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

Authors: Prasida Unni, Jack Friend, Janice Weinberg, Bolkan Okur, Jennifer Hochscherf, Isabel Dominguez

Publication Date: October 13, 2022

Research Explained By: Brad Davidson, CSNK2A1 Foundation Science Communication Intern

Link to article: https://www.frontiersin.org/articles/10.3389/fmolb.2022.851547/full

Research Explained Summary:

This paper leverages computational modeling to investigate the functional consequences of mutations in the CSNK2A1 and CSNK2B genes on the molecular level. Mutations in these genes lead to OCNDS and Poirier-Bienvenu Neurodevelopmental Syndrome (POBINDS) respectively. They are analyzed together in this paper due to the relatively similar symptoms presented by patients with these diseases and the relatedness of the proteins that are encoded by their corresponding genes. Genes are the molecular blueprint for proteins, which perform molecular functions required for life. The CSNK2A1 and CSNK2B genes encode the proteins CK2α and CK2β respectively. These proteins bind to each other and create a larger complex of proteins known simply as CK2. CK2 is an enzyme, meaning that it causes chemical reactions in a cell, potentially affecting many other proteins – CK2α performs these chemical reactions, while CK2β helps regulate the function of CK2 overall.

In this paper, all currently known OCNDS and POBINDS causing mutations were identified and tested. Overall, 68 mutations in the CSNK2A1 gene were examined as potentially causing OCNDS. 12 total locations in the CSNK2A1 gene were found to be recurrently mutated, indicating that these sites are important in development, although there were 45 total mutation sites found. Most of these mutations were clustered closely together on the gene, indicating that the regions they are found in are important to the CSNK2A1 gene and CK2α protein function. These regions are known as the Gly-rich-loop and P+1 loop, which are critical for the enzymatic function of CK2α. 

The authors tried to predict the specific molecular alterations that CSNK2A1 mutations would have on CK2 protein function using computational algorithms. First, they used computational programs to predict which mutations lead to changes in CK2 enzymatic activity. Afterwards, they compared programs which attempted to determine which mutations lead to greater changes in the overall shape and structure of the CK2 protein. The authors identified mutations in specific domains of the CK2 protein and how they might affect the protein’s function and structure based on the best algorithms identified. Broadly, this study surveys all CSNK2A1 mutations known to date in depth and computationally profiled them on the genetic and protein level to determine specifically how each mutation might impact CK2 function. More knowledge in this area may lead to patient specific treatment approaches and potentially link distinct mutations to specific symptoms.