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

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 CK2 alpha. Eighteen different missense CK2 alpha 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 CK2 alpha 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 CK2 alpha 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 CK2 alpha may underlie the OCNDS phenotype.

Automated summary

The Okur-Chung neurodevelopmental syndrome, or OCNDS, is a rare neurodevelopmental disorder characterized by intellectual disability, language deficits, and behavioral abnormalities. Researchers found that mutations in the CK2α gene in OCNDS patients lead to reduced kinase activity and abnormal localization, suggesting a potential underlying cause for the syndrome.