Abstract
The Okur-Chung neurodevelopmental syndrome, or OCNDS, is a newly discovered rare neurodevelopmental disorder. It is characterized by developmental delay, intellectual disability, behavioral problems (hyperactivity, repetitive movements and social interaction deficits), hypotonia, epilepsy and language/verbalization deficits. OCNDS is linked to de novo mutations in CSNK2A1, that lead to missense or deletion/truncating variants in the encoded protein, the protein kinase CK2α. Eighteen different missense CK2α mutations have been identified to date; however, no biochemical or cell biological studies have yet been performed to clarify the functional impact of such mutations. Here, we show that 15 different missense CK2α mutations lead to varying degrees of loss of kinase activity as recombinant purified proteins and when mutants are ectopically expressed in mammalian cells. We further detect changes in the phosphoproteome of three patient-derived fibroblast lines and show that the subcellular localization of CK2α is altered for some of the OCNDS-linked variants and in patient-derived fibroblasts. Our data argue that reduced kinase activity and abnormal localization of CK2α may underlie the OCNDS phenotype.
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Acknowledgements
The authors would like to thank Drs F Sciandra and M Bozzi for helpful discussions, D Ballardin and ML Hathorn for critical reading of the manuscript, L Hage, I El Haddid, A Mobi, Dr. J Revuelta Cervantes and G Reis for technical assistance, and K Ramsey (TGen, Phoenix, Arizona), Drs AL Bruel (INSERM UMR1231, France) and L Faivre (Hôpital d’Enfants, Dijon, France) for patient skin fibroblast lines.
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This work was supported by research grants from the CSNK2A1 foundation (to ID, SR and HR), a Rare Disease Foundation microgrant (to HR), the National Institutes of General Medical Sciences (NIGMS) (1R01GM098367) (ID), and CTSA grant UL1-TR000157.
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HR conceived and planned the experiments. HR, ID, JCG, ND and VC carried out the experiments. ID conceived and planned the experiments in mice. SR generated cell lines. HR, ID and VC contributed to the interpretation of the results. HR and ID wrote the manuscript. All authors provided critical feedback on, improved and approved the manuscript.
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The Ethics approvals are mentioned in the Methods section: The fibroblast study protocol and consent were approved by the Western Institutional Review Board research protocol (20120789). Ethics approval for work with the fibroblasts was also granted by the Cellule bioethique DGRI-SPFCO-B5 of the French Ministry of Higher Education, Research and Innovation (DC-2019-3665). Mouse experiments were approved by the Boston University Medical Center Institutional Animal Care and Use Committee (IACUC, PROTO201800107).
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Dominguez, I., Cruz-Gamero, J.M., Corasolla, V. et al. Okur-Chung neurodevelopmental syndrome-linked CK2α variants have reduced kinase activity. Hum Genet 140, 1077–1096 (2021). https://doi.org/10.1007/s00439-021-02280-5
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DOI: https://doi.org/10.1007/s00439-021-02280-5