FXPOI: Mechanisms and Modifiers

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.

Grant Number: 5P50HD104463-05
NIH Institute/Center: NIH
Principal Investigator: Emily Allen