MECP2 encodes methyl-CpG binding protein 2, a chrX protein that binds specifically to methylated DNA and mediates transcriptional regulation. The protein binds to single methyl-CpG pairs and both 5-methylcytosine and 5-hydroxymethylcytosine-containing DNA, with preference for 5-methylcytosine. Recent evidence suggests MECP2 functions as a positive cofactor for RNA polymerase II gene expression at many neuronal genes with CpG islands in promoter-proximal regions, directly interacting with RNA polymerase II 1. The protein occupies CpG-rich promoter-proximal regions in over four thousand genes in human neurons, including numerous autism risk genes 1. MECP2 dysfunction causes severe neurodevelopmental disorders through a dose-dependent mechanism - loss-of-function mutations cause Rett syndrome, while gene duplications cause MECP2 duplication syndrome 2. Rett syndrome affects approximately 1 in 10,000 females and is characterized by developmental regression, loss of purposeful hand movements, intellectual disability, and breathing disorders 3. The disorder extends beyond neurological symptoms to include metabolic dysfunction, dysautonomia, and multi-system involvement affecting cardiovascular, respiratory, and gastrointestinal systems 4. Gene therapy approaches for Rett syndrome have advanced to clinical trials, with investigational therapies administered to patients in 2023 5.