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. Their discoveries could lead to better methods for treating such diseases and provide new ways of thinking about more common neurological disorders, including autism, mental retardation, and Parkinson’s disease.
In 1975, Zoghbi enrolled in medical school at American University in western 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 was accepted at Meharry Medical College in Nashville, Tennessee, where she finished her medical training.
Zoghbi soon found herself drawn to disorders that affect the activity of 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 and her collaborators 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, losing the ability to speak, walk, and use their hands to hold, lift, or even point at things. 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 females, 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.
Zoghbi and her colleagues have also identified the mutation responsible for spinocerebellar ataxia type 1 (SCA1), a neuro-degenerative disorder that renders its victims unable to walk or talk clearly, or eventually to even swallow or breathe. 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 100 iterations. As a result, the product of the mutant gene—a protein called ataxin-1—grows large and sticky, forming clumps throughout the cell. These ataxin-1 aggregates overwhelm the molecular machinery that cells use to recycle damaged proteins and eventually disable the neurons involved in controlling movement. Using mice and flies that produce the mutant protein, Zoghbi is searching for compounds that enhance the clearance of ataxin-1 tangles. Such drugs could slow the progression of the disease or prevent it altogether.