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Distinctive chaperonopathy in skeletal muscle associated with the dominant variant in DNAJB4

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Abstract

DnaJ homolog, subfamily B, member 4, a member of the heat shock protein 40 chaperones encoded by DNAJB4, is highly expressed in myofibers. We identified a heterozygous c.270 T > A (p.F90L) variant in DNAJB4 in a family with a dominantly inherited distal myopathy, in which affected members have specific features on muscle pathology represented by the presence of cytoplasmic inclusions and the accumulation of desmin, p62, HSP70, and DNAJB4 predominantly in type 1 fibers. Both Dnajb4F90L knockin and knockout mice developed muscle weakness and recapitulated the patient muscle pathology in the soleus muscle, where DNAJB4 has the highest expression. These data indicate that the identified variant is causative, resulting in defective chaperone function and selective muscle degeneration in specific muscle fibers. This study demonstrates the importance of DNAJB4 in skeletal muscle proteostasis by identifying the associated chaperonopathy.

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Acknowledgements

We thank the patients and their families for their cooperation. We also thank Hisayoshi Nakamura, Keiko Hiraki-Kamon, and Keiko Ishikawa for technical assistance. This study was supported by the Intramural Research Grant for Neurological and Psychiatric Disorders of the National Center of Neurology and Psychiatry under Grant Numbers 2-5 (S.H., I.N.), 2-6 (S.N.), 3-8 (M.T.), and 3-9 (S.N.); KAKENHI (19K17021) from the Japan Society for the Promotion of Science (M.I.); Japan Agency for Medical Research and Development under Grant Numbers 22ek0109490h0003 (A.I., S.H., S.N., I.N.); and NIH under Grant Numbers, NIH R01AR068797 (C.C.W.) and K24AR073317 (C.C.W.).

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  1. Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo, 187–8502, Japan

    Michio Inoue, Satoru Noguchi, Megumu Ogawa, Shinichiro Hayashi & Ichizo Nishino

  2. Medical Genome Center, National Center of Neurology and Psychiatry, Tokyo, Japan

    Michio Inoue, Satoru Noguchi, Aritoshi Iida, Shinichiro Hayashi & Ichizo Nishino

  3. Department of Neurology, Washington University School of Medicine, Saint Louis, USA

    Michio Inoue, Rocio Bengoechea, Sara K. Pittman & Conrad C. Weihl

  4. Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan

    Yukiko U. Inoue & Takayoshi Inoue

  5. First Department of Medicine/Department of Neurology, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Kazuki Watanabe, Yasushi Hosoi & Hiroaki Miyajima

  6. Department of Laboratory Medicine, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan

    Terunori Sano & Masaki Takao

  7. Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan

    Yasushi Oya & Yuji Takahashi

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Contributions

MI, SN, and IN designed and oversaw this study. MI, SN, YUI, AI, MO, RB, SKP, and TI performed the experiments. MI, SN, AI, and CCW analyzed the data. MI, KW, YH, TS, MT, YO, YT, and HM provided the samples and clinical data. MI, SN, and CCW wrote the manuscript. All the authors contributed to and approved the final manuscript.

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Correspondence to Satoru Noguchi.

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Inoue, M., Noguchi, S., Inoue, Y.U. et al. Distinctive chaperonopathy in skeletal muscle associated with the dominant variant in DNAJB4. Acta Neuropathol 145, 235–255 (2023). https://doi.org/10.1007/s00401-022-02530-4

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