Predictive functional, statistical and structural analysis of CSNK2A1 and CSNK2B variants linked to neurodevelopmental diseases

Prasida Unni; Jack Friend; Janice Weinberg; Volkan Okur; Jennifer Hochscherf; Isabel Dominguez

doi:10.3389/fmolb.2022.851547

Predictive functional, statistical and structural analysis of CSNK2A1 and CSNK2B variants linked to neurodevelopmental diseases

Front Mol Biosci. 2022 Oct 13:9:851547. doi: 10.3389/fmolb.2022.851547. eCollection 2022.

Authors

Prasida Unni¹, Jack Friend¹, Janice Weinberg², Volkan Okur³, Jennifer Hochscherf⁴, Isabel Dominguez¹

Affiliations

¹ Department of Medicine, Boston University School of Medicine and Boston Medical Center, Boston University, Boston, MA, United States.
² Department of Biostatistics, Boston University School of Public Health, Boston University, Boston, MA, United States.
³ New York Genome Center, New York, NY, United States.
⁴ Department of Chemistry, Institute of Biochemistry, University of Cologne, Cologne, Germany.

Abstract

Okur-Chung Neurodevelopmental Syndrome (OCNDS) and Poirier-Bienvenu Neurodevelopmental Syndrome (POBINDS) were recently identified as rare neurodevelopmental disorders. OCNDS and POBINDS are associated with heterozygous mutations in the CSNK2A1 and CSNK2B genes which encode CK2α, a serine/threonine protein kinase, and CK2β, a regulatory protein, respectively, which together can form a tetrameric enzyme called protein kinase CK2. A challenge in OCNDS and POBINDS is to understand the genetic basis of these diseases and the effect of the various CK2⍺ and CK2β mutations. In this study we have collected all variants available to date in CSNK2A1 and CSNK2B, and identified hotspots. We have investigated CK2⍺ and CK2β missense mutations through prediction programs which consider the evolutionary conservation, functionality and structure or these two proteins, compared these results with published experimental data on CK2α and CK2β mutants, and suggested prediction programs that could help predict changes in functionality of CK2α mutants. We also investigated the potential effect of CK2α and CK2β mutations on the 3D structure of the proteins and in their binding to each other. These results indicate that there are functional and structural consequences of mutation of CK2α and CK2β, and provide a rationale for further study of OCNDS and POBINDS-associated mutations. These data contribute to understanding the genetic and functional basis of these diseases, which is needed to identify their underlying mechanisms.

Keywords: CK2α; CK2β; Okur-Chung neurodevelopmental syndrome (OCNDS); Poirier-Bienvenu neurodevelopmental syndrome (POBINDS); autism spectrum disorder (ASD); epilepsy; non-random mutation clustering (NMC); protein kinase CK2.