Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure
Por:
Weihl C.C., Topf, A, Bengoechea R., Duff J., Charlton R., Garcia S.K., Domínguez-González C., Alsaman A., Hernández-Laín A., Franco L.V., Sanchez, MEP, Beecroft S.J., Goullee H., Daw J., Bhadra A., True H., Inoue M., Findlay A.R., Laing N., Olivé M., Ravenscroft G., Straub V.
Publicada:
1 ene 2023
Ahead of Print:
1 oct 2022
Resumen:
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.
Filiaciones:
Weihl C.C.:
Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA
Topf, A:
Newcastle Univ, John Walton Muscular Dystrophy Res Ctr, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England
Newcastle Hosp NHS Fdn Trust, Newcastle Upon Tyne, Tyne & Wear, England
Bengoechea R.:
Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA
Duff J.:
Newcastle Univ, John Walton Muscular Dystrophy Res Ctr, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England
Newcastle Hosp NHS Fdn Trust, Newcastle Upon Tyne, Tyne & Wear, England
Charlton R.:
Newcastle Hosp NHS Fdn Trust, Muscle Immunoanal Unit, Newcastle Upon Tyne, Tyne & Wear, England
Garcia S.K.:
Hosp Univ Basurto, Dept Neurol, ALS & Neuromuscular Unit, Bilbao, Vizcaya, Spain
Domínguez-González C.:
Hosp 12 Octubre, Dept Neurol, Neuromuscular Unit, Imas12 Res Inst, Madrid, Spain
Alsaman A.:
King Saud Bin Abdulaziz Univ Hlth Sci, Natl Neurosci Inst, Pediat Neurol Dept, Riyadh, Saudi Arabia
Hernández-Laín A.:
Hosp 12 Octubre Res Inst Imas12, Neuropathol Unit, Madrid, Spain
Franco L.V.:
Hosp Univ Basurto, Dept Neurol, ALS & Neuromuscular Unit, Bilbao, Vizcaya, Spain
Sanchez, MEP:
Hosp Univ Basurto, Dept Pneumol, ALS & Neuromuscular Unit, Bilbao, Vizcaya, Spain
Beecroft S.J.:
Univ Western Australia, Ctr Med Res, Harry Perkins Inst Med Res, Nedlands, WA, Australia
Goullee H.:
CSIRO, Pawsey Supercomp Res Ctr, Kensington, WA, Australia
Daw J.:
Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA
Bhadra A.:
Washington Univ, Sch Med, Dept Cell Biol & Physiol, St Louis, MO 63110 USA
True H.:
Washington Univ, Sch Med, Dept Cell Biol & Physiol, St Louis, MO 63110 USA
Inoue M.:
Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA
Findlay A.R.:
Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA
Laing N.:
Univ Western Australia, Ctr Med Res, Harry Perkins Inst Med Res, Nedlands, WA, Australia
Olivé M.:
Hosp La Santa Creu & San Pau, Dept Neurol, Neuromuscular Unit, Barcelona, Spain
Biomed Res Inst St Pau IIB St Pau, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Raras CIBERER, Valencia, Spain
Ravenscroft G.:
Univ Western Australia, Ctr Med Res, Harry Perkins Inst Med Res, Nedlands, WA, Australia
Straub V.:
Newcastle Univ, John Walton Muscular Dystrophy Res Ctr, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England
Newcastle Hosp NHS Fdn Trust, Newcastle Upon Tyne, Tyne & Wear, England
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