PINS: Rett syndrome from the clinic to genomes, epigenomes and neural circuits

Huda Y. Zoghbi, MD, Investigator, Howard Hughes Medical Institute Professor, Baylor College of Medicine and Director, Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital Abstract: Rett syndrome is a delayed-onset childhood disorder, typically found in girls, that causes a broad range of severe neurological disabilities, including loss of the ability to speak and socialize, and the development of tremors, ataxia, seizures, autonomic dysfunction, and stereotypic hand-wringing movements. We discovered that mutations in the gene MECP2 cause Rett syndrome, and before long it became clear that mutations in MECP2 can also cause other neuropsychiatric phenotypes ranging from autism to bipolar disorders. Using genetically-engineered mice, we learned that the brain is acutely sensitive to MeCP2 levels; both decreases and increases in the amount of MeCP2 protein can lead to neurological problems that are also observed in humans. We learned that normalizing MeCP2 levels can reverse disease-like features in a mouse model of the human MECP2 duplication syndrome, a disorder that is usually found in boys and results from excess MeCP2. In addition, we have been gradually pinpointing the neurons and circuit abnormalities that mediate various symptoms. Building on this understanding of the relationship between neural circuits and the features of Rett syndrome, we are exploring deep brain stimulation to improve some Rett phenotypes.