ArticleFASEB journal : official publication of the Federation of American Societies for Experimental Biology2022
Evidence for a fragile X messenger ribonucleoprotein 1 (FMR1) mRNA gain-of-function toxicity mechanism contributing to the pathogenesis of fragile X-associated premature ovarian insufficiency.
Article in FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers, 1 of them a synthesis that pooled it.
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Who cites it
16 citing papers in PubMed, 1 synthesis or guideline pooled it, 22 citations in OpenAlex.
- Performance of exome sequencing in premature ovarian insufficiency: a systematic review and meta-analysis.BMC pregnancy and childbirth · 2026Pooled it
- Cerebellar GABA and executive function among adult female carriers of the fragile X messenger ribonucleoprotein 1 premutation: a pilot study to examine neural underpinnings of the clinical phenotype.Neurobiology of disease · 2026Article
- The role of FMR1 mRNA structure on the efficiency of non-canonical translation of toxic polyglycine protein.Nucleic acids research · 2026Article
- The Tale of the Guanosine Tract in Repeat Expansion Disorders.Molecular neurobiology · 2026Review
- The roles of RNA-binding proteins in ovarian aging.Journal of assisted reproduction and genetics · 2026Review
- IGF2BPs directly regulate the noncanonical translation of toxic proteins from mutant FMR1 mRNA containing expanded CGG repeats.Nature communications · 2025Article
- The implications of LncRNAs and premature ovarian insufficiency.Journal of ovarian research · 2025Review
- Premature Ovarian Insufficiency and Diminished Ovarian Reserve: From Diagnosis to Current Management and Treatment.Journal of clinical medicine · 2025Review
- Article
- Review: Utility of mass spectrometry in rare disease research and diagnosis.NPJ genomic medicine · 2025Review
- Genetic diagnosis of three intellectually disabled individuals in a pedigree and insights into fragile X syndrome diagnosis.Frontiers in neuroscience · 2025Article
- Review
- Population-based FMR1 carrier screening among reproductive women.Journal of assisted reproduction and genetics · 2024Article
- Premature ovarian insufficiency.Nature reviews. Disease primers · 2024Review
- Review
- Evidence for a fragile X messenger ribonucleoprotein 1 (FMR1) mRNA gain-of-function toxicity mechanism contributing to the pathogenesis of fragile X-associated premature ovarian insufficiency.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2022Article
Corrections and comments
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Authors and funding
6 authors at 4 institutions in 4 countries.
Funding
Abstract
Fragile X-associated premature ovarian insufficiency (FXPOI) is among a family of disorders caused by expansion of a CGG trinucleotide repeat sequence located in the 5' untranslated region (UTR) of the fragile X messenger ribonucleoprotein 1 (FMR1) gene on the X chromosome. Women with FXPOI have a depleted ovarian follicle population, resulting in amenorrhea, hypoestrogenism, and loss of fertility before the age of 40. FXPOI is caused by expansions of the CGG sequence to lengths between 55 and 200 repeats, known as a FMRI premutation, however the mechanism by which the premutation drives disease pathogenesis remains unclear. Two main hypotheses exist, which describe an mRNA toxic gain-of-function mechanism or a protein-based mechanism, where repeat-associated non-AUG (RAN) translation results in the production of an abnormal protein, called FMRpolyG. Here, we have developed an in vitro granulosa cell model of the FMR1 premutation by ectopically expressing CGG-repeat RNA and FMRpolyG protein. We show that expanded CGG-repeat RNA accumulated in intranuclear RNA structures, and these aggregates were able to cause significant granulosa cell death independent of FMRpolyG expression. Using an innovative RNA pulldown, mass spectrometry-based approach we have identified proteins that are specifically sequestered by CGG RNA aggregates in granulosa cells in vitro, and thus may be deregulated as consequence of this interaction. Furthermore, we have demonstrated reduced expression of three proteins identified via our RNA pulldown (FUS, PA2G4 and TRA2β) in ovarian follicles in a FMR1 premutation mouse model. Collectively, these data provide evidence for the contribution of an mRNA gain-of-function mechanism to FXPOI disease biology.
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