Project 3- FXPOI: Mechanisms and Modifiers

Abstract - Project 3 Up to an estimated 1 in 151 women carry a fragile X premutation (PM) allele, impacting over one million women in the US. In addition to being at risk for having a child with fragile X syndrome (FXS), the most common genetic form of intellectual and developmental disability and autism spectrum disorder, women with a PM are also at risk for other PM associated conditions (PMACs). First, women with a PM are 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, but women are also impacted by other health consequences due to early estrogen deficiency (e.g., early-onset osteoporosis and fractures, early- onset coronary heart disease, and increased overall mortality). In addition, many women with a PM experience multiple chronic health outcomes, including neurological and mental health disorders. Most striking is that the lifetime diagnosis of major depressive disorder has been cited as high as 56%, far higher than the 10-12% national average, and up to 41% for a lifetime diagnosis of an anxiety disorder, compared to 17% in non- carriers. The term fragile X-associated neuropsychiatric disorders (FXAND) was created to recognize and stimulate research on characterizing the risk and etiology of these complex health outcomes. Women with a PM are a prevalent, yet understudied population. They are at the center of families diagnosed with fragile X- associated conditions. The focus of this proposal is to identify the modifiers and mechanisms of the PMACs. Current data support two non-mutually exclusive molecular pathogenic mechanisms associated with the long PM CGG repeat track in the FMR1 transcript (rCGG): 1) expanded rCGG transcripts potentially sequester essential proteins that bind to the rCGGs and 2) the PM 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 PM repeat length explains only ~13% of the risk to develop FXPOI; thus, additional modifiers must exist. Our strong preliminary studies support the following hypothesis: PMACs are multifactorial disorders that results from the molecular consequence of PM-size rCGGs on the background of modifying genes and environmental factors that exacerbate the severity. We will test this hypothesis using a series of PM human and mouse models: we will examine environmental exposures as modifiers of PMACs, the molecular properties associated with phenotypic heterogeneity, as well as phenotypic modifiers within our established PM mouse models. This unique Center, focused on PMACs, 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 PMACs. Filling these gaps will guide the implementation of timely and effective interventions.