July 19, 2024
Rett Syndrome

Newly Identified and Characterized MECP2 Gene Variant Sheds Light on Rett Syndrome

Rett syndrome is a devastating neurological disorder that predominantly affects young girls, causing difficulties with walking, talking, and cognitive function. It is characterized by hand-wringing movements, seizures, and cognitive disabilities. The underlying cause of Rett syndrome is mutations in the methyl-CpG binding protein 2 (MECP2) gene, which impairs the role of the MeCP2 protein in regulating gene activity in brain cells.

A recent study led by Dr. Huda Zoghbi, a distinguished service professor at Baylor College of Medicine, and Dr. Robert Tjian, a professor at the University of California, Berkeley, has identified and characterized a new variant of the MECP2 gene, known as G118E. Their findings, published in the journal Genes and Development, provide insight into the molecular mechanisms of Rett syndrome and offer potential strategies for developing therapies.

Using advanced techniques in single-molecule imaging, the research team investigated how the G118E mutation affects the interactions between the MeCP2 protein and DNA. Their findings demonstrate significant molecular changes in MeCP2 protein-DNA dynamics caused by the mutation. This knowledge lays the groundwork for future research in human disease discovery and paves the way for new screening methods for Rett syndrome treatments.

Dr. Zoghbi, who first discovered the link between MECP2 mutations and Rett syndrome in 1999, highlighted the significance of this study in uncovering a previously unknown MECP2 mutation and understanding its biological effects. The team created disease models using induced pluripotent stem cells (iPSCs) to mimic the G118E mutation and found reduced levels of MeCP2 protein in neurons derived from these mutant stem cells compared to neurons with a normal MECP2 gene. They also generated a mouse model with the G118E mutation and observed a decrease in MeCP2 levels and impaired DNA binding capacity, along with Rett-like symptoms in the mice.

To further investigate the impact of the G118E mutation on MeCP2-DNA interactions, the research team collaborated with Dr. Tjian, who developed a cutting-edge single-molecule live imaging technology. This method allowed them to quantitatively measure the dynamics of MeCP2-DNA interactions in live neurons under physiological conditions. The study reveals new insights into the function of the MeCP2 protein and provides a framework for future therapeutic strategies for Rett syndrome.

Dr. Zoghbi emphasized the importance of studying mutations like G118E, which retain partial protein function and DNA binding capacity. Previous studies mainly focused on mutations with abolished DNA binding capacity, but this research expands our understanding of the wide range of mutations associated with Rett syndrome and opens up new possibilities for targeted therapies for a broader group of patients.

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