Zoghbi and Orr decided to collaborate even more intensely, recognizing they were working on the same gene. They split the region in half, and each started working from the outside in, searching for triplet repeats while moving toward the middle.
“Finally, on April 8, 1993, we both discovered the disease-causing gene [ATAXIN1] on the same day, right in the middle of the candidate region. Harry was sending me a fax of the expansion he detected in his family, while I was sending him ours. We had the pleasure of sharing the discovery and our data at an international ataxia meeting in Capri, Italy, that summer.
“After the gene discovery, we had to plan the next steps: do we continue to collaborate, or do we go our different ways? We chose to continue our collaboration,” Zoghbi said.
“Studying ataxias led me to one of the highlights of my scientific career, the collaboration with Harry Orr, and ensured that I could be productive while I was still struggling to understand Rett,” Zoghbi said.
Patient care leads to Rett discovery
Prior to her work and findings regarding ATAXIN1, Zoghbi’s first experiences with Rett syndrome began when she joined Baylor and Texas Children’s in 1983 to begin her residency in child neurology. She encountered two patients with symptoms and soon identified other children who had similar symptoms. She then began research to uncover what causes this disorder.
“From the moment Dr. Zoghbi arrived at Texas Children’s Hospital, we knew immediately that she was essential to unlocking the mystery of these devastating diseases,” said Mark A. Wallace, president and CEO of Texas Children’s Hospital. “Dr. Zoghbi continues to amaze us with her commitment to not only understanding what causes neurological diseases but also her dedication to lead the discovery and development of new treatments that will undeniably transform the landscape of neurological research and, ultimately, change lives for generations to come.”
In 1999, she and her research team were able to identify mutations in methyl-CpG-binding protein 2 gene, known as MECP2, as the root cause for Rett syndrome. The discovery of the Rett syndrome gene provided a straightforward diagnostic genetic test, allowing early and accurate diagnosis of the syndrome.
Her work also revealed how sensitive the brain is to varying levels of the protein MeCP2. The gene MECP2 is responsible for production of this protein. Too little MeCP2 causes Rett syndrome; however, doubling MECP2 levels causes extra MeCP2 production, which leads to an increase in protein function, causing neurological deficits. MECP2 duplication syndrome in humans causes a progressive neurological disorder.
Mutations in MECP2 also can cause a host of other neurological phenotypes ranging from autism to juvenile onset schizophrenia. Her findings provided evidence that an autism spectrum disorder or an intellectual disability disorder can be genetic even if it is not inherited.
Zoghbi and her team’s discoveries opened a new area of research on the role of epigenetics in neuropsychiatric phenotypes. Epigenetics is the study of changes in organisms caused by modification of gene expression rather than the genetic code. Zoghbi’s use of an antisense oligonucleotide to lower MECP2 levels provided a potential therapeutic strategy for the MECP2 duplication syndrome and is inspiring similar studies for other disorders caused by altered gene dosage.