About the Fragile X Center
About the Fragile X Center
The National Fragile X Center at Emory is focused on improving the lives of people with Fragile X-Associated Disorders through research, clinical care, and education. The history of fragile X is synonymous with Emory investigators, beginning in the mid 1980’s with Drs. Stephen T. Warren and Stephanie Sherman. Dr. Sherman first described that the risk of expressing intellectual disability (ID) in families with fragile X was dependent upon an individual’s position in the pedigree; this major finding was later named the “Sherman Paradox”. Dr. Warren used the unusual fragility of the X chromosome in patients with fragile X as a tool to begin the search for the causative gene, a tool that he shared with the other top scientists in the fragile X field. In 1991, an international team of scientists, led by Dr. Warren, discovered the FMR1 gene and the mechanisms of trinucleotide repeat expansion that caused the fragile X phenotype. Since that discovery, much of the current understanding of FXS and its consequences have come from the research carried out by Drs. Warren and Sherman and their colleagues. They have become internationally recognized leaders in the field and together represent the forefront of molecular and genetic inquiry into FXS and fragile X-associated disorders.
In 1997, fragile X research was expanded at Emory with the establishment of an NICHD Program Project (PO1) entitled “A Program of Investigation into Fragile X Syndrome” to further elucidate the molecular basis of FXS. The project brought together investigators at Emory, some heavily invested in FXS and others from different fields. This successful recruitment of basic scientists from other disciplines into fragile X research is an early example of Emory’s commitment to enhancing the field by recruitment of both junior and senior investigators into the field. Beginning in 2003, Emory investigators joined forces with the Baylor IDDRC and established a new NICHD Fragile X Research Center (P30), a “center within a center”, for 10 years. This was one of the initial three NICHD Fragile X Research Centers. In 2014, Emory Fragile X Center was funded by NIH entitled “Modifiers of FMR1-associated disorders: application of high throughput technologies”, which enabled us to identify the genetic modifiers for fragile X-associated disorders, including fragile X syndrome, FXTAS, and FXPOI.
Most recently, the National Institutes of Health has provided additional support for this Center to support its work. There are three National Fragile X Centers in the U.S. Emory leads one of these Centers that is focused on Fragile X Syndrome, and Emory researchers are also part of a second Center that focuses on carriers of the premutation.
These Centers are committed to working together to make rapid progress towards the prevention and treatment of fragile X syndrome (FXS), fragile X-associated tremor/ataxia syndrome (FXTAS), and fragile X-associated primary ovarian insufficiency (FXPOI).
The overarching goal of the Emory FX Center that is focused on Fragile X Syndrome is to take a systematic approach to investigate how FMRP may regulate human brain development and circuit functions, and develop novel therapeutic approaches to treat FXS. In collaboration with the investigators from Stanford, NYU, Penn and USC, we will use our established human 2D and 3D model systems and mouse models to determine the role of FMRP in human brain function and to develop novel therapeutic approaches for FXS. The Center brings together an outstanding team of investigators with expertise in transcriptomic analyses, genome-wide translation profiling (translatomes), FMRP-RNA interactomes, single cell genomics, cell type-specific manipulations, dissection of activity- and circuit-dependent mechanisms, and high-throughput small molecule screening.
The Baylor-Michigan-Emory Center focuses on carriers of the premutation and our central hypothesis is that a deeper understanding of genetic factors which underlie clinical disease onset and penetrance in premutation associated disorders (fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI)) and an exploration of native CGG repeat functions will reveal novel insights into both how repeats cause disease and how they might be targeted therapeutically. Led by a multidisciplinary team featuring many leaders in the Fragile X field, we will address this hypothesis in three cohesive projects all focused on premutation disorders by using data-driven genomic and bioinformatics approaches coupled with emerging tools and integrative model systems.
The Three Fragile X-Associated Disorders
Fragile X Syndrome (FXS)
FXS is the leading genetic cause of intellectual disability and the most common single-gene cause of autism spectrum disorder (ASD). It is caused by the expansion of the trinucleotide repeat (CGG) in the 5’ untranslated region of the FMR1 gene to over 200 repeats. When the repeat is this big, it becomes methylated, a process that silences the gene. This “full” mutation leads to the lack of FMRP, the protein product of FMR1. Because the FMR1 gene is located on the X chromosome, males are typically more severely affected than females, but there is a wide range of severity.
Fragile X-associated tremor/ataxia syndrome (FXTAS)
FXTAS is a late-onset disorder that typically begins with motor symptoms of intention tremor and imbalance (ataxia) in the late 50s. Eventually, motor symptoms are accompanied by cognitive problems. Males are typically more often (30-40% risk) and more severely affected than females (10-15% risk). FXTAS is due to the “pre” mutation in the FMR1 gene. The permutation is defined as having 55-200 (unmethylated) repeats. The disorder is caused by the consequence of the long repeat track in the FMR1 mRNA.
Fragile X-associated primary ovarian insufficiency (FXPOI)
FXPOI leads to ovarian dysfunction before age 40. It occurs in about 20% of women who carry the premutation. FXPOI can lead to sub-fertility, early menopausal-related symptoms (e.g., hot flashes, depression, anxiety), and to early onset of disorders associated with estrogen deficiency (e.g., loss of bone mineral density increases the risk for fractures, cardiovascular disease). It is caused by the premutation, most likely because of the long repeat track in the FMR1 mRNA.
