FXPOI: Mechanisms and Modifiers

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Project Summary Up to an estimated 1 in 151 women carry a fragile X premutation allele, impacting over one million women in the US. Women with a premutation are at risk of having a child with fragile X syndrome (FXS), the most common genetic form of intellectual and developmental disability and autism spectrum disorder. These women are also at risk for fragile X-associated primary ovarian insufficiency (FXPOI), with 20-30% experiencing cessation of menses prior to age 40. Reduced fertility is the most significant consequence of FXPOI. Other health consequences due to early estrogen deficiency include low bone density, early-onset osteoporosis and fractures, impaired endothelial function, early-onset coronary heart disease, and increased overall mortality. Women with a premutation are a prevalent, yet understudied population. They are at the center of families diagnosed with fragile X-associated disorders. The focus of this proposal is to identify the modifiers and mechanisms of FXPOI. Current data support two non-mutually exclusive molecular pathogenic mechanisms associated with the long premutation CGG repeat track in the FMR1 transcript (rCGG): 1) expanded rCGG transcripts potentially sequester essential proteins that bind to the rCGGs and 2) the premutation rCGG induces repeat-associated non-AUG (RAN) translation within the 5' UTR of FMR1 mRNA, producing polypeptides that may be toxic. With respect to modifiers of severity, we showed previously that the premutation repeat length explains only ~13% of the risk to develop FXPOI; thus, additional modifiers of must exist. Our strong preliminary studies support the following hypothesis: FXPOI is a multifactorial disorder that results from the molecular consequence of premutation-size rCGGs, primarily the toxic effect of RAN translation products, on the background of modifying genes that exacerbate the severity of FXPOI. We will test this hypothesis using a series of premutation mouse and human models and tools generated by investigators of the Center. The goal will be to test the roles of RNA sequestration and RAN-translation. In addition, we will build on our whole genome sequencing results and on other novel datasets generated by Center investigators to identify and screen candidate modifying genes in our large cohort of premutation and non-carriers on whom we have collected rich phenotype data. This unique Center, focused on fragile X premutation disorders, has gathered a multi-disciplinary collaborative team who have significant track records in the fragile X field. Their expertise provides novel resources and tools to address critical knowledge gaps related to the risk factors and pathways associated with FXPOI and other premutation- associated disorders. Filling these gaps will guide the implementation of timely and effective interventions.