PPP1R3F variants impair brain energy metabolism: a novel X-linked cause of neurodevelopmental disorders with translational therapeutic implications

Background Neurodevelopmental disorders (NDDs) are highly heterogeneous, and their genetic and metabolic underpinnings remain incompletely understood. PPP1R3F encodes a glycogen-targeting subunit of protein phosphatase 1 with poorly defined functions in the brain. Methods We identified novel PPP1R3F variants in two unrelated male patients with intellectual disability and seizures. To investigate pathogenic mechanisms, we combined transcriptomic profiling, cellular metabolic assays, and a PPP1R3F knockout (KO) mouse model. Results Transcriptomic analysis revealed enrichment of differentially expressed genes in energy metabolism pathways. Patient-derived and KO cell models exhibited impaired mitochondrial function, increased reactive oxygen species (ROS) production, and heightened vulnerability to oxygen–glucose deprivation. Consistent with these findings, PPP1R3F KO mice displayed metabolic alterations and deficits in cognition function. Conclusion Our study demonstrates that PPP1R3F loss of function disrupts neuronal energy metabolism and redox balance, providing a novel X-linked genetic cause of NDDs. These findings highlight bioenergetic dysfunction as a mechanistic link between genetic mutations and neurodevelopmental impairment, suggesting energy metabolic modulation as a potential therapeutic avenue.