THE FRAGILE X SYNDROME: PHARMACOLOGICAL REACTIVATION OF THE FMR1 GENE AND STUDY OF THE EPIGENETIC FACTORS REGULATING ITS EXPRESSION

The fragile X syndrome is the most common cause of inherited mental retardation. The population prevalence of affected males is approximately 1 in 4000, and that of carrier females, at risk of having affected children, 1 in 250. 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 the DNA sequence comprising the promoter of the gene. This change blocks the expression of the gene, preventing the production of a specific protein, in spite of the fact that the coding sequence of the gene is intact. One can say that the gene is not "broken"; it is just "switched off". We showed previously that the mutant gene can be switched back on by treating in vitro cell lines from fragile X syndrome patients with drugs that can remove the methylation from the DNA and thus relieve the block of the promoter. With the present project we intend to study in more detail the mechanisms that regulate the expression of the FMR1 gene, by looking not only at the DNA, but also at the histones. These are nuclear proteins that bind to the DNA and regulate the expression of the genes. In other words, it is our aim to investigate the "epigenetic" factors that control the expression of the FMR1 gene, to better understand why and how the mutation causes its block. Our ultimate goal is to transfer in vivo the results obtained in vitro, hoping that this may lead to the discovery of an effective cure of the syndrome.