HNRNPH2 variant linked to intellectual disability disrupts myelination by impairing oligodendrocyte differentiation

Intellectual disability (ID) arises from complex pathogenic mechanisms. Although myelin dysfunction and white matter damage have been implicated, the cellular and molecular mechanisms linking impaired myelination to cognitive deficits remain largely unknown. Here, we identify a de novo heterogeneous nuclear ribonucleoprotein H2 (HNRNPH2) variant, c.638C>T (p.Pro213Leu), in patients with ID. The Hnrnph2^P213L knock-in mice display spatial learning deficits, representing a partial phenotypic overlap with HNRNPH2-related neurodevelopmental disorder. Notably, Hnrnph2^P213L mice exhibit significant myelination defects, primarily due to the impaired differentiation of oligodendrocyte progenitor cells. Furthermore, the myelin-enhancing drug benztropine rescues myelination, restores myelin-related gene expression, and ameliorates cognitive deficits, highlighting the role of hnRNPH2 P213L-induced myelin abnormalities in the pathogenesis of ID. Mechanistically, the P213L mutation disrupts the interaction between hnRNPH2 and its target transcripts, leading to the downregulation of myelination-related genes. Collectively, these findings reveal a critical mechanistic connection between myelin dysfunction and ID, thereby offering potential therapeutic insights for X-linked neurodevelopmental disorders.