Symptoms and the progression of Rett syndrome differ between females and males. A recent study highlights the significance of recognizing these differences to create more effective treatments.
A groundbreaking study by the UC Davis MIND Institute sheds light on Rett syndrome, an uncommon genetic disorder that predominantly affects girls. The findings underscore the various ways this condition manifests in males and females, linking symptom progression to alterations in gene activity within brain cells.
Rett syndrome arises from mutations in the MECP2 gene found on the X chromosome. Initially, children with Rett syndrome develop normally before symptoms begin to emerge.
The symptoms are quite diverse, including loss of hand skills, difficulties in breathing, and seizures, which hinder the child’s ability to speak, walk, and eat. While Rett syndrome occurs less frequently in males, it tends to be more severe and appears at an earlier age compared to females.
The research, published in Communications Biology, investigated the cerebral cortices of male and female mice, both with and without MECP2 mutations, at three different stages: prior to symptom onset, at the onset of symptoms, and during the later stages of the disease. It examined gene expression across 14 distinct cell types.
“In an X-linked dominant disorder like Rett, it’s critical to recognize that females do not merely experience milder symptoms compared to males; their condition is fundamentally different,” stated Janine LaSalle, the study’s lead author and a professor at UC Davis Health. “This is why studying female mouse models of Rett syndrome is essential; they provide more relevant data for treatment development.”
Traditionally, most research relies on male mouse models for Rett syndrome. These models are genetically altered to eliminate essential components of the MECP2 gene, leading to a lack of MeCP2 protein production across all cells, since males possess only one X chromosome.
In human cases of Rett syndrome, this specific type of MECP2 gene deletion is absent. All female cells affected by Rett carry an MECP2 mutation from one parent’s X chromosome, but only half of those cells express the mutated gene. The other half expresses a normal version of the MECP2 protein inherited from the other parent.
Consequently, the brain of a girl with Rett syndrome demonstrates a mosaic pattern, with some cells producing the standard MeCP2 protein while others produce the mutant form.
“Upon separating these cell types within the brain, we discovered that the cells expressing normal MeCP2 were significantly dysregulated,” LaSalle noted.
Mosaic brains and the seesaw effect in dysregulated genes
Gene regulation is the mechanism by which genes are activated or deactivated. Dysregulated genes can either be overactive or underactive, meaning they produce too much or too little of specific proteins. In the female mouse model of Rett syndrome, this gene dysregulation unfolded in phases, which the researchers termed “the seesaw effect.”
The authors focused on the wild-type expressing cells in the mosaic brains of female Rett mice. They observed alterations in gene responses within excitatory neurons before symptoms appeared, in inhibitory neurons as symptoms began, and finally in astrocytes at a later stage.
“We noted a back-and-forth fluctuation, suggesting these genes were attempting to achieve homeostasis or balance in the brain. This concept of seesaw homeostasis is crucial to understand as symptoms evolve,” LaSalle explained.
LaSalle clarified that the wild-type expressing cells are attempting to balance out the effects of the mutant expressing cells, which in turn leads to their own dysregulation. As these wild-type cells react, they begin to variably express genes. This dysregulation peaks at the initial stages but stabilizes as the disease continues.
Finding balance as disease progresses
The study uncovered an atypical disease progression pattern. It identified a path beginning with normal infancy, then regressing, leveling off, regressing again, and finally stabilizing. The final plateau is akin to a state of equilibrium, with symptoms managing to stabilize over time.
“We anticipated that the number of impaired genes would correlate with increased symptom severity. Surprisingly, we found that females exhibited more dysregulated genes during the pre-symptomatic phase than later on,” LaSalle stated.
The study also highlighted that females displayed a greater number of dysregulated genes across different stages of the disease compared to males. This insight suggests that males are not simply experiencing a more severe variant of Rett syndrome. Notably, this research affirmed that using female mouse models yields a more accurate representation of Rett syndrome in females.
Additionally, the study explored various gene pathways, which involve grouping related genes into functional teams. For instance, one pathway might regulate heart rate, while another may manage the sleep-wake cycle.
The findings linked the MECP2 mutation to the Alzheimer’s pathway and other addiction pathways.
“In genomics, there’s been a paradigm shift from studying single genes in isolation to analyzing groups of genes that function together within pathways. These results highlight distinct pathways, suggesting that the MECP2 mutation could be linked to diseases beyond just Rett syndrome,” LaSalle noted.
This research was supported by several National Institutes of Health grants (1R01AA027075, 1S10OD010786-01, P50 HD103526, P30 ES023513), a National Cancer Institute grant (P30 CA093373), and an Astrios Cell Sorter grant (S10 OD018223). The UC Davis team included Osman Sharifi, Dag Yasui, Viktoria Haghani, Kari Neier, Sophia Hakam, Keith Fraga, Ian Korf, Gerald Quon, and Nelson Johansen.
