Fragile X Premutations, Mechanisms and Modifiers

Overall Abstract: Fragile X-associated Conditions (FXaCs) are a heterogeneous group of disorders arising from alterations in the size and epigenetic state of a polymorphic CGG repeat within FMR1. Described as the first repeat expansion disorder over 30 years ago, FMR1 CGG repeat expansions cause neurological, reproductive, and neurodevelopmental diseases while also serving as an archetype for understanding repeat expansions and the mechanisms by which they elicit dysfunction. Work over decades delineated the native functions of the fragile X protein, FMRP, and the consequences of its loss and identified toxic gain-of-function mechanisms (DNA toxicity induced by R-loop formation, RNA toxicity mediated by protein sequestration, and protein mediated toxicity from Repeat associated non-AUG (RAN) translation) elicited by transcribed CGG repeats. Despite these advances, we lack effective therapies for any FXaC – at least in part due to the enigmatic clinical heterogeneity and incomplete penetrance of FxaCs that confound targeted approaches. Here we propose a change in our approach to FXaCs. Rather than focusing solely on specific diseases (Fragile X Syndrome (FXS), fragile X-associated tremor/ataxia syndrome (FXTAS), or fragile X-associated primary ovarian insufficiency (FXPOI)), the Center structure enables us to directly engage the mechanistic crosstalk between conditions and between the FMR1 locus and related repeat expansion disorders. Our central hypothesis is that a deeper understanding of genetic, pathologic, and environmental factors which underlie the variable clinical manifestations of premutation (PM)-associated disorders will reveal novel insights into both how repeats cause disease and how we can target them therapeutically. We will address this hypothesis in three highly integrated projects all focused on premutation disorders. These projects will use data-driven genomic and bioinformatics approaches coupled with emerging tools and multiple model systems. Our outstanding team of experts from four leading sites of Fragile X research features both junior and senior investigators and runs the gamut from clinicians to neuroscientists to geneticists to reproductive biology experts. By pooling our substantial data, expertise and resources, we will pursue identification of novel pathogenic mechanisms in FX premutation disorders and develop a series of robust and viable targets and approaches for therapeutic development in FXaCs.