The GGC repeat expansion in<i>NOTCH2NLC</i>is associated with oculopharyngodistal myopathy type 3

  • Jiaxi Yu
    Department of Neurology, Peking University First Hospital, Beijing 100034, China
  • Jianwen Deng
    Department of Neurology, Peking University First Hospital, Beijing 100034, China
  • Xueyu Guo
    Grandomics Biosciences, Beijing 100176, China
  • Jingli Shan
    Research Institute of Neuromuscular and Neurodegenerative Diseases and Department of Neurology, Qilu Hospital, Shandong University, Jinan 250000, Shandong, China
  • Xinghua Luan
    Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200030, China
  • Li Cao
    Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200030, China
  • Juan Zhao
    Department of Neurology, Peking University First Hospital, Beijing 100034, China
  • Meng Yu
    Department of Neurology, Peking University First Hospital, Beijing 100034, China
  • Wei Zhang
    Department of Neurology, Peking University First Hospital, Beijing 100034, China
  • He Lv
    Department of Neurology, Peking University First Hospital, Beijing 100034, China
  • Zhiying Xie
    Department of Neurology, Peking University First Hospital, Beijing 100034, China
  • LingChao Meng
    Department of Neurology, Peking University First Hospital, Beijing 100034, China
  • Yiming Zheng
    Department of Neurology, Peking University First Hospital, Beijing 100034, China
  • Yawen Zhao
    Department of Neurology, Peking University First Hospital, Beijing 100034, China
  • Qiang Gang
    Department of Neurology, Peking University First Hospital, Beijing 100034, China
  • Qingqing Wang
    Department of Neurology, Peking University First Hospital, Beijing 100034, China
  • Jing Liu
    Department of Neurology, Peking University First Hospital, Beijing 100034, China
  • Min Zhu
    Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China
  • Binbin Zhou
    Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China
  • Pidong Li
    Grandomics Biosciences, Beijing 100176, China
  • Yinzhe Liu
    Grandomics Biosciences, Beijing 100176, China
  • Yang Wang
    Grandomics Biosciences, Beijing 100176, China
  • Chuanzhu Yan
    Research Institute of Neuromuscular and Neurodegenerative Diseases and Department of Neurology, Qilu Hospital, Shandong University, Jinan 250000, Shandong, China
  • Daojun Hong
    Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China
  • Yun Yuan
    Department of Neurology, Peking University First Hospital, Beijing 100034, China
  • Zhaoxia Wang
    Department of Neurology, Peking University First Hospital, Beijing 100034, China

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<jats:title>Abstract</jats:title><jats:p>Oculopharyngodistal myopathy (OPDM) is an adult-onset neuromuscular disease characterized by progressive ocular, facial, pharyngeal and distal limb muscle involvement. Trinucleotide repeat expansions in LRP12 or GIPC1 were recently reported to be associated with OPDM. However, a significant portion of OPDM patients have unknown genetic causes. In this study, long-read whole-genome sequencing and repeat-primed PCR were performed and we identified GGC repeat expansions in the NOTCH2NLC gene in 16.7% (4/24) of a cohort of Chinese OPDM patients, designated as OPDM type 3 (OPDM3). Methylation analysis indicated that methylation levels of the NOTCH2NLC gene were unaltered in OPDM3 patients, but increased significantly in asymptomatic carriers. Quantitative real-time PCR analysis indicated that NOTCH2NLC mRNA levels were increased in muscle but not in blood of OPDM3 patients. Immunofluorescence on OPDM muscle samples and expressing mutant NOTCH2NLC with (GGC)69 repeat expansions in HEK293 cells indicated that mutant NOTCH2NLC-polyglycine protein might be a major component of intranuclear inclusions, and contribute to toxicity in cultured cells. In addition, two RNA-binding proteins, hnRNP A/B and MBNL1, were both co-localized with p62 in intranuclear inclusions in OPDM muscle samples. These results indicated that a toxic protein gain-of-function mechanism and RNA gain-of-function mechanism may both play a vital role in the pathogenic processes of OPDM3. This study extended the spectrum of NOTCH2NLC repeat expansion-related diseases to a predominant myopathy phenotype presenting as OPDM, and provided evidence for possible pathogenesis of these diseases.</jats:p>

収録刊行物

  • Brain

    Brain 144 (6), 1819-1832, 2021-03-09

    Oxford University Press (OUP)

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