Women in science: Huda Zoghbi discovered the genetic basis of Rett syndrome
Dr. Huda Zoghbi was born Huda El Hibri in 1955 in Beirut, Lebanon. Her father owned a business manufacturing olive oil and soap, and her mother stayed at home to raise Huda and her four siblings. Although neither of her parents went to college, they were both incredibly passionate about learning, and instilled a lifelong love of reading and literature in their children.
During high school Zoghbi fell in love with the classical works of Shakespeare, Austen, and Wordsworth, and initially planned to study English literature in college. Her mother, however, made a very convincing argument for Zoghbi to study medicine. From a 2006 interview with PNAS,
“She, in her wisdom, thought I could always write on the side. But she felt that, especially as a woman growing up in the Middle East, I should pick a career that would ensure independence and security. So I did.”
Zoghbi was accepted at the American University of Beirut (AUB), one of the best universities in the Middle East. After two years of undergraduate coursework in biology, she applied to medical school at AUB, and began her medical training in the fall of 1975.
Halfway through her first year of medical school, civil war erupted in the region. Beirut was no longer the safe and stable community it had been during her childhood. The unpredictable and indiscriminate bombing throughout the city made the short walk from her home to the AUB hospital increasingly dangerous. The hospital itself was bombed less frequently, however, because it treated people on both sides of the conflict. As a result, the faculty decided that in order carry out the remaining part of the school year, the students would have to live on campus, in the hospital, since the on-campus dorms were already filled. Zoghbi recalled living in the basement of the hospital with her classmates for the Texas Medical Center Women’s History Project
“Imagine for six months, you have nowhere to go. You are studying during the day, and you absolutely have nowhere to go at night. So, that’s why the class bonded, and our only entertainment was talking, singing songs, and making desserts, and studying.”
When the school year was over in June, Zoghbi returned to her family home for a short time. But after the house was damaged and her brother injured in bombings, her parents no longer felt that Beirut was safe. They decided to send all three children to stay the summer with their sister, who was living in Austin, Texas. Zoghbi and her younger brothers arrived just in time for the bicentennial celebration on July 4, 1976.
As the summer turned to fall, it became clear that going back to Beirut wasn’t an option. Zoghbi originally planned to return to medical school in October, but at that time, it was impossible to travel back into the country. In order to complete medical school, she would have to find a university in the United States that would accept her as a transfer student.
Family friends living in Nashville reached out to help Zoghbi find a school. Vanderbilt was unable to accept her, but suggested another school where she was ultimately accepted: Meharry Medical College. She later learned that Meharry is a historically black institution, making her a minority within a minority medical school. Starting two months into the school year, in a completely new environment isolated from any family or friends, seems impossible, but she persevered.
“You reflect on it, and you think that, since you survived it, you can handle any other challenges.”
Zoghbi excelled as a medical student, and performed away rotations during her fourth year of medical school at Baylor, Stanford, and Emory. Zoghbi graduated in 1979 at the top 5% of her class, and moved back to Texas for her residency in pediatrics at Baylor College of Medicine. Even with her clinical experiences, impressive grades, and membership in Alpha Omega Alpha (AOA), it wasn’t easy finding a program that would accept her.
“Almost everybody would not want to have anything to do with us because they feel you went to a minority medical school, and you are not a minority... Even if you try to explain, it didn’t really matter.” Luckily, Baylor was able to spot the potential and innate talent in Zoghbi, and took her on for training in pediatrics.
During her residency she became captivated with the brain, and stayed on at Baylor and Texas Children’s Hospital for a three-year fellowship in pediatric neurology. During the first year of her fellowship, Zoghbi read a study on the rare neurological disorder known as Rett syndrome. Although Viennese pediatrician Andreas Rett originally defined the syndrome in a 1966 issue of the German medical journal Wiener Medizinische Wochenschrift, the language barrier prevented his work from being widely distributed and recognized. In 1983, Dr. Bengt Hagber’s case study of 35 Rett Syndrome patients brought a renewed focus to this disease, highlighting the distinct characteristics of Rett syndrome compared to other neurodevelopmental disorders.
Rett syndrome primarily affects young girls, with an onset between 6 months to two years of age. These girls achieve normal early developmental milestones, such as walking and learning to speak. But at some point parents notice their child inexplicably losing the ability to communicate and interact socially, and observe severe deficits in balance and motor skills. Patients continue to deteriorate, displaying dementia, growth abnormalities, breathing difficulties, and autistic-like features. Eventually these children stabilize, but they will require continuous medical treatment to control symptoms and prevent co-morbidities, such as epilepsy and scoliosis.
Based on Hagber’s depiction, Zoghbi was able to diagnose two girls with the rare disease within one two-week period in 1983. This was incredible, given that there were no reported clinical cases of Rett syndrome in the United States at this time. Zoghbi then worked with hospital staff to identify 30 other potential cases, and after thorough medical evaluation, determined that five of these girls were also suffering from Rett syndrome. It was (and still is) a devastating diagnosis for parents, and Zoghbi had to confront the fact that as their doctor, there was very little she could do for them.
In order to treat the disease, it was essential understand the causes and risk factors. After Zoghbi’s initial clinical study was published in 1985, Texas Children’s hospital was inundated with families looking for answers. As a result, Zoghbi acquired significant clinical expertise in neurodevelopmental disease, and ultimately came to the hypothesis that Rett syndrome was a genetic disorder. First, all the patients were girls, but none of the parents were affected, indicating the involvement of a dominant X-chromosome-linked mutation. Second, Rett syndrome was a developmental disorder, and the symptoms were very consistent, indicating discrete defects in one common pathway or regulatory process.
Zoghbi wanted to move out of the clinic and into genetics research, but she had no formal training in molecular biology. She eventually found a mentor in Dr. Arthur Beaudet, but there was one small hitch.
He didn’t want her to work on Rett syndrome. It was too complex, and since it didn’t have an obvious inheritance pattern, it would be difficult to localize with 1980s-era genome mapping technology. Zoghbi decided to study the genetic basis of spinocerebellar ataxia type 1 (SCA1), which has a strong dominant inheritance pattern in family trees.
SCA1 is a neurodegenerative disease affecting the cerebellum, brain stem, and spinal cord, with onset in early adulthood. Gradually, patients lose control of motor coordination and balance, which includes muscles involved in breathing and swallowing. Like Rett syndrome, there is no cure or prophylactic treatment for SCA1.
Zoghbi trained in Beaudet’s lab in the Department of Genetics at Baylor College of Medicine from 1985 to 1988, and then set up her own lab in the same department. She continued to work on the genetic basis of SCA1, collaborating with Dr. Harry Orr at the University of Minnesota. Between the two labs, they had enough samples to analyze genetic markers among multiple SCA1 families and isolate the genetic loci responsible for the disease.
On the exact same day in 1993, both Zoghbi and Orr independently discovered the mutation responsible for SCA1. But this wasn’t a simple genetic deletion or point mutation. Zoghbi and Orr found that the affected gene, ATXN1, has a repetitive CAG trinucleotide sequence, also known as a polyglutamine tract. They discovered that this region is prone to errors during DNA replication, resulting in expansion of the polyglutamine tract. Healthy patients have ~30 CAG repeats in ATXN1, while SCA1 patients have 40 or more. In families affected with SCA1, the number of CAG repeats increases with each generation, correlating with increased severity and an earlier age of disease onset.
CAG trinucleotide expansion is a common theme in neurodegenerative disease, with similar mechanisms underlying Huntington’s disease and Fragile X syndrome. Zoghbi’s lab also found that this altered ATXN1 gene sequence encodes a bulky, improperly folded protein that is toxic to brain cells. These studies are relevant to multiple neurodegenerative diseases, including Alzheimer’s disease, which also involves misfolded proteins and neurotoxicity.
But throughout all of this pioneering research, Zoghbi never forgot her original objective. Her lab continued to search for the genetic basis of Rett Syndrome, driven by her experiences with families now coming from all over the world to the Blue Bird Circle Rett Center based out of Texas Children’s Hospital.
Between 1991 and 1992, Zoghbi and other Rett syndrome research labs isolated the mutation to a specific region of the X-chromosome. Zoghbi’s lab meticulously analyzed each gene in this region, systematically eliminating genes based on sequence differences between healthy controls and Rett syndrome patients. In 2000, Zoghbi and colleagues reported that the underlying cause of Rett syndrome is mutations in the methyl-CpG-binding protein MECP2.
These results confirmed that Rett syndrome is an X-linked dominant disorder, meaning that only one bad copy of MECP2 is needed for the disease to be fully penetrant. Alternatively, complete loss of MECP2 is lethal to embryonic development, explaining why Rett patients are typically female. Future studies demonstrate that >99% of Rett-causing MECP2 mutations occur sporadically during development, in agreement with the fact that most parents of Rett patients are phenotypically normal.
MECP2 is a fascinating gene. It is essential for neuronal function in developing, postnatal and adult mice, and has roles in autism, movement disorders, and multiple forms of mental retardation. Zoghbi’s lab has published several studies analyzing the effects of MECP2 dosage on mouse phenotypes, and they have found that overexpression of MECP2 leads to autistic-like behaviors. In concordance with these results, MECP2 gene duplications have been reported in both men and women that suffer from autism-spectrum disorders. Zoghbi has also investigated the cell type-specific requirements for MECP2, and recently discovered that restoring MECP2 levels in certain neuronal subsets can rescue Rett phenotypes in mouse models.
Dr. Huda Zoghbi’s story and her research are remarkable. She came to the United States from a completely different part of the world, and by circumstance, had to navigate an entirely new life here. In the process, she became one of the world’s foremost experts on the genetic basis of neurological disease. Zoghbi’s steadfast dedication to completing medical school, and her relentless curiosity about the brain and Rett syndrome, have driven her to discoveries that define modern neuroscience.
Ellen Elliott, Ph.D., is a postdoctoral fellow at The Jackson Laboratory for Genomic Medicine in Farmington, Conn. Ellen works in the laboratory of Adam Williams, Ph.D., where she is studying the function of long non-coding RNAs in TH2 cells and asthma. Follow Ellen on Twitter at @EllenNichole.