Leveraging the genetic basis of Rett syndrome to ascertain pathophysiology

•Leveraging genetic findings to model Rett syndrome using genetically modified mice.•Summary of current mouse models of MeCP2 for Rett Syndrome research.•Pathophysiological insights gained from mouse modeling studies of Rett syndrome.•Establishing preclinical mouse models for translational research on Rett Syndrome. Mutations in the methyl-CpG binding protein 2 (MECP2) gene cause Rett syndrome (RTT), a progressive X-linked neurological disorder characterized by loss of developmental milestones, intellectual disability and breathing abnormality. Despite being a monogenic disorder, the pathogenic mechanisms by which mutations in MeCP2 impair neuronal function and underlie the RTT symptoms have been challenging to elucidate. The seemingly simple genetic root and the availability of genetic data from RTT patients have led to the generation and characterization of a series of mouse models recapitulating RTT-associated genetic mutations. This review focuses on the studies of RTT mouse models and describe newly obtained pathogenic insights from these studies. We also highlight the potential of studying pathophysiology using genetics-based modeling approaches in rodents and suggest a future direction to tackle the pathophysiology of intellectual disability with known or complex genetic causes.