UNDERSTANDING THE MOLECULAR AND CELLULAR MECHANIMS IN THE FRAGILE X SYNDROME: FROM TRANSLATIONAL IMPAIRMENT TO SPINE DYSMORPHOGENESIS

Fragile X syndrome is one of the most common forms of inherited mental retardation with the estimated incidence of 1 in 4000 males and 1:7000 females. Fragile X syndrome is associated with a fragile X site, designated FRAXA (Fragile site, X chromosome, A site). In Italy, almost 10.000 people are affected by this syndrome. The clinical presentations of fragile X syndrome include mild to severe mental retardation, with IQ between 20 and 60, mildly abnormal facial features of a prominent jaw and large ears, mainly in males, and macroorchidism. Many patients also display subtle connective tissue abnormalities, hyperactive and attention deficit disorder and autistic-like behaviour. In 1991 the gene associated with this syndrome has been characterised and named fragile X mental retardation 1 (FMR1). Up to now no pharmacological treatment has been developed. This application addresses the aetiology of the FXS not only based on malfunctioning of the FMR1 gene but also on malfunctioning of mRNA localization and translation. The understanding of the mechanisms responsible will constitute a significant contribution to the future understanding of the syndrome for example in cases where the Syndrome appears with no expansion in the 5’UTR of the FMR1 gene. This proposal combines cellular and molecular biology as well as neurobiology approaches to unravel FMRP function. This knowledge will be extremely useful in the future to develop effective intervention to fragile X syndrome.