Decoding Rett Syndrome

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A newborn girl arrives, a blessing and a joy to her family. As she grows, she smiles, she laughs, sits up, rolls over. She may even crawl, walk or speak. But, sometime between 12 and 18 months of age, she loses those abilities, succumbing to involuntary hand movements, a wide stepping gate, and often seizures. The child suffers from Rett syndrome, a neurological disorder occurring almost exclusively in girls. While some neurological disorders of early childhood are degenerative and lead to death, Rett syndrome is not; patients can live into adulthood.

Huda Zoghbi, a genetics professor at Baylor College of Medicine, and Adrian Bird, a genetics professor from the University of Edinburgh, have spent years researching this rare and devastating neurological disorder. In 1992, Bird uncovered a protein called MeCP2, which is encoded by the MECP2 gene. MeCP2 protein binds to DNA molecules containing a methyl group — a carbon atom chemically bound to three hydrogen molecules. Adding methyl groups to DNA serves as a signal for cellular machinery to turn down expression of certain genes, like a dimmer switch. Seven years later, Zoghbi discovered that mutations in the MECP2 gene cause Rett Syndrome.

This year, Zoghbi and Bird were awarded The Brain Prize by the Lundbeck Foundation for their groundbreaking work. Together, their research has deepened scientists’ understanding of this disorder, bringing them one step closer to developing a treatment.

Huda, what fascinates you about Rett syndrome?

Huda Zoghbi: I was really intrigued by one thing about this syndrome — the girls are healthy and look healthy when they’re born and achieve certain milestones, and then they lose those acquired skills. And we know that it’s not degenerative because they can live into adulthood. I found it both intriguing and heart-wrenching to imagine having a healthy girl and then watch her lose those abilities. So, that’s what inspired me to go into research.

Adrian, why did you start looking into the MeCP2 protein?

Adrian Bird: We were interested in it for blue-sky reasons: How does DNA methylation work? How is it read to regulate gene expression? We set out to identify proteins that bind to methylated DNA and didn’t bind to unmethylated DNA. And MeCP2 was the second one we detected, but the first one we managed to purify, or isolate from a mixture of cells.

Huda, the search for the Rett gene took years — how did you finally identify MECP2?

HZ: Knowing that Rett syndrome is only in girls helped us narrow the gene location from the whole genome down to the X chromosome. So, I was marching down the X chromosome, literally to try to find genes and particularly areas shared by a couple of half-sisters with Rett syndrome. I had one patient with Rett syndrome that was thrown in among a control group for my postdoc, who was studying DNA methylation. Using that DNA sample, she serendipitously identified an atypical DNA methylation pattern. So, we went back and searched for genes on the X chromosome that have anything to do with DNA methylation and focused on this one protein, MeCP2. To our surprise, we found MECP2 mutations in the first handful of Rett syndrome DNA samples we analyzed. It was pure serendipity to prioritize MECP2 as a candidate after many, many years.

How do the mutations impact brain function?

HZ: Once we found the gene then we were interested in the next question: how does it cause the brain dysfunction? That’s really complicated. It’s important for almost every cell in the brain. While we don’t understand the precise molecular changes that drive the neurological dysfunction, we have learned that when distinct types of neurons lose MECP2 they function at a reduced capacity. We’ve shown if you take it out from certain populations of neurons, you reproduce most of the features of Rett syndrome.

Adrian, how did this discovery influence your research?

AB: We were already making a mouse model without the MECP2 gene for those blue-sky questions and now we had a separate reason — creating a potential model for the human disorder, Rett syndrome. Sometimes with developmental disorders, the models are not terribly close to what we see in humans. But in this case, the result was remarkably similar to the human condition. Whatever MECP2 does in humans, it does more or less the same thing in mice. When mice don’t have the MECP2 gene, they develop symptoms typical of Rett syndrome like impaired movement and coordination as well as irregular breathing.

Our most impressive finding was that if you restore this protein, you can reverse many symptoms of the disease. In our experiment, the animals acquired those symptoms because they grew without the MeCP2 protein, and then we put the protein back. In both the males and the females, this led to a remarkable reversal of the disease symptoms. The effect is dramatic: breathing arrhythmia goes away; mobility and hind limb clasping are lost, as is tremor. In fact, every defect that has been looked at so far is reversed.

What does your work mean for Rett syndrome treatments?

HZ: There are so many studies that laid the foundation for hopefully coming up with interventions that will make a difference for people with Rett syndrome: from identifying the gene to having very wonderful animal models to Adrian’s work showing that normalizing the activity of this protein can reverse the syndrome. Current treatments are supportive, targeting specific symptoms. For example, antiepileptics help control seizures. We hope more definitive therapies that restore the function of MECP2 will become available in the near future.

About the Author

Helen Santoro

Helen Santoro is a science journalist based in Gunnison, Colorado who covers neuroscience, health, wildlife and LGBTQ+ communities. She graduated from Hamilton College in 2015 with a degree in neuroscience.