Okur-Chung neurodevelopmental syndrome-linked CK2α variants have reduced kinase activity

• Published in: Human genetics 2021-07, Vol.140 (7), p.1077-1096
• Main Authors: Dominguez, I., Cruz-Gamero, J. M., Corasolla, V., Dacher, N., Rangasamy, S., Urbani, A., Narayanan, V., Rebholz, H.
• Format: Article
• Language: English
• Subjects: Biomedical and Life Sciences; Biomedicine; Epilepsy; Fibroblasts; Gene deletion; Gene Function; Human Genetics; Hyperactivity; Intellectual disabilities; Kinases; Localization; Mammalian cells; Metabolic Diseases; Molecular Medicine; Movement disorders; Mutation; Neurodevelopmental disorders; Original Investigation; Phenotypes; Protein kinase; Protein kinase C
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-021-02280-5

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.