Investigation of the pathogenic mechanisms and potential therapeutic strategies for Houge-Janssens Syndrome 1 (HJS1)

Houge-Janssens Syndrome 1 (HJS1) is a rare neurodevelopmental disorder resulting from heterozygous de novo missense mutations in the PPP2R5D gene, which encodes the δ isoform of the B' regulatory subunit family (B'δ) of protein phosphatase 2A (PP2A), a key serine/threonine phosphatase involved in many cellular functions. To investigate the underlying disease mechanisms, we developed three clinically relevant knock-in mouse models (E198K, E200K, and E420K). Our findings reveal that E198K, E420K, and E200K mice exhibit core patient features such as macrocephaly and frontal bossing. Behaviorally, E198K and E420K mice showed physical and motor developmental delays, hyperactivity, context-dependent anxiety, and deficits in spatial and associative memory, whereas E200K mice displayed only short-term memory deficits. Biochemical analyses indicated reduced phosphorylation of PKA substrates, GluR1-S831, GluR1-S845, and CaMKII-T286 in E198K and E420K mouse brains, with no such changes in E200K mice. Additionally, adult neurogenesis in the dentate gyrus of E198K mice showed increased dendritic branching and length in DCX+ cells, along with depletion of SOX2+ nuclei in the inner blade of the granule layer. These biochemical changes provided insights into pathogenic mechanisms of HJS1.