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dc.contributor.authorŠoltić, Darija
dc.contributor.authorShorrock, Hannah K.
dc.contributor.authorAllardyce, Hazel
dc.contributor.authorWilson, Emma L.
dc.contributor.authorHolt, Ian
dc.contributor.authorSynowsky, Silvia A.
dc.contributor.authorShirran, Sally L.
dc.contributor.authorParson, Simon H.
dc.contributor.authorGillingwater, Thomas H.
dc.contributor.authorFuller, Heidi R.
dc.date.accessioned2019-08-18T00:37:24Z
dc.date.available2019-08-18T00:37:24Z
dc.date.issued2019-08-09
dc.identifierdoi: 10.1093/hmg/ddz195
dc.identifier.citationHuman Molecular Genetics
dc.identifier.urihttp://hdl.handle.net/10034/622507
dc.descriptionFrom Crossref via Jisc Publications Router
dc.descriptionHistory: epub 2019-08-09, issued 2019-08-09
dc.descriptionArticle version: AM
dc.descriptionFunder: British Heart Foundation; FundRef: 10.13039/501100000274; Grant(s): PG/16/68/31991
dc.descriptionFunder: Wellcome Trust; FundRef: 10.13039/100010269; Grant(s): 094476/Z/10/Z
dc.descriptionFunder: SMA Trust; FundRef: 10.13039/100011708; Grant(s): UK SMA Research Consortium
dc.descriptionFunder: Keele University; FundRef: 10.13039/501100005044; Grant(s): ACORN funding
dc.descriptionFunder: the Euan MacDonald Centre for Motor Neurone Disease Research
dc.descriptionFunder: Newlife Charity; Grant(s): SG/15-16/1
dc.description.abstractAbstract Cardiac pathology is emerging as a prominent systemic feature of spinal muscular atrophy (SMA), but little is known about the underlying molecular pathways. Using quantitative proteomics analysis, we demonstrate widespread molecular defects in heart tissue from the Taiwanese mouse model of severe SMA. We identify increased levels of lamin A/C as a robust molecular phenotype in the heart of SMA mice, and show that lamin A/C dysregulation is also apparent in SMA patient fibroblast cells and other tissues from SMA mice. Lamin A/C expression was regulated in-vitro by knockdown of the E1 ubiquitination factor UBA1, a key downstream mediator of SMN-dependent disease pathways, converging on β-catenin signalling. Increased levels of lamin A are known to increase the rigidity of nuclei, inevitably disrupting contractile activity in cardiomyocytes. The increased lamin A/C levels in the hearts of SMA mice therefore provide a likely mechanism explaining morphological and functional cardiac defects, leading to blood pooling. Therapeutic strategies directed at lamin A/C may therefore offer a new approach to target cardiac pathology in SMA.
dc.publisherOxford University Press (OUP)
dc.rightsLicence for AM version of this article starting on 2019-08-09: https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model
dc.sourcepissn: 0964-6906
dc.sourceeissn: 1460-2083
dc.subjectGenetics(clinical)
dc.subjectGenetics
dc.subjectMolecular Biology
dc.subjectGeneral Medicine
dc.titleLamin A/C dysregulation contributes to cardiac pathology in a mouse model of severe spinal muscular atrophy
dc.typearticle
dc.date.updated2019-08-18T00:37:23Z


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