CGG repeat expansion in <i>LOC642361/NUTM2B-AS1</i> typically presents as oculopharyngodistal myopathy

Yan Shi; Chunyan Cao; Yiheng Zeng; Yuanliang Ding; Long Chen; Fuze Zheng; Xuejiao Chen; Fanggui Zhou; Xiefeng Yang; Jinjing Li; Liuqing Xu; Guorong Xu; Minting Lin; Hiroyuki Ishiura; Shoji Tsuji; Ning Wang; Zhiqiang Wang; Wan-Jin Chen; Kang Yang

doi:10.1016/j.jgg.2023.12.009

Volume 51 Issue 2

Feb. 2024

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Article Navigation > Journal of Genetics and Genomics > 2024 > 51(2): 184-196

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CGG repeat expansion in LOC642361/NUTM2B-AS1 typically presents as oculopharyngodistal myopathy

doi: 10.1016/j.jgg.2023.12.009

a. Department of Neurology and Institute of Neurology of First Affiliated Hospital, Institute of Neuroscience, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian 350005, China;
b. Department of Neurology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian 350212, China;
c. The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan 471000, China;
d. Department of Neurology, Zhangzhou Municipal Hospital of Fujian Province and Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, Fujian 363000, China;
e. Department of Neurology, Jian'ou Municipal Hospital of Fujian Province, Jian'ou, Fujian 353100, China;
f. Department of Radiology, First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, China;
g. Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan;
h. Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan;
i. Institute of Medical Genomics, International University of Health and Welfare, Chiba 286-0048, Japan

Funds:

from the Major Scientific Research Program for Middle-aged and Young Scientists of Fujian Province 2021ZQNZD003 (to W.-J.C.)

from the Joint Funds for the Innovation of Science and Technology of Fujian Province 2021Y9011 (to W.-J.C.), and 2020Y9016 (to Z.Q.W.)

from the National Key Research and Development Program of China grants 2022YFC2703900 (to W.-J.C.) and 2022YFC2703904 (to W.-J.C.)

and from Fujian Medical University Affiliated First Hospital Talent Recruitment Research Initiation grants YJRC4185 (to K.Y.)

from the Fujian Provincial Health Technology projects grants 2022ZD01002 (to W.-J.C.)

and from the Key Clinical Specialty Discipline Construction Program of Fujian (to N.W.).

from the Local Science and Technology Development Project guided by the central government grants 2020L3010 (to W.-J.C.)

We thank the patients for granting permission to publish this information. We thank the patients and their families for their help and participation in this study. We thank Dr. Linying Zhou and Dr. Yan Hu (Electron Microscopy Lab of Public Technology Service Center, Fujian Medical University) for kindly providing technical assistance with electron microscopy. We also thank Depeng Wang (Grandomics Biosciences, Beijing, China), Jingjing Li (Grandomics Biosciences, Beijing, China), Qian Yu (Berry Genomics Corporation, Beijing, China), and Ji Zhang (Berry Genomics Corporation, Beijing, China) for their technical assistance. This study has been supported by grants from the National Natural Science Foundation of China, including 82025012 (to W.-J.C.), U1905210 (to W.-J.C.), 82230039 (to N.W.), U2005201 (to N.W.), 81974193 (to Z.Q.W.), and 82001217 (to J.J.L)

Received Date: 2023-09-26
Accepted Date: 2023-12-25
Rev Recd Date: 2023-12-25

Available Online: 2025-06-07

Publish Date: 2023-12-29

Abstract

Abstract

CGG repeat expansions in LOC642361/NUTM2B-AS1 have recently been identified as a cause of oculopharyngeal myopathy with leukoencephalopathy. However, since only three patients from a single family were reported, it remains unknown whether their clinicopathological features are typical for CGG repeat expansions in LOC642361/NUTM2B-AS1. Here, using repeat-primed-polymerase chain reaction and long-read sequencing, we identify 12 individuals from 3 unrelated families with CGG repeat expansions in LOC642361/NUTM2B-AS1, typically presenting with oculopharyngodistal myopathy. The CGG repeat expansions range from 161 to 669 repeat units. Most of the patients present with ptosis, restricted eye movements, dysphagia, dysarthria, and diffuse limb muscle weakness. Only one patient shows T2-weighted hyperintensity in the cerebellar white matter surrounding the deep cerebellar nuclei on brain magnetic resonance imaging. Muscle biopsies from three patients show a myopathic pattern and rimmed vacuoles. Analyses of muscle biopsies suggest that CGG repeat expansions in LOC642361/NUTM2B-AS1 may deleteriously affect aggrephagic capacity, suggesting that RNA toxicity and mitochondrial dysfunction may contribute to pathogenesis. Our study thus expands the phenotypic spectrum for the CGG repeat expansion of LOC642361/NUTM2B-AS1 and indicates that this genetic variant typically manifests as oculopharyngodistal myopathy with chronic myopathic changes with rimmed vacuoles and filamentous intranuclear inclusions in muscle fibers.
- Oculopharyngeal myopathy with leukoencephalopathy,
- Oculopharyngodistal myopathy,
- CGG repeat expansion,
- Rimmed vacuoles

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References(55)

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