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

Mutations in heterogeneous nuclear ribonucleoprotein H2 (HNRNPH2) lead to an X-linked neurodevelopmental disorders (NDDs) characterized by abnormal brain development and cognitive impairments. However, the underlying cellular and molecular mechanisms remain poorly understood. Here, we report that mice carrying the homologous P213L point mutation exhibit cognitive deficits and behavioral abnormalities resembling intellectual disability (ID). Notably, Hnrnph2P213L mice exhibit significant myelination defects, primarily due to impaired differentiation of oligodendrocyte progenitor cells. Mechanistically, the P213L mutation downregulates myelination-related genes by disrupting the interaction between hnRNPH2 and its target transcripts. Moreover, 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. This study uncovers a crucial mechanistic link between myelin dysfunction and ID, providing potentially therapeutic ways for X-linked NDDs.