Molecular characterization of Okur—Chung neurodevelopmental syndrome (OCNDS) through cell and animal models
Okur-Chung Neurodevelopmental Syndrome (OCNDS), a neurodevelopmental disorder, is caused by mutations in the CSNK2A1 gene. Developmental delay, language and speech issues, behavioral problems, brain malformations, and dysmorphic features are often described in patients with OCNDS. Despite encoding Protein Kinase CK2, a ubiquitous and highly conserved protein kinase in eukaryotic cells, there is still significant debate over the mechanism of and phenotypes caused by mutations on CSNK2A1. At the Center for Rare Childhood Disorders (C4RCD) we identified patients with three different mutations with variable phenotype: 1) K198R mutation located in the activation segment, 2) D156E mutation on the active site, and 3) R47G on the ATP/GTP binding loop and established patient-derived cell lines with these mutations. Our overall goal is to understand the neurobiological mechanisms of OCNDs and understand the phenotypic variability using patient-derived cell and zebrafish models. Patient fibroblast cell lines were grown for RNA and protein lysates to conduct RNAseq analysis and phosphoproteome analysis. RNAseq data analysis revealed dysregulation of key genes involved in growth factor signaling and the mitophagy pathways. Inhibition of CK2 in zebrafish embryos displayed a phenotype of an enlarged heart and deformed heads. Our study indicates that the compromised growth factor signaling pathways that may contribute to the disease pathophysiology. Our ongoing studies from patient-derived cells and the zebrafish model will provide a better understanding of the molecular mechanisms involved in the OCNDS.