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

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 car...

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Autores: 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.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Institución:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repositorio:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:oai:iibsantpau.fundanetsuite.com:p13854
Acceso en línea:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=13854
https://europepmc.org/article/MED/36264506
Access Level:acceso abierto
Palabra clave:Myopathy
Chaperone
Protein aggregation
Congenital myopathy
Myofibrillar myopathy
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spelling Loss of function variants in DNAJB4 cause a myopathy with early respiratory failureWeihl C.C.Topf, ABengoechea R.Duff J.Charlton R.Garcia S.K.Domínguez-González C.Alsaman A.Hernández-Laín A.Franco L.V.Sanchez, MEPBeecroft S.J.Goullee H.Daw J.Bhadra A.True H.Inoue M.Findlay A.R.Laing N.Olivé M.Ravenscroft G.Straub V.MyopathyChaperoneProtein aggregationCongenital myopathyMyofibrillar myopathyDNAJ/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.SPRINGER2023info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=13854https://europepmc.org/article/MED/36264506ACTA NEUROPATHOLOGICAISSN: 00016322ISSNe: 14320533reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pauinstname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)Inglésinfo:eu-repo/semantics/openAccessoai:iibsantpau.fundanetsuite.com:p138542026-06-14T12:41:47Z
dc.title.none.fl_str_mv Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure
title Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure
spellingShingle Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure
Weihl C.C.
Myopathy
Chaperone
Protein aggregation
Congenital myopathy
Myofibrillar myopathy
title_short Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure
title_full Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure
title_fullStr Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure
title_full_unstemmed Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure
title_sort Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure
dc.creator.none.fl_str_mv 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.
author Weihl C.C.
author_facet 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.
author_role author
author2 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.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Myopathy
Chaperone
Protein aggregation
Congenital myopathy
Myofibrillar myopathy
topic Myopathy
Chaperone
Protein aggregation
Congenital myopathy
Myofibrillar myopathy
description 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.
publishDate 2023
dc.date.none.fl_str_mv 2023
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=13854
https://europepmc.org/article/MED/36264506
url https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=13854
https://europepmc.org/article/MED/36264506
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv SPRINGER
publisher.none.fl_str_mv SPRINGER
dc.source.none.fl_str_mv ACTA NEUROPATHOLOGICA
ISSN: 00016322
ISSNe: 14320533
reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
instname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
instname_str Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
reponame_str r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
collection r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
repository.name.fl_str_mv
repository.mail.fl_str_mv
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