title: Translation of Expanded CGG Repeats into FMRpolyG Is Pathogenic and May Contribute to Fragile X Tremor Ataxia Syndrome.
abstract: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by a limited expansion of CGG repeats in the 5' UTR of FMR1. Two mechanisms are proposed to cause FXTAS: RNA gain-of-function, where CGG RNA sequesters specific proteins, and translation of CGG repeats into a polyglycine-containing protein, FMRpolyG. Here we developed transgenic mice expressing CGG repeat RNA with or without FMRpolyG. Expression of FMRpolyG is pathogenic, while the sole expression of CGG RNA is not. FMRpolyG interacts with the nuclear lamina protein LAP2β and disorganizes the nuclear lamina architecture in neurons differentiated from FXTAS iPS cells. Finally, expression of LAP2β rescues neuronal death induced by FMRpolyG. Overall, these results suggest that translation of expanded CGG repeats into FMRpolyG alters nuclear lamina architecture and drives pathogenesis in FXTAS.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR7104, University of Strasbourg, 67400 Illkirch, France. Electronic address: sellier@igbmc.fr.
authors.forename: Chantal
authors.initials: C
authors.lastname: Sellier
authors.affiliation: Department of Clinical Genetics, Erasmus MC, 3015 Rotterdam, the Netherlands.
authors.forename: Ronald A M
authors.initials: RAM
authors.lastname: Buijsen
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA; Veteran Association Health System, Ann Arbor, MI 48105, USA; Department of Biological and Health Sciences, Texas A&M University - Kingsville, Kingsville, TX 78363, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: He
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Sam
authors.initials: S
authors.lastname: Natla
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR7104, University of Strasbourg, 67400 Illkirch, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Jung
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR7104, University of Strasbourg, 67400 Illkirch, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Tropel
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR7104, University of Strasbourg, 67400 Illkirch, France.
authors.forename: Angeline
authors.initials: A
authors.lastname: Gaucherot
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR7104, University of Strasbourg, 67400 Illkirch, France; PHENOMIN, Institut Clinique de la Souris (ICS), INSERM U964, CNRS UMR7104, University of Strasbourg, 67400 Illkirch, France.
authors.forename: Hugues
authors.initials: H
authors.lastname: Jacobs
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR7104, University of Strasbourg, 67400 Illkirch, France; PHENOMIN, Institut Clinique de la Souris (ICS), INSERM U964, CNRS UMR7104, University of Strasbourg, 67400 Illkirch, France.
authors.forename: Hamid
authors.initials: H
authors.lastname: Meziane
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR7104, University of Strasbourg, 67400 Illkirch, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Vincent
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR7104, University of Strasbourg, 67400 Illkirch, France; PHENOMIN, Institut Clinique de la Souris (ICS), INSERM U964, CNRS UMR7104, University of Strasbourg, 67400 Illkirch, France.
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Champy
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR7104, University of Strasbourg, 67400 Illkirch, France; PHENOMIN, Institut Clinique de la Souris (ICS), INSERM U964, CNRS UMR7104, University of Strasbourg, 67400 Illkirch, France.
authors.forename: Tania
authors.initials: T
authors.lastname: Sorg
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR7104, University of Strasbourg, 67400 Illkirch, France; PHENOMIN, Institut Clinique de la Souris (ICS), INSERM U964, CNRS UMR7104, University of Strasbourg, 67400 Illkirch, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Pavlovic
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR7104, University of Strasbourg, 67400 Illkirch, France; PHENOMIN, Institut Clinique de la Souris (ICS), INSERM U964, CNRS UMR7104, University of Strasbourg, 67400 Illkirch, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Wattenhofer-Donze
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR7104, University of Strasbourg, 67400 Illkirch, France; PHENOMIN, Institut Clinique de la Souris (ICS), INSERM U964, CNRS UMR7104, University of Strasbourg, 67400 Illkirch, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Birling
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR7104, University of Strasbourg, 67400 Illkirch, France.
authors.forename: Mustapha
authors.initials: M
authors.lastname: Oulad-Abdelghani
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR7104, University of Strasbourg, 67400 Illkirch, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Eberling
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR7104, University of Strasbourg, 67400 Illkirch, France.
authors.forename: Frank
authors.initials: F
authors.lastname: Ruffenach
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR7104, University of Strasbourg, 67400 Illkirch, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Joint
authors.affiliation: Department of Neurology, University Hospital of Strasbourg, Hôpital de Hautepierre, 67200 Strasbourg, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Anheim
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA 95817, USA; Institute for Pediatric Regenerative Medicine and Shriners Hospitals for Children Northern California, Sacramento, CA 95817, USA; M.I.N.D. Institute, University of California, Davis, Health System, Sacramento, CA 95817, USA.
authors.forename: Veronica
authors.initials: V
authors.lastname: Martinez-Cerdeno
authors.affiliation: M.I.N.D. Institute, University of California, Davis, Health System, Sacramento, CA 95817, USA.
authors.forename: Flora
authors.initials: F
authors.lastname: Tassone
authors.affiliation: Department of Clinical Genetics, Erasmus MC, 3015 Rotterdam, the Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Willemsen
authors.affiliation: Department of Clinical Genetics, Erasmus MC, 3015 Rotterdam, the Netherlands.
authors.forename: Renate K
authors.initials: RK
authors.lastname: Hukema
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR7104, University of Strasbourg, 67400 Illkirch, France; Laboratoire de Diagnostic Génétique, UF3472 - Infertilité, Nouvel Hôpital Civil, 1 place de l'Hôpital, 67091 Strasbourg, France; IPPTS, 3 rue Koeberlé, 67000 Strasbourg, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Viville
authors.affiliation: INSERM/UEVE UMR 861, I-STEM, AFM, 91030 Evry, France.
authors.forename: Cecile
authors.initials: C
authors.lastname: Martinat
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA; Veteran Association Health System, Ann Arbor, MI 48105, USA.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Todd
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR7104, University of Strasbourg, 67400 Illkirch, France; Université de Strasbourg, 67000 Strasbourg, France; Centre National de la Recherche Scientifique, UMR7104, 67400 Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, 67400 Illkirch, France. Electronic address: ncharlet@igbmc.fr.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Charlet-Berguerand
mesh_terms: D000818:Animals; D001259:Ataxia / Q000235:genetics* / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics* / Q000378:metabolism; D005600:Fragile X Syndrome / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D034881:Nuclear Lamina / Q000378:metabolism* / Q000473:pathology; D010455:Peptides / Q000235:genetics* / Q000378:metabolism; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D014202:Tremor / Q000235:genetics* / Q000378:metabolism; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D051860:Fragile X Messenger Ribonucleoprotein 1; D008565:Membrane Proteins; D010455:Peptides; D012333:RNA, Messenger; C497683:FMR1 protein, human; C093413:lamina-associated polypeptide 2; C011080:polyglycine
keywords: RAN translation; microsatellite expansion; near-cognate codon; neurodegeneration