Lamin A/C dysregulation contributes to cardiac pathology in a mouse model of severe spinal muscular atrophy"
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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.
Šoltić , D , Shorrock , H K , Allardyce , H , Wilson , E L , Holt , I , Synowsky , S A , Shirran , S L , Parson , S , Gillingwater , T & Fuller , H 2019 , ' Lamin A/C dysregulation contributes to cardiac pathology in a mouse model of severe spinal muscular atrophy" ' , Human Molecular Genetics , vol. Advance Article . https://doi.org/10.1093/hmg/ddz195
Human Molecular Genetics
Copyright © The Author(s) 2019. Published by Oxford University Press. All rights reserved. This work has been made available online in accordance with publisher policies or with permission. Permission for further reuse of this content should be sought from the publisher or the rights holder. This is the author created accepted manuscript following peer review and may differ slightly from the final published version. The final published version of this work is available at https://doi.org/10.1093/hmg/ddz195