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Translation of GGC repeat expansions into a toxic polyglycine protein in NIID defines a novel class of human genetic disorders: The polyG diseases.
Boivin, Manon; Deng, Jianwen; Pfister, Véronique; Grandgirard, Erwan; Oulad-Abdelghani, Mustapha; Morlet, Bastien; Ruffenach, Frank; Negroni, Luc; Koebel, Pascale; Jacob, Hugues; Riet, Fabrice; Dijkstra, Anke A; McFadden, Kathryn; Clayton, Wiley A; Hong, Daojun; Miyahara, Hiroaki; Iwasaki, Yasushi; Sone, Jun; Wang, Zhaoxia; Charlet-Berguerand, Nicolas.
Affiliation
  • Boivin M; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U 1258, CNRS UMR 7104, University of Strasbourg, 67404 Illkirch, France.
  • Deng J; Department of Neurology, Peking University First Hospital, Beijing 100034, China.
  • Pfister V; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U 1258, CNRS UMR 7104, University of Strasbourg, 67404 Illkirch, France.
  • Grandgirard E; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U 1258, CNRS UMR 7104, University of Strasbourg, 67404 Illkirch, France.
  • Oulad-Abdelghani M; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U 1258, CNRS UMR 7104, University of Strasbourg, 67404 Illkirch, France.
  • Morlet B; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U 1258, CNRS UMR 7104, University of Strasbourg, 67404 Illkirch, France.
  • Ruffenach F; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U 1258, CNRS UMR 7104, University of Strasbourg, 67404 Illkirch, France.
  • Negroni L; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U 1258, CNRS UMR 7104, University of Strasbourg, 67404 Illkirch, France.
  • Koebel P; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U 1258, CNRS UMR 7104, University of Strasbourg, 67404 Illkirch, France.
  • Jacob H; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U 1258, CNRS UMR 7104, University of Strasbourg, 67404 Illkirch, France.
  • Riet F; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U 1258, CNRS UMR 7104, University of Strasbourg, 67404 Illkirch, France.
  • Dijkstra AA; Department of Pathology, Amsterdam University Medical Centre, Amsterdam Neuroscience, VUmc, Amsterdam, the Netherlands.
  • McFadden K; Department of Pathology, IWK Health Centre, Halifax, NS B3K 6R8, Canada.
  • Clayton WA; Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
  • Hong D; Department of Neurology, First Affiliated Hospital of Nanchang University, Nanchang, China.
  • Miyahara H; Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Japan.
  • Iwasaki Y; Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Japan.
  • Sone J; Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Japan; Department of Neurology, Suzuka National Hospital, Suzuka 513-8501, Japan.
  • Wang Z; Department of Neurology, Peking University First Hospital, Beijing 100034, China.
  • Charlet-Berguerand N; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U 1258, CNRS UMR 7104, University of Strasbourg, 67404 Illkirch, France. Electronic address: ncharlet@igbmc.fr.
Neuron ; 109(11): 1825-1835.e5, 2021 06 02.
Article in En | MEDLINE | ID: mdl-33887199
ABSTRACT
Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease characterized by the presence of intranuclear inclusions of unknown origin. NIID is caused by an expansion of GGC repeats in the 5' UTR of the NOTCH2NLC (N2C) gene. We found that these repeats are embedded in a small upstream open reading frame (uORF) (uN2C), resulting in their translation into a polyglycine-containing protein, uN2CpolyG. This protein accumulates in intranuclear inclusions in cell and mouse models and in tissue samples of individuals with NIID. Furthermore, expression of uN2CpolyG in mice leads to locomotor alterations, neuronal cell loss, and premature death of the animals. These results suggest that translation of expanded GGC repeats into a novel and pathogenic polyglycine-containing protein underlies the presence of intranuclear inclusions and neurodegeneration in NIID.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Peptides / Neurodegenerative Diseases / Trinucleotide Repeat Expansion Limits: Animals / Humans / Male Language: En Journal: Neuron Journal subject: NEUROLOGIA Year: 2021 Type: Article Affiliation country: France
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Peptides / Neurodegenerative Diseases / Trinucleotide Repeat Expansion Limits: Animals / Humans / Male Language: En Journal: Neuron Journal subject: NEUROLOGIA Year: 2021 Type: Article Affiliation country: France