@article{b4494db5c38543ed825e607fccebfedd,
title = "Translation of GGC repeat expansions into a toxic polyglycine protein in NIID defines a novel class of human genetic disorders: The polyG diseases",
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.",
keywords = "RAN translation, genetic diseases, neurodegeneration, polyG, polyglycine, trinucleotide repeat disorder",
author = "Manon Boivin and Jianwen Deng and Pfister, {V. ronique} and Erwan Grandgirard and Mustapha Oulad-Abdelghani and Bastien Morlet and Frank Ruffenach and Luc Negroni and Pascale Koebel and Hugues Jacob and Fabrice Riet and Dijkstra, {Anke A.} and Kathryn McFadden and Clayton, {Wiley A.} and Daojun Hong and Hiroaki Miyahara and Yasushi Iwasaki and Jun Sone and Zhaoxia Wang and Nicolas Charlet-Berguerand",
note = "Funding Information: This work was supported by the National Natural Science Foundation of China ( 81571219 , 82071409 , and U20A20356 to Z.W.); the Double Thousand Talents Program of Jiangxi Province (to D.H.); the Peking University Medicine Fund of Fostering Young Scholars{\textquoteright} Scientific & Technological Innovation (to J.D.); the Japan Society for the Promotion of Science ( KAKENHI JP19H03577 ) and the MHLW FC Program ( JPMH19189624 ) (to J.S.); ERC-2012-StG 310659 , ANR-18-CE16-0019 , and FRM EQU202103012936 (to N.C.B.); and ANR-10-LABX-0030-INRT and ANR-10-IDEX-0002-02 (to I.G.B.M.C.). Funding Information: This work was supported by the National Natural Science Foundation of China (81571219, 82071409, and U20A20356 to Z.W.); the Double Thousand Talents Program of Jiangxi Province (to D.H.); the Peking University Medicine Fund of Fostering Young Scholars? Scientific & Technological Innovation (to J.D.); the Japan Society for the Promotion of Science (KAKENHI JP19H03577) and the MHLW FC Program (JPMH19189624) (to J.S.); ERC-2012-StG 310659, ANR-18-CE16-0019, and FRM EQU202103012936 (to N.C.B.); and ANR-10-LABX-0030-INRT and ANR-10-IDEX-0002-02 (to I.G.B.M.C.). Experiments were performed by M.B. J.D. J.S. V.P. B.M. F. Ruffenach, F. Riet, E.G. P.K. H.J. and M.O.-A. Control and NIID cases originated from K.M. W.A.C. A.A.D. D.H. H.M. Y.I. J.S. and Z.W. Data were collected and analyzed by M.B. J.D. J.S. Z.W. W.A.C. A.A.D. E.G. L.N. and N.C.-B. The study was designed, coordinated, and written by N.C.-B. with input from all authors. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021 The Author(s) Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",
year = "2021",
month = jun,
day = "2",
doi = "https://doi.org/10.1016/j.neuron.2021.03.038",
language = "English",
volume = "109",
pages = "1825--1835.e5",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "11",
}