title: CGG Repeats in the 5'UTR of FMR1 RNA Regulate Translation of Other RNAs Localized in the Same RNA Granules.
abstract: CGG repeats in the 5'UTR of Fragile X Mental Retardation 1 (FMR1) RNA mediate RNA localization and translation in granules. Large expansions of CGG repeats (> 200 repeats) in FMR1, referred to as full mutations, are associated with fragile X syndrome (FXS). Smaller expansions (55-200 repeats), referred to as premutations, are associated with fragile X tremor ataxia syndrome (FXTAS) and fragile X premature ovarian insufficiency (FXPOI). TMPyP4 is a porphyrin ring compound that destabilizes CGG repeat RNA secondary structure. Here we show that exogenous CGG repeat RNA by itself, lacking the FMRP ORF, microinjected into hippocampal neurons is localized in RNA granules and inhibits translation of ARC RNA, which is localized in the same granules. TMPyP4 rescues translation of ARC RNA in granules. We also show that in human premutation fibroblasts with endogenous CGG repeat expansions in the FMR1 gene, translation of ARC RNA is inhibited and calcium homeostasis is disrupted and both phenotypes are rescued by TMPyP4. Inhibition of granule translation by expanded CGG repeats and rescue of granule translation by TMPy4, represent potential pathogenic mechanism and therapeutic strategy, respectively, for FXTAS and FXPOI.
authors.affiliation: Center for Cell Analysis and Modeling, UConn Health, Farmington, Connecticut, United States of America.
authors.forename: René
authors.initials: R
authors.lastname: Rovozzo
authors.affiliation: Department of Molecular Biology and Biophysics, UConn Health, Farmington, Connecticut, United States of America.
authors.forename: George
authors.initials: G
authors.lastname: Korza
authors.affiliation: Departments of Pediatrics, School of Medicine and Public Health, University of Wisconsin-Madison, Wisconsin State Laboratory of Hygiene, Newborn Screening Laboratory, Madison, Wisconsin, United States of America.
authors.forename: Mei W
authors.initials: MW
authors.lastname: Baker
authors.affiliation: Waisman Center, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Meng
authors.initials: M
authors.lastname: Li
authors.affiliation: Waisman Center, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Anita
authors.initials: A
authors.lastname: Bhattacharyya
authors.affiliation: Department of Neuroscience, UConn Health, Farmington, Connecticut, United States of America.
authors.forename: Elisa
authors.initials: E
authors.lastname: Barbarese
authors.affiliation: Center for Cell Analysis and Modeling, UConn Health, Farmington, Connecticut, United States of America.
authors.forename: John H
authors.initials: JH
authors.lastname: Carson
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics*; D000818:Animals; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D016649:Primary Ovarian Insufficiency / Q000235:genetics*; D014176:Protein Biosynthesis; D012313:RNA / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: D020121:5' Untranslated Regions; D003598:Cytoskeletal Proteins; D051860:Fragile X Messenger Ribonucleoprotein 1; D009419:Nerve Tissue Proteins; D012313:RNA; C497683:FMR1 protein, human; C092069:activity regulated cytoskeletal-associated protein