The CGG repeat expansion in RILPL1 is associated with oculopharyngodistal myopathy type 4

Jiaxi Yu; Jingli Shan; Meng Yu; Li Di; Zhiying Xie; Wei Zhang; He Lv; Lingchao Meng; Yiming Zheng; Yawen Zhao; Qiang Gang; Xueyu Guo; Yang Wang; Jianying Xi; Wenhua Zhu; Yuwei Da; Daojun Hong; Yun Yuan; Chuanzhu Yan; Zhaoxia Wang; Jianwen Deng

doi:10.1016/j.ajhg.2022.01.012

The CGG repeat expansion in RILPL1 is associated with oculopharyngodistal myopathy type 4

Am J Hum Genet. 2022 Mar 3;109(3):533-541. doi: 10.1016/j.ajhg.2022.01.012. Epub 2022 Feb 10.

Authors

Jiaxi Yu¹, Jingli Shan², Meng Yu³, Li Di⁴, Zhiying Xie³, Wei Zhang³, He Lv³, Lingchao Meng³, Yiming Zheng³, Yawen Zhao³, Qiang Gang³, Xueyu Guo⁵, Yang Wang⁵, Jianying Xi⁶, Wenhua Zhu⁶, Yuwei Da⁴, Daojun Hong⁷, Yun Yuan³, Chuanzhu Yan², Zhaoxia Wang⁸, Jianwen Deng⁹

Affiliations

¹ Department of Neurology, Peking University First Hospital, Beijing, 100034, China; Beijing Key Laboratory of Neurovascular Disease Discovery, Beijing, 100034, China.
² 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, China, Brain Science Research Institute, Shandong University, Jinan, China.
³ Department of Neurology, Peking University First Hospital, Beijing, 100034, China.
⁴ Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China.
⁵ Grandomics Biosciences, Beijing, 100000, China.
⁶ Department of Neurology, Huashan Hospital Fudan University, Shanghai, 200040, China.
⁷ Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China.
⁸ Department of Neurology, Peking University First Hospital, Beijing, 100034, China; Beijing Key Laboratory of Neurovascular Disease Discovery, Beijing, 100034, China. Electronic address: [email protected].
⁹ Department of Neurology, Peking University First Hospital, Beijing, 100034, China; Beijing Key Laboratory of Neurovascular Disease Discovery, Beijing, 100034, China. Electronic address: [email protected].

Abstract

Recent studies indicate that CGG repeat expansions in LRP12, GIPC1, and NOTCH2NLC are associated with oculopharyngodistal myopathy (OPDM) types 1, 2, and 3, respectively. However, some clinicopathologically confirmed OPDM cases continue to have unknown genetic causes. Here, through a combination of long-read whole-genome sequencing (LRS), repeat-primed polymerase chain reaction (RP-PCR), and fluorescence amplicon length analysis PCR (AL-PCR), we found that a CGG repeat expansion in the 5' UTR of RILPL1 is associated with familial and simplex OPDM type 4 (OPDM4). The number of repeats ranged from 139 to 197. Methylation analysis indicates that the methylation levels in RILPL1 were unaltered in OPDM4 individuals. Analyses of muscle biopsies suggested that the expanded CGG repeat might be translated into a toxic poly-glycine protein that co-localizes with p62 in intranuclear inclusions. Moreover, analyses suggest that the toxic RNA gain-of-function effects also contributed to the pathogenesis of this disease. Intriguingly, all four types of OPDM have been found to be associated with the CGG repeat expansions located in 5' UTRs. This finding suggests that a common pathogenic mechanism, driven by the CGG repeat expansion, might underlie all cases of OPDM.

Keywords: CGG repeat expansion; RILPL1; co-regulation; intranuclear inclusion; long-read whole-genome sequencing; oculopharyngodistal myopathy; polyG disease.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

5' Untranslated Regions
Adaptor Proteins, Signal Transducing
Humans
Intranuclear Inclusion Bodies / genetics
Muscular Dystrophies* / genetics
Trinucleotide Repeat Expansion* / genetics

Substances

5' Untranslated Regions
Adaptor Proteins, Signal Transducing
RILPL1 protein, human

Supplementary concepts

Oculopharyngodistal Myopathy