Molecular chaperones play a pivotal role in regulating protein homeostasis, and their function includes the capacity to regulate protein folding, aggregation, and degradation. DNAJ proteins belong to the HSP40 co-chaperone family and are known to recruit client proteins (substrates) to Hsp70 chaperone machinery. DNAJB4, a member of DNAJ co-chaperones, is highly expressed in striated muscles. No human disease related to DNAJB4 has been reported.
We identified 1) one family with a dominantly inherited missense variant c.270 T>A (p.F90L) in DNAJB4, which is analogous to the F93L mutation in DNAJB6 associated with limb-girdle muscular dystrophy (LGMD) D1, and 2) three unrelated families carrying unreported homozygous stop gain (c.856A>T; p.K286*), or homozygous missense variants (c.74G>A; p.R25Q and c.785T>C; p.L262S) in DNAJB4. Patients with the dominant variant (1) showed adult-onset distal myopathy, while patients with the recessive variants (2) demonstrated axial rigidity and early respiratory failure.
DNAJB4 localized to the Z-disc in muscle and was absent from muscle and fibroblasts of patients with recessive mutations, consistent with a loss of function. This was distinct from the dominant variant, which was stable and enhanced the aggregation of TDP-43 post-heat shock in an HSP70-dependent manner.
To model the recessive and dominant DNAJB4 diseases, we generated two mouse lines, Dnajb4 knockout and F90L knock-in mice. Both mice showed muscle weakness and characteristic aggregate pathology with myofibrillar disorganization at 28 months. Notably, pathology was most prominent in the soleus muscle where p62 and ubiquitinated inclusions accumulated. This is consistent with RNAseq and immunoblotting data supporting that DNAJB4 is most highly expressed in mouse soleus muscle.
These studies define a novel DNAJB4-associated chaperonopathy. Dysfunction or loss of function mutations in DNAJB4 may lead to the accumulation of DNAJB4 client proteins resulting in muscle degeneration in selective muscle groups requiring high levels of DNAJB4.