Rett Syndrome (RTT) is a severe, rare, and progressive developmental disorder with patients displaying neurological regression and autism spectrum features. The affected individuals are primarily young females, and more than 95% of patients carry de novo mutation(s) in the Methyl-CpG-Binding Protein 2 (MECP2) gene. While the majority of RTT patients have MECP2 mutations (classical RTT), a small fraction of the patients (atypical RTT) may carry genetic mutations in other genes such as the cyclin-dependent kinase-like 5 (CDKL5) and FOXG1. Due to the neurological basis of RTT symptoms, MeCP2 function was originally studied in nerve cells (neurons). However, later research highlighted its importance in other cell types of the brain including glia. In this regard, scientists benefitted from modeling the disease using many different cellular systems and transgenic mice with loss- or gain-of-function mutations. Additionally, limited research in human postmortem brain tissues provided invaluable findings in RTT pathobiology and disease mechanism. MeCP2 expression in the brain is tightly regulated, and its altered expression leads to abnormal brain function, implicating MeCP2 in some cases of autism spectrum disorders. In certain disease conditions, MeCP2 homeostasis control is impaired, the regulation of which in rodents involves a regulatory microRNA (miR132) and brain-derived neurotrophic factor (BDNF). Here, we will provide an overview of recent advances in understanding the underlying mechanism of disease in RTT and the associated genetic mutations in the MECP2 gene along with the pathobiology of the disease, the role of the two most studied protein variants (MeCP2E1 and MeCP2E2 isoforms), and the regulatory mechanisms that control MeCP2 homeostasis network in the brain, including BDNF and miR132.
Mutational Analysis of Methyl-CpG Binding Protein 2 (MECP2) Gene in Indian Cases of Rett Syndrome