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Vacuolar myopathy caused by CASQ1 p.Asp244His: pathogenic evidence from two unrelated Chinese families

Journal of Human Genetics (2026)Cite this article

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Abstract

Calsequestrin-1 (CASQ1)-related myopathy is a rare skeletal muscle disorder caused by mutations in CASQ1 gene, which encodes a major calcium-buffering protein of the sarcoplasmic reticulum (SR). It is characterized histopathologically by tubular aggregates or optically empty vacuoles, predominantly affecting type II muscle fibers. In this study, we report two unrelated Chinese patients presenting with late-onset, slowly progressive muscle weakness, fatigue, and myalgia. Both had mildly to moderately elevated serum creatine kinase levels. Muscle biopsies revealed typical optically empty vacuoles primarily in type II fibers. Whole-exome sequencing identified an identical heterozygous CASQ1 variant, c.730G > C (p.Asp244His), located at a highly conserved residue. In vitro expression of the mutant CASQ1 in HeLa cells confirmed its aggregation tendency, suggesting impaired protein folding or calcium handling. Immunofluorescence revealed abnormal aggregation of CASQ1 protein around the edge of vacuoles, co-localized with SQSTM1/p62, and the endoplasmic reticulum (ER) stress marker PERK. Our findings support the pathogenic role of the p.Asp244His variant and provide further insights into CASQ1-related myopathy in Asian populations.

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Funding

WHZ was supported by the National Key R&D Program of China (2024YFC3406700, 2024YFC3406705) and the Clinical Research Project Supported by Huashan Hospital, Fudan University (YN-013).

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Authors and Affiliations

  1. Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China

    Xingyu Xia, Kexin Jiao, Nachuan Cheng, Bochen Zhu, Meining Diao, Chongbo Zhao & Wenhua Zhu

  2. Huashan Rare Disease Center, Shanghai Medical College, Huashan Hospital, Fudan University, Shanghai, China

    Xingyu Xia, Kexin Jiao, Nachuan Cheng, Bochen Zhu, Meining Diao, Mingshi Gao, Chongbo Zhao & Wenhua Zhu

  3. National Center for Neurological Disorders (NCND), Shanghai, China

    Xingyu Xia, Kexin Jiao, Nachuan Cheng, Bochen Zhu, Meining Diao, Mingshi Gao, Chongbo Zhao & Wenhua Zhu

  4. Folkhälsan Research Center, Helsinki, Finland

    Milla Laarne

  5. Department of Medical Genetics, Medicum, University of Helsinki, Helsinki, Finland

    Milla Laarne

  6. Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China

    Tonglin Pan

  7. Department of Pathology, Huashan Hospital, Fudan University, Shanghai, China

    Mingshi Gao

  8. Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China

    Ying Liu

  9. Department of Neurology, Hebei Medical University Third Hospital, Hebei, China

    Zhe Zhao

Authors
  1. Xingyu Xia
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  2. Milla Laarne
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  3. Tonglin Pan
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  4. Kexin Jiao
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  5. Nachuan Cheng
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  6. Bochen Zhu
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  7. Meining Diao
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  9. Ying Liu
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  10. Chongbo Zhao
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  11. Zhe Zhao
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  12. Wenhua Zhu
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Contributions

XYX contributed to the draft of the manuscript and data analysis. ML contributed to the cellular experiments and draft reviewing. TLP, KXJ, NCC, MSG, BCZ, MND, and DYY contributed to the acquisition and analysis of data. CBZ, YL, ZZ, and WHZ contributed to the design of the study and draft reviewing.

Corresponding authors

Correspondence to Zhe Zhao or Wenhua Zhu.

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The authors declare no competing interests.

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This study was approved by the Ethics Committee of Huashan Hospital, Fudan University, and the patient gave consent.

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Xia, X., Laarne, M., Pan, T. et al. Vacuolar myopathy caused by CASQ1 p.Asp244His: pathogenic evidence from two unrelated Chinese families. J Hum Genet (2026). https://doi.org/10.1038/s10038-026-01461-2

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