Skip to main content
Log in

Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure

Acta Neuropathologica Aims and scope Submit manuscript

Cite this article


DNAJ/HSP40 co-chaperones are integral to the chaperone network, bind client proteins and recruit them to HSP70 for folding. We performed exome sequencing on patients with a presumed hereditary muscle disease and no genetic diagnosis. This identified four individuals from three unrelated families carrying an unreported homozygous stop gain (c.856A > T; p.Lys286Ter), or homozygous missense variants (c.74G > A; p.Arg25Gln and c.785 T > C; p.Leu262Ser) in DNAJB4. Affected patients presented with axial rigidity and early respiratory failure requiring ventilator support between the 1st and 4th decade of life. Selective involvement of the semitendinosus and biceps femoris muscles was seen on MRI scans of the thigh. On biopsy, muscle was myopathic with angular fibers, protein inclusions and occasional rimmed vacuoles. DNAJB4 normally localizes to the Z-disc and was absent from muscle and fibroblasts of affected patients supporting a loss of function. Functional studies confirmed that the p.Lys286Ter and p.Leu262Ser mutant proteins are rapidly degraded in cells. In contrast, the p.Arg25Gln mutant protein is stable but failed to complement for DNAJB function in yeast, disaggregate client proteins or protect from heat shock-induced cell death consistent with its loss of function. DNAJB4 knockout mice had muscle weakness and fiber atrophy with prominent diaphragm involvement and kyphosis. DNAJB4 knockout muscle and myotubes had myofibrillar disorganization and accumulated Z-disc proteins and protein chaperones. These data demonstrate a novel chaperonopathy associated with DNAJB4 causing a myopathy with early respiratory failure. DNAJB4 loss of function variants may lead to the accumulation of DNAJB4 client proteins resulting in muscle dysfunction and degeneration.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8


  1. Arndt V et al (2010) Chaperone-assisted selective autophagy is essential for muscle maintenance. Curr Biol 20:143–148.

    Article  CAS  Google Scholar 

  2. Bengoechea R et al (2020) Inhibition of DNAJ-HSP70 interaction improves strength in muscular dystrophy. J Clin Invest 130:4470–4485.

    Article  CAS  Google Scholar 

  3. Del Bigio MR et al (2011) Infantile muscular dystrophy in Canadian aboriginals is an alphaB-crystallinopathy. Ann Neurol 69:866–871.

    Article  CAS  Google Scholar 

  4. Blumen SC et al (2012) A rare recessive distal hereditary motor neuropathy with HSJ1 chaperone mutation. Ann Neurol 71:509–519.

    Article  CAS  Google Scholar 

  5. Dagvadorj A et al (2003) Respiratory insufficiency in desminopathy patients caused by introduction of proline residues in desmin c-terminal alpha-helical segment. Muscle Nerve 27:669–675.

    Article  CAS  Google Scholar 

  6. Donkervoort S et al (2020) Pathogenic variants in the myosin chaperone UNC-45B cause progressive myopathy with eccentric cores. Am J Hum Genet 107:1078–1095.

    Article  CAS  Google Scholar 

  7. Fischer D et al (2008) Distinct muscle imaging patterns in myofibrillar myopathies. Neurology 71:758–765.

    Article  CAS  Google Scholar 

  8. Gazda L et al (2013) The myosin chaperone UNC-45 is organized in tandem modules to support myofilament formation in C. elegans. Cell 152:183–195.

    Article  CAS  Google Scholar 

  9. Gonzaga-Jauregui C et al (2015) Exome sequence analysis suggests that genetic burden contributes to phenotypic variability and complex neuropathy. Cell Rep 12:1169–1183.

    Article  CAS  Google Scholar 

  10. Harms MB et al (2012) Exome sequencing reveals DNAJB6 mutations in dominantly-inherited myopathy. Ann Neurol 71:407–416.

    Article  CAS  Google Scholar 

  11. Hohfeld J et al (2021) Maintaining proteostasis under mechanical stress. EMBO Rep 22:e52507.

    Article  CAS  Google Scholar 

  12. Martin-Jimenez P et al (2022) Adult-onset nemaline myopathy due to a novel homozygous variant in the TNNT1 gene. Muscle Nerve.

    Article  Google Scholar 

  13. Meister-Broekema M et al (2018) Myopathy associated BAG3 mutations lead to protein aggregation by stalling Hsp70 networks. Nat Commun 9:5342.

    Article  CAS  Google Scholar 

  14. Naddaf E, Milone M (2017) Hereditary myopathies with early respiratory insufficiency in adults. Muscle Nerve 56:881–886.

    Article  Google Scholar 

  15. Palmio J et al (2019) Expanding the importance of HMERF titinopathy: new mutations and clinical aspects. J Neurol 266:680–690.

    Article  Google Scholar 

  16. Pullen MY, Weihl CC, True HL (2020) Client processing is altered by novel myopathy-causing mutations in the HSP40 J domain. PLoS ONE 15:e0234207.

    Article  CAS  Google Scholar 

  17. Ravenscroft G et al (2015) Mutations of GPR126 are responsible for severe arthrogryposis multiplex congenita. Am J Hum Genet 96:955–961.

    Article  CAS  Google Scholar 

  18. Sarparanta J et al (2012) Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy. Nat Genet 44(450–455):S451-452.

    Article  CAS  Google Scholar 

  19. Sarparanta J, Jonson PH, Kawan S, Udd B (2020) Neuromuscular diseases due to chaperone mutations: a review and some new results. Int J Mol Sci.

    Article  Google Scholar 

  20. Selcen D et al (2009) Mutation in BAG3 causes severe dominant childhood muscular dystrophy. Ann Neurol 65:83–89.

    Article  CAS  Google Scholar 

  21. Stein KC, Bengoechea R, Harms MB, Weihl CC, True HL (2014) Myopathy-causing mutations in an HSP40 chaperone disrupt processing of specific client conformers. J Biol Chem 289:21120–21130.

    Article  CAS  Google Scholar 

  22. Topf A et al (2020) Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness. Genet Med 22:1478–1488.

    Article  CAS  Google Scholar 

  23. Unger A et al (2017) Translocation of molecular chaperones to the titin springs is common in skeletal myopathy patients and affects sarcomere function. Acta Neuropathol Commun 5:72.

    Article  CAS  Google Scholar 

  24. Vicart P et al (1998) A missense mutation in the alphaB-crystallin chaperone gene causes a desmin-related myopathy. Nat Genet 20:92–95.

    Article  CAS  Google Scholar 

  25. Zhang R, Malinverni D, Cyr DM, Rios PL, Nillegoda NB (2022) J-domain protein chaperone circuits in proteostasis and disease. Trends Cell Biol.

    Article  Google Scholar 

Download references


The results reported here were generated using funding received from the Solve-RD project within the European Rare Disease Models & Mechanisms Network (RDMM-Europe). The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. MYO-SEQ was funded by Sanofi Genzyme, Ultragenyx, LGMD2I Research Fund, Samantha J. Brazzo Foundation, LGMD2D Foundation and Kurt + Peter Foundation, Muscular Dystrophy UK, and Coalition to Cure Calpain 3. Analysis was provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung, and Blood Institute grant UM1 HG008900, and in part by National Human Genome Research Institute grant R01 HG009141. CCW is funded by R01AR068797 and K24AR073317. This research was also supported by a grant from the Australian NHMRC (APP2002640). GR is supported by an Emerging Leader Fellowship from the NHMRC (APP2007769). MO is supported by a grant from the Spanish Ministry of Health, Fondos FEDER-ISCIII PI21/01621. CD, AHL and MO are members of the ERN EURO-NMD.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Conrad C. Weihl.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Weihl, C.C., Töpf, A., Bengoechea, R. et al. Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure. Acta Neuropathol 145, 127–143 (2023).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: