Limited restoration of MECP2 gene expression may relieve symptoms in Rett syndrome

July 23, 2018, Massachusetts General Hospital
Human chromosomes during metaphase. Credit: Steffen Dietzel/Wikipedia

A Massachusetts General Hospital (MGH) research team has developed a new female mouse model for the neurodevelopmental disorder Rett syndrome and in the process found evidence that relieving symptoms of the genetic disorder may require only partial expression of the normal copy of the involved gene, MECP2. The strategy used in the study, reported in the journal PNAS, may be useful in developing models for other disorders caused by mutations on the X chromosome.

"Developing an improved, easier-to-work-with female model for Rett is important, since the male models that have been used cannot fully replicate a disease that primarily affects females," says lead author Lieselot Carrette, Ph.D., a research fellow in the laboratory of senior author Jeannie T. Lee, MD, Ph.D., MGH Department of Molecular Biology. "Besides many more subtle differences between males and females that we don't yet fully comprehend, males obviously do not have a second, inactive X chromosome that we can target for reactivation as a potential cure."

Rett syndrome is an X-linked disorder, caused by a mutation on the X chromosome. Females inherit two copies of the X chromosome, and in each cell one copy of the chromosome is activated—meaning the genes are available for transcription—and one is inactivated. Which copy is inactivated in a particular cell is totally random, so the effects of an X chromosome mutation depend on the cells in which a mutated chromosome is activated. Rett syndrome occurs rarely in males, as the MECP2 mutation typically emerges spontaneously in the reproductive cells of the father, whose X chromosome is passed on only to daughters. However, in those cases when a human male's single X chromosome does carry the mutation, the child is severely affected and rarely survives long.

The MECP2 protein is known to be essential for normal neuronal development, and females with the mutation appear to develop normally for the first year of life. Their physical and cognitive development then slows and regresses, leading to symptoms including loss of mobility, seizures, lack of speech and social withdrawal. Affected females also exhibit repetitive behaviors such as hand-wringing and self-biting that can lead to injury. Females with Rett syndrome eventually require round-the-clock care, and the disorder is second only to Down syndrome as the most common cause of severe intellectual disability in females.

Lee's team has been investigating methods of X chromosome reactivation to treat Rett syndrome and other X-linked disorders, and earlier this year they reported a first successful attempt at doing so by combining two methods—blocking both the expression of Xist, an RNA molecule that is key to silencing the inactive X chromosome, and the gene-silencing process of DNA methylation. While their approach produced some reactivation of the dormant X chromosome in cultured cells and a genetic animal model, the systems used in that study did not carry the Rett syndrome mutation.

Lee explains, "This previous work enabled us to achieve an unprecedented level of MECP2 upregulation from the inactive X chromosome. A major goal of our present study was to develop a female mouse model that would enable us to test this drug combination in a living animal."

The challenge with creating a useful female animal model of Rett syndrome stems from the random nature of X inactivation. Because the number of neuronal cells expressing the mutated MECP2 gene can vary widely, affected female mice often only develop some symptoms, which are usually mild and appear late in life. Such a model makes testing potential therapies more difficult, since whether or when symptoms develop could be the result of an animal's original MECP2 expression level and not the drug being tested. What would be needed is a female model in which the chromosome with the mutated gene was broadly and consistently activated.

To create such a model, the MGH team targeted another RNA molecule called Tsix, which regulates Xist expression early in development when the silencing of one X chromosome is being established. Targeting Tsix could essentially "un-randomize" X inactivation, inducing more cells to express the mutated version of MECP2. The team developed two strains of mice with different Tsix mutations—one of which resulted in females with lifespans between those of the traditional female and male mouse models, a difference that was traced in part to MECP2 levels in the brain ranging as high as 20 percent of that seen in normal mice. In the other strain, MECP2 expression was reduced to less than 5 percent of normal, and those animals had significantly reduced lifespans and neurologic symptoms mimicking those of the male mouse model relied upon in most Rett syndrome research.

"What was remarkable," Lee says, "was the therapeutic benefit observed in female mice in which MECP2 was expressed in only 5 to 10 percent of brain cells. The mice showed significantly extended life and reduced disease severity."

Carrette adds, "Even small amounts of MECP2 expression appear to have big effects, which is very promising for the development of Rett syndrome treatments. Full reactivation of the inactive X chromosome might be difficult to achieve and have toxic effects due to a dosage imbalance of other genes. Partial reactivation could yield therapeutic effect while reducing potential side effects. The X reactivation approach would also be an alternative to gene therapy, which is challenging because MECP2 expression needs to carefully controlled, since too much leads to neurologic disease. Finding that not every cell needs to express MECP2 for therapeutic benefit indicates that a very low, safe dose could be effective."

A professor of Genetics at Harvard Medical School, Lee says, "We are also excited that the new female mouse model appears to mimic the repetitive and self-injurious behaviors that characterize human Rett Syndrome. With this animal model, we will also be able to examine the efficacy of MECP2-reactivating drugs for symptoms that have been difficult to recapitulate in other disease models. We can now test our drug combinations using this ."

Explore further: X chromosome reactivation could treat Rett syndrome, other X-linked disorders

More information: Lieselot L. G. Carrette el al., "Tsix–Mecp2 female mouse model for Rett syndrome reveals that low-level MECP2 expression extends life and improves neuromotor function," PNAS (2018). www.pnas.org/cgi/doi/10.1073/pnas.1800931115

Related Stories

X chromosome reactivation could treat Rett syndrome, other X-linked disorders

January 4, 2018
A study from a team of Massachusetts General Hospital (MGH) investigators points toward a potential strategy for treating X-linked disorders - those caused by mutations in the X chromosome - in females. Their report published ...

A new drug shows preclinical efficacy in Rett syndrome

May 15, 2018
A new article published in the Cell Reports describes how a new drug is able to reduce the symptoms and activate the dormant neurons characteristic of Rett syndrome in preclinical models. The study was led by Dr. Manel Esteller, ...

Scientists uncover possible therapeutic targets for rare autism spectrum disorder

January 30, 2017
Researchers have uncovered 30 genes that could, one day, serve as therapeutic targets to reverse Rett syndrome, a rare neurological disorder that affects only girls and is a severe form of an autism spectrum disorder.

Structural protein found essential to X chromosome inactivation

June 7, 2018
A Massachusetts General Hospital (MGH) research team has identified the essential role of a structural protein in the silencing of the inactive X chromosome, a process that prevents both copies of the same gene from being ...

Small-molecule therapeutic boosts spatial memory and motor function in Rett syndrome mice

July 5, 2017
New research into Rett syndrome therapeutics suggests that a small molecule already reported to improve respiratory problems associated with the disease may also improve spatial memory and motor skill defects.

Insights into neurons that cause symptoms of Rett syndrome could guide new therapy search

June 28, 2016
Two studies in mice from Baylor College of Medicine, Texas, reveal new insights into neurons that mediate symptoms typical of the postnatal neurological disorder Rett syndrome.

Recommended for you

The importins of anxiety

December 11, 2018
According to some estimates, up to one in three people around the world may experience severe anxiety in their lifetime. In a study described today in Cell Reports, researchers at the Weizmann Institute of Science have revealed ...

How returning to a prior context briefly heightens memory recall

December 11, 2018
Whether it's the pleasant experience of returning to one's childhood home over the holidays or the unease of revisiting a site that proved unpleasant, we often find that when we return to a context where an episode first ...

Neurons in the brain work as a team to guide movement of arms, hands

December 11, 2018
The apparent simplicity of picking up a cup of coffee or turning a doorknob belies the complex sequence of calculations and processes that the brain must undergo to identify the location of an item in space, move the arm ...

The richer the reward, the faster you'll likely move to reach it, study shows

December 11, 2018
If you are wondering how long you personally are willing to stand in line to buy that hot new holiday gift, scientists at Johns Hopkins Medicine say the answer may be found in the biological rules governing how animals typically ...

Using neurofeedback to prevent PTSD in soldiers

December 11, 2018
A team of researchers from Israel, the U.S. and the U.K. has found that using neurofeedback could prevent soldiers from experiencing PTSD after engaging in emotionally difficult situations. In their paper published in the ...

Receiving genetic information can change risk

December 11, 2018
Millions of people in the United States alone have submitted their DNA for analysis and received information that not only predicts their risk for disease but, it turns out, in some cases might also have influenced that risk, ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.