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

Autor: Weihl CC; Department of Neurology, Washington University School of Medicine, Saint Louis, USA. weihlc@wustl.edu., Töpf A; John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK., Bengoechea R; Department of Neurology, Washington University School of Medicine, Saint Louis, USA., Duff J; John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK., Charlton R; Muscle Immunoanalysis Unit, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK., Garcia SK; ALS and Neuromuscular Unit, Department of Neurology, Hospital Universitario de Basurto, Bilbao, Vizcaya, Spain., Domínguez-González C; Neuromuscular Unit, Department of Neurology, imas12 Research Institute, Hospital 12 de Octubre, Madrid, Spain., Alsaman A; Pediatric Neurology Department, National Neuroscience Institute, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia., Hernández-Laín A; Neuropathology Unit, Hospital 12 de Octubre Research Institute (imas12), Madrid, Spain., Franco LV; ALS and Neuromuscular Unit, Department of Neurology, Hospital Universitario de Basurto, Bilbao, Vizcaya, Spain., Sanchez MEP; ALS and Neuromuscular Unit, Department of Pneumology, Hospital Universitario de Basurto, Bilbao, Vizcaya, Spain., Beecroft SJ; Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, WA, Australia., Goullee H; Pawsey Supercomputing Research Centre, Commonwealth Scientific and Industrial Research Organisation, Kensington, WA, Australia., Daw J; Department of Neurology, Washington University School of Medicine, Saint Louis, USA., Bhadra A; Department of Cell Biology and Physiology, Washington University School of Medicine, Saint Louis, USA., True H; Department of Cell Biology and Physiology, Washington University School of Medicine, Saint Louis, USA., Inoue M; Department of Neurology, Washington University School of Medicine, Saint Louis, USA., Findlay AR; Department of Neurology, Washington University School of Medicine, Saint Louis, USA., Laing N; Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, WA, Australia., Olivé M; Neuromuscular Unit, Department of Neurology, Hospital de La Santa Creu I San Pau, Barcelona, Spain.; Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Valencia, Spain., Ravenscroft G; Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, WA, Australia., Straub V; John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
Jazyk: angličtina
Zdroj: Acta neuropathologica [Acta Neuropathol] 2023 Jan; Vol. 145 (1), pp. 127-143. Date of Electronic Publication: 2022 Oct 20.
DOI: 10.1007/s00401-022-02510-8
Abstrakt: 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.
(© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Databáze: MEDLINE
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