{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T08:40:53Z","timestamp":1790498453040,"version":"4.1.0"},"reference-count":64,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2022,10,17]],"date-time":"2022-10-17T00:00:00Z","timestamp":1665964800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000325","name":"Wellbeing of Women","doi-asserted-by":"publisher","award":["PRF005"],"award-info":[{"award-number":["PRF005"]}],"id":[{"id":"10.13039\/501100000325","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Fragile X\u2010associated premature ovarian insufficiency (FXPOI) is among a family of disorders caused by expansion of a CGG trinucleotide repeat sequence located in the 5\u2032 untranslated region (UTR) of the fragile X messenger ribonucleoprotein 1 (\n                    <jats:italic>FMR1<\/jats:italic>\n                    ) 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\n                    <jats:italic>FMRI<\/jats:italic>\n                    premutation, however the mechanism by which the premutation drives disease pathogenesis remains unclear. Two main hypotheses exist, which describe an mRNA toxic gain\u2010of\u2010function mechanism or a protein\u2010based mechanism, where repeat\u2010associated non\u2010AUG (RAN) translation results in the production of an abnormal protein, called FMRpolyG. Here, we have developed an in vitro granulosa cell model of the\n                    <jats:italic>FMR1<\/jats:italic>\n                    premutation by ectopically expressing CGG\u2010repeat RNA and FMRpolyG protein. We show that expanded CGG\u2010repeat 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\u2010based 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 TRA2\u03b2) in ovarian follicles in a\n                    <jats:italic>FMR1<\/jats:italic>\n                    premutation mouse model. Collectively, these data provide evidence for the contribution of an mRNA gain\u2010of\u2010function mechanism to FXPOI disease biology.\n                  <\/jats:p>","DOI":"10.1096\/fj.202200468rr","type":"journal-article","created":{"date-parts":[[2022,10,17]],"date-time":"2022-10-17T10:24:12Z","timestamp":1666002252000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Evidence for a fragile X messenger ribonucleoprotein 1 (\n                    <i>FMR1<\/i>\n                    )\n                    <scp>mRNA<\/scp>\n                    gain\u2010of\u2010function toxicity mechanism contributing to the pathogenesis of fragile X\u2010associated premature ovarian insufficiency"],"prefix":"10.1096","volume":"36","author":[{"given":"Roseanne","family":"Rosario","sequence":"first","affiliation":[{"name":"MRC Centre for Reproductive Health, Queen's Medical Research Institute University of Edinburgh  Edinburgh UK"},{"name":"Biomedical Sciences University of Edinburgh  Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hazel L.","family":"Stewart","sequence":"additional","affiliation":[{"name":"MRC Centre for Reproductive Health, Queen's Medical Research Institute University of Edinburgh  Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nila Roy","family":"Choudhury","sequence":"additional","affiliation":[{"name":"Infection Medicine University of Edinburgh  Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7409-9619","authenticated-orcid":false,"given":"Gracjan","family":"Michlewski","sequence":"additional","affiliation":[{"name":"Infection Medicine University of Edinburgh  Edinburgh UK"},{"name":"Zhejiang University\u2010University of Edinburgh Institute Zhejiang University  Zhejiang P.R. China"},{"name":"Dioscuri Centre for RNA\u2010Protein Interactions in Human Health and Disease International Institute of Molecular and Cell Biology in Warsaw  Warsaw Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Charlet\u2010Berguerand","sequence":"additional","affiliation":[{"name":"Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire et Cellulaire (IGBMC) INSERM U 1258, CNRS UMR 7104, Universit\u00e9 of Strasbourg  Illkirch France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard A.","family":"Anderson","sequence":"additional","affiliation":[{"name":"MRC Centre for Reproductive Health, Queen's Medical Research Institute University of Edinburgh  Edinburgh 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