Functional impact of the ATP1A3-p.A813V variant: insights into a calcium-driven hyperexcitability cascade in rapid-onset dystonia-Parkinsonism

BACKGROUND: -ATPase subunit ATP1A3 are linked to a spectrum of neurological disorders, including rapid-onset dystonia-parkinsonism (RDP), yet their pathogenic mechanisms remain incompletely understood. We describe the complex clinical characteristics of a patient with early-onset movement disorders and a likely pathogenic de novo variant in ATP1A3(c·2483C>T, p.A813V). METHODS: We identified a de novo heterozygous ATP1A3 p.A813V variant in a patient with clinically confirmed RDP and employed an integrative approach combining molecular dynamics (MD) simulations, zebrafish models, and patient-derived induced neurons (iNeurons) to delineate its pathogenesis. RESULTS: -ATPase activity. CONCLUSIONS: homeostasis, triggers neuronal hyperexcitability, and culminates in progressive neurodegeneration. This work provides a molecular and functional framework for targeting ionic and calcium homeostasis as a promising therapeutic strategy for ATP1A3-related disorders.