Distinctive chaperonopathy in skeletal muscle associated with the dominant variant inDNAJB4

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 Dnajb4-F90L knock-in 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.

Multi-Faceted Roles of DNAJB Protein in Cancer Metastasis and Clinical Implications

“…DNAJB4 is implicated in skeletal muscle proteostasis [ 74 ] and Alzheimer’s disease [ 75 ]. In addition, accumulating studies have suggested that DNAJB4 is involved in various cancers as a tumor suppressor that could inhibit cancer cell proliferation, invasion, and metastasis.…”