Characterizing CSNK2A1 Mutant-Induced Morphological Phenotypes in Zebrafish (Danio rerio): Insights into Okur-Chung Neurodevelopmental Syndrome (OCNDS)

Abstract

Okur-Chung Neurodevelopmental Syndrome (OCNDS) is a rare, autosomal dominant disorder caused by heterozygous pathogenic variants in the CSNK2A1 gene. CSNK2A1 encodes the subunit of protein kinase CK2, involved in diverse biological processes. In 2016, Okur et al. reported the discovery of germline de novo missense and canonical splice site mutations in CSNK2A1 in five female patients with OCNDS. The syndrome is characterized by developmental delays, intellectual disability, hypotonia, feeding difficulties, dysmorphic facial features, and disrupted circadian rhythms, leading to sleep disturbances. The complex phenotypic spectrum of OCNDS underscores the need for robust model systems to investigate genotype-phenotype correlations, disease mechanisms, and potential therapies. In this study, we employed an overexpression strategy in a zebrafish model to investigate the functional consequences of select CSNK2A1 variants implicated in OCNDS. Our findings revealed distinct morphological phenotypes resulting from the overexpression of different CSNK2A1 mutants, indicating a direct correlation between genetic alterations and phenotypic manifestations. Notably, the CSNK2A1 p.Arg191Ter (R191X) mutation had a significant impact on the phenotype. Co-injection of wild-type CSNK2A1 mRNA with mutant CSNK2A1 mRNA rescued morphological abnormalities in zebrafish embryos. Overall our study highlights the utility of zebrafish as an adaptable model system for examining the functional impact of CSNK2A1 mutations and exploring novel therapeutic avenues.