Expansion of GGC Repeat in GIPC1 Is Associated with Oculopharyngodistal Myopathy

Am J Hum Genet. 2020 Jun 4;106(6):793-804. doi: 10.1016/j.ajhg.2020.04.011.

Jianwen Deng ¹, Jiaxi Yu ¹, Pidong Li ², Xinghua Luan ³, Li Cao ³, Juan Zhao ¹, Meng Yu ¹, Wei Zhang ¹, He Lv ¹, Zhiying Xie ¹, LingChao Meng ¹, Yiming Zheng ¹, Yawen Zhao ¹, Qiang Gang ¹, Qingqing Wang ¹, Jing Liu ¹, Min Zhu ⁴, Xueyu Guo ², Yanan Su ², Yu Liang ², Fan Liang ², Tomohiro Hayashi ⁵, Meiko Hashimoto Maeda ⁶, Tatsuro Sato ⁷, Shigehisa Ura ⁸, Yasushi Oya ⁹, Masashi Ogasawara ¹⁰, Aritoshi Iida ¹¹, Ichizo Nishino ¹², Chang Zhou ¹³, Chuanzhu Yan ¹⁴, Yun Yuan ¹, Daojun Hong ¹⁵, Zhaoxia Wang ¹⁶

Affiliations

1 Department of Neurology, Peking University First Hospital, Beijing 100034, China.
2 Grandomics Biosciences, Beijing 101312, China.
3 Department of Neurology, Rui Jin Hospital & Rui Jin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
4 Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China.
5 Department of Neurology, Toyama University Hospital, Toyama 930-0194, Japan.
6 Department of Neurology, Federation of National Public Service Personnel Mutual Aid Associations Toranomon Hospital, Tokyo 105-8470, Japan.
7 Department of Neurology, Hakodate Medical Association Hospital, Hakodate 041-8522, Japan.
8 Department of Neurology, Japanese Red Cross Asahikawa Hospital, Asahikawa 070-8530, Japan.
9 Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo 187-8551, Japan.
10 Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8551, Japan.
11 Department of Clinical Genome Analysis, Medical Genome Center, National Center of Neurology and Psychiatry, Tokyo 187-8551, Japan.
12 Department of Clinical Genome Analysis, Medical Genome Center, National Center of Neurology and Psychiatry, Tokyo 187-8551, Japan; Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8551, Japan.
13 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
14 Research Institute of Neuromuscular and Neurodegenerative Diseases and Department of Neurology, Qilu Hospital, Shandong University, Jinan 250012, China; Mitochondrial Medicine Laboratory, Qilu Hospital (Qingdao), Shandong University, Qingdao 266035, China; Brain Science Research Institute, Shandong University, Jinan 250012, China.
15 Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China. Electronic address: hongdaojun@hotmail.com.
16 Department of Neurology, Peking University First Hospital, Beijing 100034, China. Electronic address: drwangzx@163.com.

PMID: 32413282 DOI: 10.1016/j.ajhg.2020.04.011

Abstract

Oculopharyngodistal myopathy (OPDM) is an adult-onset inherited neuromuscular disorder characterized by progressive ptosis, external ophthalmoplegia, and weakness of the masseter, facial, pharyngeal, and distal limb muscles. The myopathological features are presence of rimmed vacuoles (RVs) in the muscle fibers and myopathic changes of differing severity. Inheritance is variable, with either putative autosomal-dominant or autosomal-recessive pattern. Here, using a comprehensive strategy combining whole-genome Sequencing (WGS), long-read whole-genome Sequencing (LRS), linkage analysis, repeat-primed polymerase chain reaction (RP-PCR), and fluorescence amplicon length analysis polymerase chain reaction (AL-PCR), we identified an abnormal GGC repeat expansion in the 5' UTR of GIPC1 in one out of four families and three sporadic case subjects from a Chinese OPDM cohort. Expanded GGC repeats were further confirmed as the cause of OPDM in an additional 2 out of 4 families and 6 out of 13 sporadic Chinese individuals with OPDM, as well as 7 out of 194 unrelated Japanese individuals with OPDM. Methylation, qRT-PCR, and western blot analysis indicated that GIPC1 mRNA levels were increased while protein levels were unaltered in OPDM-affected individuals. RNA Sequencing indicated p53 signaling, vascular smooth muscle contraction, ubiquitin-mediated proteolysis, and ribosome pathways were involved in the pathogenic mechanisms of OPDM-affected individuals with GGC repeat expansion in GIPC1. This study provides further evidence that OPDM is associated with GGC repeat expansions in distinct genes and highly suggests that expanded GGC repeat units are essential in the pathogenesis of OPDM, regardless of the genes in which the expanded repeats are located.

Keywords

GGC repeat expansions; GIPC1; RNA-seq; intranuclear inclusions; oculopharyngodistal myopathy.

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