Characterizing CSNK2A1 Mutant-Induced Morphological Phenotypes in Zebrafish (Danio rerio): Insights into Okur-Chung Neurodevelopmental Syndrome (OCNDS)
Okur-Chung Neurodevelopmental Syndrome (OCNDS) is a rare autosomal dominant disorder caused by mutations in the CSNK2A1 gene. The CSNK2A1 gene encodes for an subunit of the protein kinase CK2, which is involved in various biological processes. Aberrant functioning of CK2 is associated with several conditions and diseases. In 2016, Okur and colleagues reported the discovery of germline de novo missense and canonical splice site mutations in the CSNK2A1 gene from five female patients with neurodevelopmental syndrome. The clinical features commonly observed in individuals with OCNDS include developmental delays, intellectual disability, hypotonia, feeding difficulties, dysmorphic facial features, and disrupted circadian rhythm leading to sleep disturbances. Despite advancements in understanding the genetic underpinnings of OCNDS, significant gaps remain in our knowledge of the molecular mechanisms driving this syndrome. The complex phenotypic spectrum of OCNDS underscores the need to develop robust model systems to bridge the gap between genetic discoveries, genotype-phenotype correlations, molecular mechanisms of disease pathogenesis, and therapeutic advancements. We utilized an overexpression strategy to investigate the functional consequences of CSNK2A1 variants that cause diseases in zebrafish embryos. We observed unique and distinct morphological phenotypes resulting from the overexpression of various CSNK2A1 mutants. Each mutant variant of the CSNK2A1 gene showed a unique morphological phenotype, suggesting a direct connection between the genetic alteration and its phenotypic expression. Among the variants studied, the p.R191X mutation was particularly noteworthy for its severe phenotypic impact. This finding highlights the potential of this variant to serve as a critical marker in understanding the pathophysiology of OCNDS. The use of zebrafish models in this study is advantageous as they provide a highly relevant and adaptable system for investigating the functional consequences of CSNK2A1 mutations and exploring new therapeutic approaches. This approach enhances our understanding of OCNDS at a molecular level and opens up new avenues for developing potential treatments.