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

• Published in: Acta neuropathologica Vol. 145; no. 2; pp. 235 - 255
• Main Authors: Inoue, Michio, Noguchi, Satoru, Inoue, Yukiko U., Iida, Aritoshi, Ogawa, Megumu, Bengoechea, Rocio, Pittman, Sara K., Hayashi, Shinichiro, Watanabe, Kazuki, Hosoi, Yasushi, Sano, Terunori, Takao, Masaki, Oya, Yasushi, Takahashi, Yuji, Miyajima, Hiroaki, Weihl, Conrad C., Inoue, Takayoshi, Nishino, Ichizo
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.02.2023; Springer Nature B.V
• Subjects: Animals; Biotechnology; CRISPR; Degeneration; Desmin; Disease; Distal Myopathies - pathology; Genomes; Heat shock proteins; HSP40 Heat-Shock Proteins - genetics; HSP40 Heat-Shock Proteins - metabolism; Hsp70 protein; Inclusion bodies; Medicine; Medicine & Public Health; Mice; Mice, Knockout; Molecular Chaperones - genetics; Muscle Weakness - pathology; Muscle, Skeletal - pathology; Musculoskeletal system; Mutation; Myopathy; Neurology; Neuromuscular diseases; Neurosciences; Original Paper; Pathology; Proteins; Psychiatry; Skeletal muscle; Soleus muscle
• ISSN: 0001-6322; 1432-0533
• DOI: 10.1007/s00401-022-02530-4

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.