Noegel^{2

3}, Janine Altmüller^{1

11

12}, Holger Thiele¹, Susanne Motameny¹, Nicole Fleischer¹³, Idan Segal¹⁴, Lynn Pais¹⁵, Sigrid Tinschert¹⁶, Nadra Nasser Samra^{14

17}, Juliann M Savatt¹⁸, Natasha L Rudy¹⁹, Chiara De Luca²⁰; Italian Undiagnosed Diseases Network; Paola Fortugno^{20

21}, Susan M White^{22

23}, Peter Krawitz⁷, Anna C E Hurst¹⁹, Karsten Niefind⁹, Joachim Jose⁶, Francesco Brancati^{20

21}, Peter Nürnberg^{1

3}, Muhammad Sajid Hussain^{1

2

3}

Affiliations

¹ Cologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine and University Hospital Cologne, 50931 Cologne, Germany.
² Center for Biochemistry, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
³ Center for Molecular Medicine Cologne (CMMC), University of Cologne, Faculty of Medicine and University Hospital Cologne, 50931 Cologne, Germany.
⁴ Bilecik Şeyh Edebali University, Molecular Biology and Genetics, Gülümbe Campus, 11230 Bilecik, Turkey.
⁵ Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.
⁶ Institute of Pharmaceutical and Medicinal Chemistry, Westphalian Wilhelms-University, Münster, Germany.
⁷ Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Rheinische Friedrich Wilhelms, Universität Bonn, Bonn, Germany.
⁸ Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
⁹ Department of Chemistry, Institute of Biochemistry, University of Cologne, Cologne, Germany.
¹⁰ University Institute of Biochemistry and Biotechnology (UIBB), PMAS-Arid Agriculture University, Rawalpindi, Pakistan.
¹¹ Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Core Facility Genomics, Charitéplatz 1, 10117 Berlin, Germany.
¹² Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
¹³ FDNA Inc., Boston, MA, USA.
¹⁴ Hospital Center, Safed, Israel.
¹⁵ Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁶ Zentrum Medizinische Genetik, Medizinische Universität, Innsbruck, Austria.
¹⁷ Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel.
¹⁸ Genomic Medicine Institute, Geisinger, Danville, PA, USA.
¹⁹ Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.
²⁰ Department of Life, Health and Environmental Science, University of L'Aquila, 67100 L'Aquila, Italy.
²¹ IRCCS, San Raffaele Roma, 00163 Roma, Italy.
²² Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC, Australia.
²³ Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.

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.

Keywords: CK2; CK2α; CK2β; CSNK2B; DVL3; GestaltMatcher; POBINDS; Wnt signaling; intellectual disability-craniodigital syndrome; whole transcriptome profiling; whole-phosphoproteome profiling; β-catenin.

Abstract

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