TY - JOUR
T1 - Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure
AU - Weihl, Conrad C.
AU - Töpf, Ana
AU - Bengoechea, Rocio
AU - Duff, Jennifer
AU - Charlton, Richard
AU - Garcia, Solange Kapetanovic
AU - Domínguez-González, Cristina
AU - Alsaman, Abdulaziz
AU - Hernández-Laín, Aurelio
AU - Franco, Luis Varona
AU - Sanchez, Monica Elizabeth Ponce
AU - Beecroft, Sarah J.
AU - Goullee, Hayley
AU - Daw, Jil
AU - Bhadra, Ankan
AU - True, Heather
AU - Inoue, Michio
AU - Findlay, Andrew R.
AU - Laing, Nigel
AU - Olivé, Montse
AU - Ravenscroft, Gianina
AU - Straub, Volker
N1 - Funding Information:
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.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2023/1
Y1 - 2023/1
N2 - 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.
AB - 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.
KW - Chaperone
KW - Congenital myopathy
KW - Myofibrillar myopathy
KW - Myopathy
KW - Protein aggregation
UR - http://www.scopus.com/inward/record.url?scp=85140223207&partnerID=8YFLogxK
U2 - 10.1007/s00401-022-02510-8
DO - 10.1007/s00401-022-02510-8
M3 - Article
C2 - 36264506
AN - SCOPUS:85140223207
SN - 0001-6322
VL - 145
SP - 127
EP - 143
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 1
ER -