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Open Access | 10.1172/JCI194757
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Published May 15, 2025 - More info
Dominant mutations in the HSP70 cochaperone DNAJB6 cause a late-onset muscle disease termed limb-girdle muscular dystrophy type D1 (LGMDD1), which is characterized by protein aggregation and vacuolar myopathology. Disease mutations reside within the G/F domain of DNAJB6, but the molecular mechanisms underlying dysfunction are not well understood. Using yeast, cell culture, and mouse models of LGMDD1, we found that the toxicity associated with disease-associated DNAJB6 required its interaction with HSP70 and that abrogating this interaction genetically or with small molecules was protective. In skeletal muscle, DNAJB6 localizes to the Z-disc with HSP70. Whereas HSP70 normally diffused rapidly between the Z-disc and sarcoplasm, the rate of diffusion of HSP70 in LGMDD1 mouse muscle was diminished, probably because it had an unusual affinity for the Z-disc and mutant DNAJB6. Treating LGMDD1 mice with a small-molecule inhibitor of the DNAJ-HSP70 complex remobilized HSP70, improved strength, and corrected myopathology. These data support a model in which LGMDD1 mutations in DNAJB6 are a gain-of-function disease that is, counterintuitively, mediated via HSP70 binding. Thus, therapeutic approaches targeting HSP70-DNAJB6 may be effective in treating this inherited muscular dystrophy.
Rocio Bengoechea, Andrew R. Findlay, Ankan K. Bhadra, Hao Shao, Kevin C. Stein, Sara K. Pittman, Jil A.W. Daw, Jason E. Gestwicki, Heather L. True, Conrad C. Weihl
Original citation: J Clin Invest. 2020;130(8):4470–4485. https://doi.org/10.1172/JCI136167
Citation for this corrigendum: J Clin Invest. 2025;135(10):e194757. https://doi.org/10.1172/JCI194757
In Figure 2B of the original article, an incorrect image was included for the DNAJB6 WT sample, which was an inadvertent duplication and rotation of the image for the DNAJB6 F93L-H31Q sample. The corrected figure, based on the original source data, is provided below. The HTML and PDF versions of the paper have been updated.
The authors regret the error.
See the related article at Inhibition of DNAJ-HSP70 interaction improves strength in muscular dystrophy.