The distinct methylation landscape of maturing neurons and its role in Rett syndrome pathogenesis

•Rett syndrome (RTT) is caused by mutations in the gene encoding methyl-CpG binding protein 2 (MECP2).•Diverse pathogenic mutations reveal modes for MeCP2 dysfunction in children with RTT and inform molecular mechanism.•MeCP2 binds to methyl marks that are set during neuronal maturation.•MeCP2 has different affinities for methyl marks depending on sequence context and oxidative status.•Loss of function for MeCP2 at methyl marks during neuronal maturation may underlie delayed, brain-specific symptoms in RTT patients. Rett syndrome (RTT) is one of the most common causes of intellectual and developmental disabilities in girls, and is caused by mutations in the gene encoding methyl-CpG binding protein 2 (MECP2). Here we will review our current understanding of RTT, the landscape of pathogenic mutations and function of MeCP2, and culminate with recent advances elucidating the distinct DNA methylation landscape in the brain that may explain why disease symptoms are delayed and selective to the nervous system.