Epigenetic and synaptic mechanisms affected in Fragile X Syndrome

The fragile X syndrome (FXS) is the most common cause of inherited intellectual disability. The prevalence of affected males in the general population is approximately 1 in 4000, and that of affected females 1 in 6000. The prevalence of carrier females at high risk of having an affected child is 1 in 250 or higher. The syndrome is caused by a mutation of the FMR1 gene localized on the X chromosome. The mutation consists in an amplification and methylation of a DNA sequence within the promoter of the gene. This change blocks the expression of the gene, preventing the production of the FMRP protein, even though the coding sequence of the gene remains intact. Starting from lymphocytes of FXS patients, we established cell lines called “induced Pluripotent Stem Cells' (iPS). These cells can be differentiated into neurons and therefore represent an ideal human cellular model that recapitulates the development of functional neurons and offers the opportunity to study and understand the mechanisms at the origin of the disease. The goal of this project is to identify new approaches to cure FXS. On one side we will try to modulate the epigenetic configuration of the FMR1 gene, on the other side we aim at correcting/ameliorating the critical synaptic malfunctions. The promising results already obtained using these two approaches convinced us that the discovery of an effective cure for FXS could be feasible in the future.