NEUROIMMUNE, EPIGENETIC, AND METABOLIC INTERACTIONS DURING SYMPTOM PROGRESSION IN A MOUSE MODEL OF RETT SYNDROME

Mutations in the X-linked gene MECP2 cause Rett syndrome (RTT), a neurodevelopmental disorder in females. Because of the complex MeCP2 mutant/wild-type mosaicism observed in MeCP2 mutant female mice, the majority of RTT preclinical studies are performed only on MeCP2 null male mice lacking MeCP2 in all cells. But RTT patients are heterozygous females that exhibit delayed and progressive symptom onset beginning in late infancy, including neurologic as well as metabolic, immune, respiratory, and gastrointestinal phenotypes. Two differentially spliced isoforms of exons 1 and 2 (MeCP2-e1 and MeCP2-e2) contribute to the diverse functions of MeCP2, but only mutations in exon 1 are observed in RTT. We developed an MeCP2-e1–deficient mouse model based on a human RTT mutation that lacks MeCP2-e1, while preserving expression of MeCP2-e2.