Huda Y. Zoghbi, MD

Professor, Departments of Pediatrics, of Molecular and Human Genetics, of Neurology, and of Neuroscience, Baylor College of Medicine

Director, Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital

Investigator, Howard Hughes Medical Institute

Huda Y. Zoghbi was born and grew up in Beirut, Lebanon. She earned her bachelor’s degree in science and entered medical school at the American University of Beirut in 1975, but was displaced by the civil war in Lebanon and sent, along with her brothers, by her family to join relatives in Texas. Zoghbi earned her MD at Meharry Medical College in Nashville, Tenn., in 1979. She completed two residencies at Baylor College of Medicine, the first in pediatrics in 1982, and the second in neurology and pediatric neurology in 1985.

Although Zoghbi initially trained to be a clinical pediatric neurologist, she found herself drawn to research. After encountering patients with devastating neurological conditions—many of them genetic—she sought to uncover the causes. In 1988, after completing a postdoctoral fellowship with Arthur L. Beaudet, MD, at Baylor’s Institute of Molecular Genetics (now the Department of Molecular and Human Genetics), Zoghbi joined the faculty as an assistant professor of pediatrics.

In 1985, she began work on the spinocerebellar ataxias when she met a family with a history of ataxia, dysarthria, and cerebellar atrophy in rural Montgomery, Texas, 50 miles north of Houston. In 1993, in collaboration with Harry Orr, PhD, Zoghbi discovered that expansion of a CAG trinucleotide repeat causes spinocerebellar ataxia type 1 (SCA1), a deadly neurodegenerative disorder characterized by a progressive worsening of balance and coordination. Experiments on SCA1 mouse models revealed the roles of protein misfolding and altered interactions with protein partners that lead to both loss and gain of function of the SCA1 protein ataxin-1 (ATXN1). With that project, Zoghbi’s lab combined experimental and bioinformatics approaches to create a protein interaction network that revealed key hub proteins involved in several other ataxias and degenerative diseases.

In 1999, Zoghbi identified the mutation in the gene encoding methyl CpG binding protein 2 (MeCP2) that causes Rett syndrome, an autism spectrum disorder that appears after a period of apparently normal development, robbing girls of acquired language and motor skills and causing gastrointestinal problems and anxiety. Before that discovery, it was not even clear that Rett syndrome was genetic, and many physicians doubted that Rett syndrome was a unique brain disorder. Her lab’s recent development of an adult onset mouse model of Rett syndrome showed the continued dependence of the mature brain on MeCP2 function and suggested that therapies for Rett syndrome will need to be constantly maintained throughout life.

Another major finding from Zoghbi’s lab was the identification of Math1, a gene that plays a critical role in the formation of a wide range of cell types, including inner ear hair cells and intestinal secretory cells. She demonstrated that Math1 is essential for the genesis of specialized neurons in the cerebellum that are part of the sensory pathway for conscious and unconscious proprioception (the sense of one’s position in space). Math1 is also a factor in the development of medulloblastoma, a common brain tumor that primarily affects children and young adults.

Most recently, Zoghbi has focused on autism. Her 2003 description of autism as a disease of the synapse in an editorial in Science has been supported by numerous discoveries in the last decade. Zoghbi’s lab compiled a network of protein-protein interactions based on autism-associated genes, with the aim of finding common molecular pathways that underpin both classic and syndromic autism. This is potentially the framework around which a larger autism interactome could be used to development treatment.

Zoghbi’s current research projects include the use of genotype-phenotype correlations to identify key functional domains of MeCP2. Her lab discovered that MeCP2 is evolutionarily related to the protein HGMA1 and that an AT-hook domain in its C-terminus is a key determinant of Rett syndrome severity. Along with her collaborators, she embarked on parallel forward genetic screens in human cells and in the Drosophila SCA1 model to identify genes whose inhibition reduces modulators of ATXN1 levels and toxicity. The success of this strategy prompted its use to screen for modulators of APP, tau, and α-synuclein proteins, where the protein levels are crucial in the development of Alzheimer’s and Parkinson’s diseases. Zoghbi’s lab has delineated the role of Math1 in the retrotrapezoid nucleus neurons and the importance of these cells for neonatal respiration and CO2 chemosensitivity. Ongoing studies will focus on identifying other components of the respiratory hindbrain neurons that are Math1/Atoh1 dependent and on elucidating the molecular functions of Math1 by identifying its interactors and targets in different cellular contexts.

Zoghbi’s career elegantly demonstrates the role that basic genetics and molecular neuroscience can play in understanding complex brain disorders. She is the recipient of numerous awards, including the E. Mead Johnson Award in Pediatric Research, the Bristol-Myers Squibb Award for Distinguished Achievement in Neuroscience Research, the Vilcek Prize in Biomedical Science, and the Gruber Neuroscience Prize. She is a member of the Institute of Medicine, the National Academy of Sciences, the Texas Women’s Hall of Fame, and a fellow of the American Association for the Advancement of Science.