To better understand what causes symptoms of Rett syndrome, researchers at the Duncan Neurological Institute (Duncan NRI) at Baylor College of Medicine and Texas Children’s Hospital took a closer look at pre-symptomatic brain cells in mice that model Rett syndrome. They identified a set of malfunctioning genes and specific cell types that are early susceptible to genetic changes. This research Science progresses.
Rett syndrome is a rare genetic neurological disorder that primarily affects girls. Girls with Rett syndrome usually develop normally during infancy, but between the ages of 6 and 18 months, they begin to lose skills such as language, purposeful movement, and social engagement.
Rett syndrome is caused by a mutation in a gene called . MECP2This plays a key role in controlling how other genes are turned on or off within brain cells. ”
Dr. Huda Zoghbi, Corresponding Author, Distinguished Service Professor, Baylor University, Duncan NRI Director, Howard Hughes Medical Institute Research Fellow
Mutations cause a gene to lose function and affect the proper regulation of thousands of other genes. ”MECP2 “The gene is located on the X chromosome,” said co-first author Ashley Anderson, Ph.D., a postdoctoral fellow in molecular and human genetics in the Zoghbi lab. “Female cells have two X chromosomes, but each cell randomly turns off one of these chromosomes, creating a mosaic cellular environment in which about half of the brain cells use a healthy version of the X chromosome. MECP2 (MeCP2-positive cells), and the other half use the mutant version (MeCP2-negative cells). However, men only have one X chromosome, so all of their cells carry the variant. MECP2which can lead to more severe disease earlier in life. ”
“What makes Rett’s study uniquely difficult is that healthy and mutated cells interact in ways that we are only beginning to understand,” said co-first author Yang Li, a graduate student in Zogbi’s lab. “By studying female mice that reflect this mosaic state and male mice that carry only the mutant copy, we will begin to unravel their effects.”
The researchers studied gene expression patterns, or gene activity, in cells in the hippocampus, a brain region involved in learning and memory that is known to be affected early in the disease. A key technical advance in this study was physically separating MeCP2-positive and MeCP2-negative cells before studying the cells, allowing the researchers to compare gene activity in mutant and healthy cells from the same mosaic female brain for the first time.
“We applied two molecular techniques to measure which genes are turned on or turned off within these cells,” Lee said. “Bulk RNA-sequencing tells us about gene activity throughout the tissue, while single-nuclear RNA-seq allows us to analyze gene activity in individual cells. Using both techniques, we can see the ‘big picture’ and zoom in on specific cell types.”
In female mice, overall changes in gene activity appeared modest when measured across brain tissue. But when the researchers looked at individual cells, a very different picture emerged. “We found that important changes occur only in specific cells and are therefore not evident in bulk measurements,” Lee said. “for example, Mecp2 The mutations showed strong gene disruption only in specific cell types, but were not detected when mixtures of cells were analyzed in bulk studies. This shows that in mosaic conditions like Rett syndrome, studying individual cells is essential to fully understand the disease. ”
“We found 12 genes that consistently change at the very early stages of the disease, and 12 genes that change only at the early stages. Mecp2 “These genes were elevated or depressed in the same way, regardless of gender or disease severity,” Anderson said. We propose that these genes likely represent early “core disease signatures.” Many of these genes are involved in the transmission of information between brain cells (synapses), suggesting that disruptions in how neurons connect and signal may be one of the early stages of Rett syndrome. ”
Although the study found core disease symptoms, Mecp2 It has also become clear that even if the cells are negative, there are also healthy cells (normal cells). Mecp2 Genes) are not completely unaffected even in women. “We found that some brain cells are normal. Mecp2 “There were changes in gene activity due to the presence of neighboring defective cells. This shows that the cells can be affected by the environment and helps explain why Rett syndrome causes widespread brain dysfunction even though many cells are genetically normal,” Professor Anderson said.
One surprising finding was that a type of neuron called trilayer interneurons, not previously associated with Rett syndrome, showed stronger destruction than other types of neurons when MeCP2 became dysfunctional. These cells connect across multiple layers of the hippocampus and help coordinate communication within the brain. Further studies are needed to better understand the role of these interneurons in Rett syndrome.
“Understanding these early cell-specific changes not only provides markers to monitor the effectiveness of interventions, but also provides an entry point for understanding the brain circuits that drive Rett function,” Zoghbi said. “If scientists can target the earliest molecular disruptions or protect the most vulnerable cell types, they may be able to slow or prevent the progression of Rett syndrome. Additionally, this study will inform research into other genetic conditions that involve mosaicism or affect specific brain cell populations.”
Guantong Qi, Sih-Rong Wu, Jean-Pierre Revelli, Hu Chen, and Zhandong Liu from Baylor College of Medicine and/or Duncan NRI also contributed to this research.
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Baylor College of Medicine
Reference magazines:
Lee, Y. Others. (2026). Mononuclear profiling reveals core disease features and cell type-specific vulnerabilities in early Rett syndrome. Science progresses. DOI: 10.1126/sciadv.aeb4265. https://www.science.org/doi/10.1126/sciadv.aeb4265
