Study shows Rett syndrome in women is not only less severe, but different

A new study from the UC Davis MIND Institute offers critical information about Rett syndrome, a rare genetic disorder that primarily affects girls. Research reveals how this disease affects men and women differently, with the progression of symptoms linked to changes in genetic responses in brain cells.

Rett syndrome is caused by mutations in the MECP2 gene located on the X chromosome. Children with Rett initially show typical development before symptoms appear.

Symptoms vary widely. They include loss of hand function, difficulty breathing and seizures that affect the child’s ability to speak, walk and eat. Rett is less common in men, but when affected, symptoms are usually more severe and present earlier than in women.

The study, published in Communication biologyanalyzed the cerebral cortices of male and female mice with and without MECP2 mutations at three time points: before symptoms, at the onset of symptoms, and at an advanced stage of the disease. He looked at gene expression in 14 different cell types.

“In an X-linked dominant disorder such as Rett, it’s important to know that women not only have less severe symptoms than men. Their condition is different,” said Janine LaSalle, lead author of the study. study and professor of microbiology and immunology. at UC Davis Health. “This is why it is important to study female mouse models of Rett. They are more relevant for developing treatments.”

Most studies use male mouse models for Rett syndrome. These models involve artificial deletion of key elements of the MECP2 gene. This disables MeCP2 protein production in all cells, because males only have one X chromosome.

In humans with Rett, this type of MECP2 gene deletion does not exist. All cells from females with Rett have a MECP2 mutation inherited from a parent on the X chromosome, but only half of the cells express the mutant gene. This means that the other half of the cells with a wild-type copy of MECP2 inherited from the other parent express normal MeCP2 protein.

Thus, the brain of a girl with Rett syndrome shows a mosaic distribution of cells expressing wild-type MeCP2 and cells expressing mutant MeCP2 protein.

“When we separated the two cell types in the brain, we could see that the cells expressing the wild type are actually dysregulated,” LaSalle said.

Mosaic brain and seesaw effect in dysregulated genes

Gene regulation is the process of turning genes on and off. Dysregulated genes are either overexpressed or underexpressed, meaning they produce more or less of certain functional proteins. In the female mouse model of Rett syndrome, this genetic alteration occurred in stages. The researchers called this the “seesaw effect.”

The authors studied cells expressing wild type from mosaic female Rett mouse brains. They found changes in genetic responses in excitatory neurons before symptoms appeared, in inhibitory neurons when symptoms began, and then in astrocytes at a later stage.

“There has been a back and forth oscillation where it appears that genes are trying to achieve homeostasis or balance in the brain. This idea of ​​seesaw homeostasis is important to examine over time. time, as symptoms progress,” LaSalle said.

LaSalle explained that cells expressing the wild type attempt to counteract the effects of cells expressing the mutant. In doing so, they themselves become dysregulated. Wild-type cells begin to express genes from top to bottom. This dysregulation is worse at first and then stabilizes as Rett progresses.

Finding balance as the disease progresses

The study revealed an unusual progression of the disease. We can start with a normal childhood, regress, then reach a plateau, then regress again and finally reach a plateau. The plateau resembles a state of homeostasis, a stabilization of symptoms over time.

“We expected that the number of altered genes would be accompanied by an increase in symptoms. To our surprise, females actually had more dysregulated genes in the pre-symptomatic stage than later,” LaSalle said.

The study also found that women, overall, had more dysregulated genes and were at different stages of the disease than men. This suggests that men don’t just experience a more severe version of Rett. Importantly, this study confirmed that using a female mouse model provides a better representation of Rett syndrome in females.

The study also looked at various genetic pathways. One pathway involves taking a diverse group of genes and placing them into a functional group. If the human body is a factory, a journey would be a team within the factory. For example, a team would maintain a normal heart rate. Another would work on the sleep-wake cycle.

The study showed a link between MECP2 mutation and the Alzheimer’s disease pathway as well as various addiction pathways.

“In genomics, we have moved from looking at one gene at a time to thinking about groups of genes that act together in pathways. The results point to different pathways, meaning that the MECP2 mutation could be relevant to other diseases beyond Rett syndrome,” LaSalle said. explain.