Pathological disruption of CELF2 shuttling causes neuronal hyperactivity, learning deficits, and seizures

De novo heterozygous variants in CELF2 have recently been associated with a rare neurodevelopmental disorder, yet the mechanisms linking specific variants to distinct clinical phenotypes remain poorly understood. Here, we report a cohort of 18 individuals and provide evidence that variants causing CELF2 mislocalization, but not protein-null variants, are associated with seizures. Using proband-derived induced pluripotent stem cells and transgenic mouse models, we demonstrate that CELF2 undergoes activity-dependent nucleocytoplasmic shuttling in excitatory neurons and that its cytoplasmic retention causes neuronal hyperactivity, elevated seizure susceptibility, and learning and memory deficits. Cytoplasmic CELF2 regulates mRNAs critical for synaptic function and neuronal excitability and is implicated in epileptic seizures and intellectual disability. Drug screening further identifies AKT signaling as a key regulator of CELF2 nucleocytoplasmic shuttling and a candidate target for reversing neuronal hyperactivity. Together, our findings expand the clinical and genetic spectrum of CELF2-related neurodevelopmental disorders and establish a variant-specific mechanism that links CELF2 mislocalization to neuronal hyperactivity, seizures, and cognitive impairment.