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dc.contributor.authorGómez-Domínguez, Déborah 
dc.contributor.authorEpifano, Carolina 
dc.contributor.authorde Miguel, Fernando 
dc.contributor.authorCastaño, Albert García
dc.contributor.authorVilaplana-Martí, Borja 
dc.contributor.authorMartín, Alberto 
dc.contributor.authorAmarilla-Quintana, Sandra
dc.contributor.authorBertrand, Anne T
dc.contributor.authorBonne, Gisèle
dc.contributor.authorRamón-Azcón, Javier
dc.contributor.authorRodriguez-Milla, Miguel A 
dc.contributor.authorPérez de Castro, Ignacio 
dc.date.accessioned2020-08-06T17:48:07Z
dc.date.available2020-08-06T17:48:07Z
dc.date.issued2020
dc.identifier.citationCells . 2020 May 21;9(5):1286.es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/10852
dc.description.abstractLaminopathies are causally associated with mutations on the Lamin A/C gene (LMNA). To date, more than 400 mutations in LMNA have been reported in patients. These mutations are widely distributed throughout the entire gene and are associated with a wide range of phenotypes. Unfortunately, little is known about the mechanisms underlying the effect of the majority of these mutations. This is the case of more than 40 mutations that are located at exon 4. Using CRISPR/Cas9 technology, we generated a collection of Lmna exon 4 mutants in mouse C2C12 myoblasts. These cell models included different types of exon 4 deletions and the presence of R249W mutation, one of the human variants associated with a severe type of laminopathy, LMNA-associated congenital muscular dystrophy (L-CMD). We characterized these clones by measuring their nuclear circularity, myogenic differentiation capacity in 2D and 3D conditions, DNA damage, and levels of p-ERK and p-AKT (phosphorylated Mitogen-Activated Protein Kinase 1/3 and AKT serine/threonine kinase 1). Our results indicated that Lmna exon 4 mutants showed abnormal nuclear morphology. In addition, levels and/or subcellular localization of different members of the lamin and LINC (LInker of Nucleoskeleton and Cytoskeleton) complex were altered in all these mutants. Whereas no significant differences were observed for ERK and AKT activities, the accumulation of DNA damage was associated to the Lmna p.R249W mutant myoblasts. Finally, significant myogenic differentiation defects were detected in the Lmna exon 4 mutants. These results have key implications in the development of future therapeutic strategies for the treatment of laminopathies.es_ES
dc.description.sponsorshipThis research was funded by Ministerio de Ciencia e Innovación (Acción estratégica en Salud intramural PI16III/00017-TPY1348/16) and by Fundación Andrés Marcio, niños contra la laminopatía (TPY-259/19). F.M. was funded by a Miguel Servet II contract from Instituto de Salud Carlos III (ISCIII).es_ES
dc.language.isoenges_ES
dc.publisherMDPIes_ES
dc.relation.isversionofPublisher's versiones_ES
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subject.meshCRISPRes_ES
dc.subject.meshLMNAes_ES
dc.subject.meshlaminopathyes_ES
dc.subject.meshNuclear Envelope es_ES
dc.titleConsequences of Lmna Exon 4 Mutations in Myoblast Functiones_ES
dc.typeArtículoes_ES
dc.rights.licenseAtribución 4.0 Internacional*
dc.identifier.pubmedID32455813es_ES
dc.format.volume9es_ES
dc.format.number5es_ES
dc.format.page1286es_ES
dc.identifier.doi10.3390/cells9051286es_ES
dc.contributor.funderMinisterio de Ciencia e Innovación (España)es_ES
dc.description.peerreviewedes_ES
dc.identifier.e-issn2073-4409es_ES
dc.relation.publisherversionhttps://doi.org/10.3390/cells9051286es_ES
dc.identifier.journalCellses_ES
dc.repisalud.centroISCIII::Instituto de Investigación de Enfermedades Rarases_ES
dc.repisalud.institucionISCIIIes_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/AESi-PI16III/00017-TPY1348/16/es_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/TPY-259/19es_ES
dc.rights.accessRightsinfo:eu-repo/semantics/openAccesses_ES


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Atribución 4.0 Internacional
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