Altered myogenesis and premature senescence underlie human TRIM32-related myopathy

TRIM32 is a E3 ubiquitin -ligase containing RING, B-box, coiled-coil and six C-terminal NHL domains. Mutations involving NHL and coiled-coil domains result in a pure myopathy (LGMD2H/STM) while the only described mutation in the B-box domain is associated with a multisystemic disorder without myopat...

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Autores: Servián Morilla, E., Cabrera-Serrano, Macarena, Rivas Infante, Eloy, Carvajal, A., Lamont, P. J., Pelayo-Negro, Ana L., Ravenscroft, Gianina, Junckerstorff, R., Dyke, J. M., Fletcher, S., Adams, A. M., Mavillard, Fabiola, Fernández-García, M. A., Nieto-González, J., Laing, Nigel G., Paradas, Carmen
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2019
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/202186
Acceso en línea:http://hdl.handle.net/10261/202186
Access Level:acceso abierto
Palabra clave:Muscle dystrophy
TRIM32
E3 ubiquitin -ligase
Proliferation/differentiation
Autophagy
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spelling Altered myogenesis and premature senescence underlie human TRIM32-related myopathyServián Morilla, E.Cabrera-Serrano, MacarenaRivas Infante, EloyCarvajal, A.Lamont, P. J.Pelayo-Negro, Ana L.Ravenscroft, GianinaJunckerstorff, R.Dyke, J. M.Fletcher, S.Adams, A. M.Mavillard, FabiolaFernández-García, M. A.Nieto-González, J.Laing, Nigel G.Paradas, CarmenMuscle dystrophyTRIM32E3 ubiquitin -ligaseProliferation/differentiationAutophagyTRIM32 is a E3 ubiquitin -ligase containing RING, B-box, coiled-coil and six C-terminal NHL domains. Mutations involving NHL and coiled-coil domains result in a pure myopathy (LGMD2H/STM) while the only described mutation in the B-box domain is associated with a multisystemic disorder without myopathy (Bardet-Biedl syndrome type11), suggesting that these domains are involved in distinct processes. Knock-out (T32KO) and knock-in mice carrying the c.1465G > A (p.D489N) involving the NHL domain (T32KI) show alterations in muscle regrowth after atrophy and satellite cells senescence. Here, we present phenotypical description and functional characterization of mutations in the RING, coiled-coil and NHL domains of TRIM32 causing a muscle dystrophy. Reduced levels of TRIM32 protein was observed in all patient muscle studied, regardless of the type of mutation (missense, single amino acid deletion, and frameshift) or the mutated domain. The affected patients presented with variable phenotypes but predominantly proximal weakness. Two patients had symptoms of both muscular dystrophy and Bardet-Biedl syndrome. The muscle magnetic resonance imaging (MRI) pattern is highly variable among patients and families. Primary myoblast culture from these patients demonstrated common findings consistent with reduced proliferation and differentiation, diminished satellite cell pool, accelerated senescence of muscle, and signs of autophagy activation.Supported in part by grants from the Health Institute Carlos III and FEDER a way to achieve Europe (PI16–01843 to CP, JR15/00042 to MC-S), the Fundación Progreso y Salud, Junta de Andalucía (PI-0085-2016 to JLN-G), and Australian National Health and Medical Research Council (NHMRC) Fellowships (APP1122952 and APP1117510 to GR and NGL).Peer reviewedSpringer NatureInstituto de Salud Carlos IIIEuropean CommissionJunta de AndalucíaNational Health and Medical Research Council (Australia)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202020202019info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/202186reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttps://doi.org/10.1186/s40478-019-0683-9Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2021862026-05-22T06:33:51Z
dc.title.none.fl_str_mv Altered myogenesis and premature senescence underlie human TRIM32-related myopathy
title Altered myogenesis and premature senescence underlie human TRIM32-related myopathy
spellingShingle Altered myogenesis and premature senescence underlie human TRIM32-related myopathy
Servián Morilla, E.
Muscle dystrophy
TRIM32
E3 ubiquitin -ligase
Proliferation/differentiation
Autophagy
title_short Altered myogenesis and premature senescence underlie human TRIM32-related myopathy
title_full Altered myogenesis and premature senescence underlie human TRIM32-related myopathy
title_fullStr Altered myogenesis and premature senescence underlie human TRIM32-related myopathy
title_full_unstemmed Altered myogenesis and premature senescence underlie human TRIM32-related myopathy
title_sort Altered myogenesis and premature senescence underlie human TRIM32-related myopathy
dc.creator.none.fl_str_mv Servián Morilla, E.
Cabrera-Serrano, Macarena
Rivas Infante, Eloy
Carvajal, A.
Lamont, P. J.
Pelayo-Negro, Ana L.
Ravenscroft, Gianina
Junckerstorff, R.
Dyke, J. M.
Fletcher, S.
Adams, A. M.
Mavillard, Fabiola
Fernández-García, M. A.
Nieto-González, J.
Laing, Nigel G.
Paradas, Carmen
author Servián Morilla, E.
author_facet Servián Morilla, E.
Cabrera-Serrano, Macarena
Rivas Infante, Eloy
Carvajal, A.
Lamont, P. J.
Pelayo-Negro, Ana L.
Ravenscroft, Gianina
Junckerstorff, R.
Dyke, J. M.
Fletcher, S.
Adams, A. M.
Mavillard, Fabiola
Fernández-García, M. A.
Nieto-González, J.
Laing, Nigel G.
Paradas, Carmen
author_role author
author2 Cabrera-Serrano, Macarena
Rivas Infante, Eloy
Carvajal, A.
Lamont, P. J.
Pelayo-Negro, Ana L.
Ravenscroft, Gianina
Junckerstorff, R.
Dyke, J. M.
Fletcher, S.
Adams, A. M.
Mavillard, Fabiola
Fernández-García, M. A.
Nieto-González, J.
Laing, Nigel G.
Paradas, Carmen
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Instituto de Salud Carlos III
European Commission
Junta de Andalucía
National Health and Medical Research Council (Australia)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Muscle dystrophy
TRIM32
E3 ubiquitin -ligase
Proliferation/differentiation
Autophagy
topic Muscle dystrophy
TRIM32
E3 ubiquitin -ligase
Proliferation/differentiation
Autophagy
description TRIM32 is a E3 ubiquitin -ligase containing RING, B-box, coiled-coil and six C-terminal NHL domains. Mutations involving NHL and coiled-coil domains result in a pure myopathy (LGMD2H/STM) while the only described mutation in the B-box domain is associated with a multisystemic disorder without myopathy (Bardet-Biedl syndrome type11), suggesting that these domains are involved in distinct processes. Knock-out (T32KO) and knock-in mice carrying the c.1465G > A (p.D489N) involving the NHL domain (T32KI) show alterations in muscle regrowth after atrophy and satellite cells senescence. Here, we present phenotypical description and functional characterization of mutations in the RING, coiled-coil and NHL domains of TRIM32 causing a muscle dystrophy. Reduced levels of TRIM32 protein was observed in all patient muscle studied, regardless of the type of mutation (missense, single amino acid deletion, and frameshift) or the mutated domain. The affected patients presented with variable phenotypes but predominantly proximal weakness. Two patients had symptoms of both muscular dystrophy and Bardet-Biedl syndrome. The muscle magnetic resonance imaging (MRI) pattern is highly variable among patients and families. Primary myoblast culture from these patients demonstrated common findings consistent with reduced proliferation and differentiation, diminished satellite cell pool, accelerated senescence of muscle, and signs of autophagy activation.
publishDate 2019
dc.date.none.fl_str_mv 2019
2020
2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/202186
url http://hdl.handle.net/10261/202186
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv https://doi.org/10.1186/s40478-019-0683-9
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Springer Nature
publisher.none.fl_str_mv Springer Nature
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.811543

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