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.

Biography

Huda Zoghbi, M.D., is Distinguished Service Professor at Baylor College of Medicine, an Investigator with the Howard Hughes Medical Institute, and founding Director of the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital.

Dr. Zoghbi graduated from the American University of Beirut (AUB). She attended AUB’s medical school for one year, but due to the civil war, she moved to the U.S. and received her medical degree from Meharry Medical College. She joined Baylor College of Medicine for her residency and subsequently obtained additional training in molecular genetics.

Dr. Zoghbi’s expertise ranges from neurodevelopment to neurodegeneration. She and Dr. Harry Orr discovered that Spinocerebellar Ataxia type 1 is caused by expansion of a polyglutamine tract. Her subsequent studies demonstrating that such expansion leads to accumulation of the mutant protein in neurons has had profound ramifications since many late-onset neurological disorders involve similar accumulations of disease-driving proteins and inspired her studies in Alzheimer disease. Her work in neurodevelopment led to the discovery of the gene Math1/Atoh1 and showed that it governs the development of several components of the proprioceptive, balance, hearing, vestibular, and breathing pathways. She also discovered that mutations in MECP2 cause the postnatal neurological disorder Rett syndrome and revealed the importance of this gene for various neuropsychiatric features.

Dr. Zoghbi has trained over 100 scientists and physician-scientists and is committed to educating the next generation. She has been elected to the National Academy of Medicine, the National Academy of Sciences, and the American Academy of Arts and Sciences. Dr. Zoghbi’s honors include the Pearl Meister Greengard Prize from Rockefeller University; the Shaw Prize in Life Science and Medicine; the Breakthrough Prize in Life Sciences; the Canada Gairdner International Prize; the Lundbeck Foundation’s 2020 Brain Prize; and the Kavli Prize from the Kavli Foundation. She has honorary degrees from Harvard University, the University of Massachusetts, Yale University and KU Leuven.

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