In the nervous system, even small genetic blunders can have huge biological consequences. Mistakes in key genes can cripple our ability to move, speak, and interact with the world. Using some of the most advanced techniques in genetics and cell biology, Huda Zoghbi and her collaborators have unraveled the genetic underpinnings of a number of devastating neurological disorders, including Rett syndrome and spinocerebellar ataxia type 1 (SCA1). Their discoveries have provided new ways of thinking about more common neurological disorders, including autism, intellectual disability, and Parkinson's disease, and could lead to better treatments for such diseases.
In 1975, Zoghbi enrolled in medical school at American University in Beirut. Then, war erupted in Lebanon. "Bombs were falling everywhere," she says. "It soon became dangerous to leave the campus." When her first year was completed, Zoghbi went home, fully intending to return to school in the fall. But when she got there, she learned that her younger brother had been hit by shrapnel. He wasn't badly injured, but Zoghbi's parents decided to send her and her brothers to stay with relatives in the United States. She transferred to Meharry Medical College in Nashville, Tennessee—the only medical school that would accept transfers mid-stream—where she finished her medical training. (Zoghbi's future husband, William Zoghbi, M.D., also transferred to Meharry a year later.)
Initially interested in cardiology, Zoghbi soon found herself drawn to disorders that affect the brain. "Neurology grabbed me because of how logical it is," she says. "You observe the patient, analyze her symptoms, and work backward to figure out exactly which part of the brain is responsible for the problem. It's like a puzzle." In her second year of residency, Zoghbi encountered a very puzzling patient indeed. The girl had been a perfectly healthy child, playing and singing and otherwise acting like a typical toddler. Around the age of two, she stopped making eye contact, shied away from social interactions, ceased to communicate, and started obsessively wringing her hands. "She made a huge impression on me," says Zoghbi, who set out to determine what could have caused this sudden neurological deterioration.
Sixteen years after she saw that first patient, Zoghbi's lab identified MECP2, the gene responsible for Rett syndrome. Children afflicted with this rare neurodevelopmental disorder develop normally for about 6 to 18 months and then start to regress: They lose their acquired language and motor skills and invariably develop stereotypic movements such as hand-wringing or hand-flapping. MECP2, it turns out, encodes a protein whose activity is critical for the normal functioning of mature neurons in the brain; it is produced when nerve cells are forming connections as a child interacts with the world. The disease occurs primarily in girls, because boys who inherit an inactive form of MECP2—which lies on the X chromosome—usually die shortly after birth. Girls survive because, with two X chromosomes, they stand a good chance of inheriting a healthy copy of the gene. (Indeed, if X inactivation is skewed in a particularly favorable way, there may be virtually no sign of disease.)
Zoghbi and her colleagues have also identified the mutation responsible for SCA1, one of several polyglutamine neurodegenerative disorders that slowly rob its victims of balance and motor control. The culprit is a sort of genetic stutter that increases the size of the SCA1 gene. The normal gene harbors a stretch of nucleotides in which the sequence CAG is repeated about 30 times. In individuals with the disease, the tract expands to include 40 to 80 triplet repeats. As a result, the product of the mutant gene—a protein called Ataxin-1—grows large and misshapen, unable to interact normally with its usual protein partners. As it happens, the polyglutamine diseases are part of a larger class of neurodegenerative diseases known as proteinopathies, a class that includes Parkinson's disease and Alzheimer's disease. Zoghbi's work on the pathogenic mechanisms of polyglutamine proteinopathies has proven to be relevant to this larger class of disorders. The Zoghbi lab is currently searching for compounds that enhance the clearance of mutant proteins in several of these diseases. The hope is that such drugs could slow the progression of the disease or prevent it altogether.
Dr. Zoghbi is also Professor in the Departments of Pediatrics, Molecular and Human Genetics, Neuroscience, and Neurology at Baylor College of Medicine.
RESEARCH ABSTRACT SUMMARY:
Huda Zoghbi's research interests grew out of her early clinical encounters with patients suffering rare and enigmatic disorders, yet her investigations into the pathogenesis of triplet repeat neurodegenerative diseases and Rett syndrome have had broad implications, not only for other more common diseases but also for our understanding of neurobiology. Conversely, the Zoghbi lab's initial foray into fundamental neurodevelopmental processes governed by Math1 has led to unexpected clinical insights.
View Research Abstract
Photo: Bob Levey/AP, ©HHMI