Pathogenic Ppp2r5d Variants Impair RNA Metabolism and Protein Homeostasis in Novel Murine Models of Neurodevelopmental Delay
Pathogenic de novo mutations in PPP2R5D, a regulatory subunit of Protein Phosphatase 2A (PP2A), cause Jordan's syndrome (JS), a rare neurodevelopmental disorder characterized by global developmental delay and moderate to severe intellectual disability. In this study, using heterozygous knock-in E198K and E200K Ppp2r5d variant mice, we investigated how PPP2R5D variants affect brain development and function, aiming to elucidate the molecular and cellular mechanisms underlying JS pathogenesis. Bulk RNA sequencing from microdissected brain regions, including the prefrontal cortex (PFC), striatum (STR), hippocampus (HIP), and cerebellum (CER), revealed widespread transcriptomic dysregulation in Ppp2r5d variant mice when compared to wild-type mice.