A CK2α–G3BP1 signaling axis regulates local translation in developing neurons and is disrupted in OCNDS

Abstract

Neurodevelopmental disorders are frequently caused by mutations in pleiotropic kinases, yet downstream effectors driving neuronal pathology remain undefined. Here, we identify the G3BP1-dependent stress granule pathway as the dominant effector of casein kinase 2 (CK2α) in developing neurons, implying that its dysregulation underlies the neurodevelopmental deficits of Okur-Chung neurodevelopmental syndrome (OCNDS). OCNDS-associated CK2α mutations reduce phosphorylation of G3BP1 at serine 149, promoting aberrant phase separation and persistent granules that sequester neuronal mRNAs and suppress local protein synthesis across axonal and dendritic compartments. These phenotypes produce allele-specific deficits in neuronal morphogenesis, synaptic abundance, and network excitability, which are conserved in a knock-in mouse model and in patient-derived iPSC neurons. G3bp1 knockdown rescues translational and morphological phenotypes across all OCNDS alleles, demonstrating that restoring granule homeostasis reverses neuronal pathology. Together, these findings establish OCNDS as a disorder of compartment-specific translational dysregulation driven by impaired CK2α–G3BP1 control of RNA granule homeostasis. Summary OCNDS mutations disrupt CK2α–G3BP1 signaling, causing persistent granules and defective neuronal translation and development.