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

Michio Inoue; Satoru Noguchi; Yukiko U. Inoue; Aritoshi Iida; Megumu Ogawa; Rocio Bengoechea; Sara K. Pittman; Shinichiro Hayashi; Kazuki Watanabe; Yasushi Hosoi; Terunori Sano; Masaki Takao; Yasushi Oya; Yuji Takahashi; Hiroaki Miyajima; Conrad C. Weihl; Takayoshi Inoue; Ichizo Nishino

doi:10.1007/s00401-022-02530-4

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

Michio Inoue, Satoru Noguchi, Yukiko U. Inoue, Aritoshi Iida, Megumu Ogawa, Rocio Bengoechea, Sara K. Pittman, Shinichiro Hayashi, Kazuki Watanabe, Yasushi Hosoi, Terunori Sano, Masaki Takao, Yasushi Oya, Yuji Takahashi, Hiroaki Miyajima, Conrad C. Weihl, Takayoshi Inoue, Ichizo Nishino

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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.

Original language	English
Pages (from-to)	235-255
Number of pages	21
Journal	Acta Neuropathologica
Volume	145
Issue number	2
DOIs	https://doi.org/10.1007/s00401-022-02530-4
State	Published - Feb 2023

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Inoue, M., Noguchi, S., Inoue, Y. U., Iida, A., Ogawa, M., Bengoechea, R., Pittman, S. K., Hayashi, S., Watanabe, K., Hosoi, Y., Sano, T., Takao, M., Oya, Y., Takahashi, Y., Miyajima, H., Weihl, C. C., Inoue, T., & Nishino, I. (2023). Distinctive chaperonopathy in skeletal muscle associated with the dominant variant in DNAJB4. Acta Neuropathologica, 145(2), 235-255. https://doi.org/10.1007/s00401-022-02530-4

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title = "Distinctive chaperonopathy in skeletal muscle associated with the dominant variant in DNAJB4",

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.",

author = "Michio Inoue and Satoru Noguchi and Inoue, {Yukiko U.} and Aritoshi Iida and Megumu Ogawa and Rocio Bengoechea and Pittman, {Sara K.} and Shinichiro Hayashi and Kazuki Watanabe and Yasushi Hosoi and Terunori Sano and Masaki Takao and Yasushi Oya and Yuji Takahashi and Hiroaki Miyajima and Weihl, {Conrad C.} and Takayoshi Inoue and Ichizo Nishino",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.",

year = "2023",

month = feb,

doi = "10.1007/s00401-022-02530-4",

language = "English",

volume = "145",

pages = "235--255",

journal = "Acta Neuropathologica",

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Inoue, M, Noguchi, S, Inoue, YU, Iida, A, Ogawa, M, Bengoechea, R, Pittman, SK, Hayashi, S, Watanabe, K, Hosoi, Y, Sano, T, Takao, M, Oya, Y, Takahashi, Y, Miyajima, H, Weihl, CC, Inoue, T & Nishino, I 2023, 'Distinctive chaperonopathy in skeletal muscle associated with the dominant variant in DNAJB4', Acta Neuropathologica, vol. 145, no. 2, pp. 235-255. https://doi.org/10.1007/s00401-022-02530-4

TY - JOUR

T1 - Distinctive chaperonopathy in skeletal muscle associated with the dominant variant in DNAJB4

AU - Inoue, Michio

AU - Noguchi, Satoru

AU - Inoue, Yukiko U.

AU - Iida, Aritoshi

AU - Ogawa, Megumu

AU - Bengoechea, Rocio

AU - Pittman, Sara K.

AU - Hayashi, Shinichiro

AU - Watanabe, Kazuki

AU - Hosoi, Yasushi

AU - Sano, Terunori

AU - Takao, Masaki

AU - Oya, Yasushi

AU - Takahashi, Yuji

AU - Miyajima, Hiroaki

AU - Weihl, Conrad C.

AU - Inoue, Takayoshi

AU - Nishino, Ichizo

PY - 2023/2

Y1 - 2023/2

N2 - 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.

AB - 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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EP - 255

JO - Acta Neuropathologica

JF - Acta Neuropathologica

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ER -

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

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