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
N1 - Funding Information:
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.).
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
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.
UR - http://www.scopus.com/inward/record.url?scp=85143902946&partnerID=8YFLogxK
U2 - 10.1007/s00401-022-02530-4
DO - 10.1007/s00401-022-02530-4
M3 - Article
C2 - 36512060
AN - SCOPUS:85143902946
SN - 0001-6322
VL - 145
SP - 235
EP - 255
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 2
ER -