De novo variants of CSNK2B cause a new intellectual disability-craniodigital syndrome by disrupting the canonical Wnt signaling pathway
Summary: 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 funct...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-07-01
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| Series: | HGG Advances |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666247722000276 |
| _version_ | 1818192318883168256 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Maria Asif |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-12-12T00:28:36Z |
| format | Article |
| id | doaj.art-9ab8572fe2874d66a9f70e678cec119a |
| institution | Directory Open Access Journal |
| issn | 2666-2477 |
| language | English |
| last_indexed | 2024-12-12T00:28:36Z |
| publishDate | 2022-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | HGG Advances |
| spelling | doaj.art-9ab8572fe2874d66a9f70e678cec119a2022-12-22T00:44:32ZengElsevierHGG Advances2666-24772022-07-0133100111De novo variants of CSNK2B cause a new intellectual disability-craniodigital syndrome by disrupting the canonical Wnt signaling pathwayMaria Asif0Emrah Kaygusuz1Marwan Shinawi2Anna Nickelsen3Tzung-Chien Hsieh4Prerana Wagle5Birgit S. Budde6Jennifer Hochscherf7Uzma Abdullah8Stefan Höning9Christian Nienberg10Dirk Lindenblatt11Angelika A. Noegel12Janine Altmüller13Holger Thiele14Susanne Motameny15Nicole Fleischer16Idan Segal17Lynn Pais18Sigrid Tinschert19Nadra Nasser Samra20Juliann M. Savatt21Natasha L. Rudy22Chiara De Luca23 Paola Fortugno24Susan M. White25Peter Krawitz26Anna C.E. Hurst27Karsten Niefind28Joachim Jose29Francesco Brancati30Peter Nürnberg31Muhammad Sajid Hussain32Cologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine and University Hospital Cologne, 50931 Cologne, Germany; Center for Biochemistry, Medical Faculty, University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Faculty of Medicine and University Hospital Cologne, 50931 Cologne, GermanyCenter for Biochemistry, Medical Faculty, University of Cologne, 50931 Cologne, Germany; Bilecik Şeyh Edebali University, Molecular Biology and Genetics, Gülümbe Campus, 11230 Bilecik, TurkeyDivision of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USAInstitute of Pharmaceutical and Medicinal Chemistry, Westphalian Wilhelms-University, Münster, GermanyInstitute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Rheinische Friedrich Wilhelms, Universität Bonn, Bonn, GermanyCologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, GermanyCologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine and University Hospital Cologne, 50931 Cologne, GermanyDepartment of Chemistry, Institute of Biochemistry, University of Cologne, Cologne, GermanyUniversity Institute of Biochemistry and Biotechnology (UIBB), PMAS-Arid Agriculture University, Rawalpindi, PakistanCenter for Biochemistry, Medical Faculty, University of Cologne, 50931 Cologne, GermanyInstitute of Pharmaceutical and Medicinal Chemistry, Westphalian Wilhelms-University, Münster, GermanyDepartment of Chemistry, Institute of Biochemistry, University of Cologne, Cologne, GermanyCenter for Biochemistry, Medical Faculty, University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Faculty of Medicine and University Hospital Cologne, 50931 Cologne, GermanyCologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine and University Hospital Cologne, 50931 Cologne, Germany; Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Core Facility Genomics, Charitéplatz 1, 10117 Berlin, Germany; Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, GermanyCologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine and University Hospital Cologne, 50931 Cologne, GermanyCologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine and University Hospital Cologne, 50931 Cologne, GermanyFDNA Inc., Boston, MA, USAHospital Center, Safed, IsraelCenter for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USAZentrum Medizinische Genetik, Medizinische Universität, Innsbruck, AustriaHospital Center, Safed, Israel; Azrieli Faculty of Medicine, Bar-Ilan University, Safed, IsraelGenomic Medicine Institute, Geisinger, Danville, PA, USADepartment of Genetics, University of Alabama at Birmingham, Birmingham, AL, USADepartment of Life, Health and Environmental Science, University of L’Aquila, 67100 L’Aquila, ItalyDepartment of Life, Health and Environmental Science, University of L’Aquila, 67100 L’Aquila, Italy; IRCCS, San Raffaele Roma, 00163 Roma, ItalyVictorian Clinical Genetics Services, Murdoch Children’s Research Institute, Melbourne, VIC, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC, AustraliaInstitute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Rheinische Friedrich Wilhelms, Universität Bonn, Bonn, GermanyDepartment of Genetics, University of Alabama at Birmingham, Birmingham, AL, USADepartment of Chemistry, Institute of Biochemistry, University of Cologne, Cologne, GermanyInstitute of Pharmaceutical and Medicinal Chemistry, Westphalian Wilhelms-University, Münster, GermanyDepartment of Life, Health and Environmental Science, University of L’Aquila, 67100 L’Aquila, Italy; IRCCS, San Raffaele Roma, 00163 Roma, ItalyCologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine and University Hospital Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Faculty of Medicine and University Hospital Cologne, 50931 Cologne, GermanyCologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine and University Hospital Cologne, 50931 Cologne, Germany; Center for Biochemistry, Medical Faculty, University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Faculty of Medicine and University Hospital Cologne, 50931 Cologne, Germany; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2666247722000276intellectual disability-craniodigital syndromeCSNK2BCK2βCK2Wnt signalingβ-catenin |
| spellingShingle | 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 De novo variants of CSNK2B cause a new intellectual disability-craniodigital syndrome by disrupting the canonical Wnt signaling pathway HGG Advances intellectual disability-craniodigital syndrome CSNK2B CK2β CK2 Wnt signaling β-catenin |
| title | De novo variants of CSNK2B cause a new intellectual disability-craniodigital syndrome by disrupting the canonical Wnt signaling pathway |
| title_full | De novo variants of CSNK2B cause a new intellectual disability-craniodigital syndrome by disrupting the canonical Wnt signaling pathway |
| title_fullStr | De novo variants of CSNK2B cause a new intellectual disability-craniodigital syndrome by disrupting the canonical Wnt signaling pathway |
| title_full_unstemmed | De novo variants of CSNK2B cause a new intellectual disability-craniodigital syndrome by disrupting the canonical Wnt signaling pathway |
| title_short | De novo variants of CSNK2B cause a new intellectual disability-craniodigital syndrome by disrupting the canonical Wnt signaling pathway |
| title_sort | de novo variants of csnk2b cause a new intellectual disability craniodigital syndrome by disrupting the canonical wnt signaling pathway |
| topic | intellectual disability-craniodigital syndrome CSNK2B CK2β CK2 Wnt signaling β-catenin |
| url | http://www.sciencedirect.com/science/article/pii/S2666247722000276 |
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