A recent study shows that this rare disease affects men and women differently.
- In cases of Rett syndrome, women overall had more dysregulated genes than men.
- The progression of their symptoms is linked to changes in genetic responses in brain cells (excitatory, inhibitory neurons and astrocytes).
- According to the researchers, cells expressing the wild type of the MECP2 gene located on the X chromosome normalize transcriptional homeostasis.
Loss of manual function, breathing difficulties, epileptic seizures… These are the symptoms that can occur after normal development in cases of Rett syndrome. This rare pathology is caused by mutations in the MECP2 gene located on the X chromosome and is less common in boys. “In the case of this disease that impairs the development of the central nervous system, it is important to know that girls do not simply have less severe symptoms than boys. Their condition is different,” declared Janine LaSalleprofessor of microbiology and immunology at UC Davis Health (United States). To reach this conclusion, she conducted a study published in the journal Communications Biology.
Rett syndrome: women have more dysregulated genes at the pre-symptomatic stage
In women with Rett syndrome, all cells 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. As part of the work, the researcher and her team examined gene expression in 14 different cell types expressing the wild type in the cerebral cortices of male and female mice with or without a MECP2 mutation at three different times: before symptoms appear, when symptoms have started and in advanced stages of the disease.
“Across all cell types, we observed sex differences in the number of differentially expressed genes (DEGs), with 6 times more DEGs in females than in males,” can we read in the results. Clearly, women overall had more dysregulated genes than men, suggesting that men do not just have a more severe version of the disease. The scientists also found changes in genetic responses in excitatory neurons before symptoms appeared, in inhibitory neurons at the time of symptom onset, and then in astrocytes at a later stage.
“This idea of seesaw homeostasis is important to examine over time”
“There was 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 , as symptoms progress”indicated Janine LaSalle. She explained that the cells expressing the wild type were trying to counteract the effects of the cells expressing the mutant type. As a result, they themselves become dysregulated. Wild-type cells begin to express genes from top to bottom. This disruption is more significant at the beginning, then it stabilizes as Rett syndrome progresses. “These results allow us to better understand the progression and treatment of the disease”concluded the authors.
