Neurodevelopmental disorders (NDDs) affect normal brain development and function, with 15% caused by single-gene mutations. Approximately 90% of NDDs lack effective treatments, making it essential to understand their pathogenic mechanisms for developing targeted therapies. Professor Gu Shen Linda’s team previously identified an autosomal recessive NDD linked to mutations in the MED27 gene. To further investigate the disease-causing mechanism, they generated human stem cell models and transgenic mouse models with patient-specific MED27 mutations, successfully recapitulating core phenotypes such as progressive cerebellar atrophy and motor defects. Molecular studies revealed that MED27 mutations disrupt the stability of the mediator complex, weaken its chromatin-binding ability, alter chromatin structure, and downregulate its direct downstream targets — key transcription factors EGR1 and FOS during early neurogenesis, as well as Lhx1 in cerebellar development. These findings establish valuable preclinical models and provide insights into the roles of other Mediator subunits in neurodevelopment, laying the groundwork for future gene therapies development.

The research has been published in Advanced Science in Sep 2025 and selected as the inside cover story for the issue.

Link:https://doi.org/10.1002/advs.202505535