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

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


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 languageEnglish
Pages (from-to)235-255
Number of pages21
JournalActa Neuropathologica
Issue number2
StatePublished - Feb 2023


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