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Lookup NU author(s): Professor Giorgio TascaORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2019, The Author(s).Nemaline myopathy (NM) is a skeletal muscle disorder caused by mutations in genes that are generally involved in muscle contraction, in particular those related to the structure and/or regulation of the thin filament. Many pathogenic aspects of this disease remain largely unclear. Here, we report novel pathological defects in skeletal muscle fibres of mouse models and patients with NM: irregular spacing and morphology of nuclei; disrupted nuclear envelope; altered chromatin arrangement; and disorganisation of the cortical cytoskeleton. Impairments in contractility are the primary cause of these nuclear defects. We also establish the role of microtubule organisation in determining nuclear morphology, a phenomenon which is likely to contribute to nuclear alterations in this disease. Our results overlap with findings in diseases caused directly by mutations in nuclear envelope or cytoskeletal proteins. Given the important role of nuclear shape and envelope in regulating gene expression, and the cytoskeleton in maintaining muscle fibre integrity, our findings are likely to explain some of the hallmarks of NM, including contractile filament disarray, altered mechanical properties and broad transcriptional alterations.
Author(s): Ross JA, Levy Y, Ripolone M, Kolb JS, Turmaine M, Holt M, Lindqvist J, Claeys KG, Weis J, Monforte M, Tasca G, Moggio M, Figeac N, Zammit PS, Jungbluth H, Fiorillo C, Vissing J, Witting N, Granzier H, Zanoteli E, Hardeman EC, Wallgren-Pettersson C, Ochala J
Publication type: Article
Publication status: Published
Journal: Acta Neuropathologica
Year: 2019
Volume: 138
Issue: 3
Pages: 477-495
Print publication date: 01/09/2019
Online publication date: 19/06/2019
Acceptance date: 05/06/2019
Date deposited: 01/03/2023
ISSN (print): 0001-6322
ISSN (electronic): 1432-0533
Publisher: Springer Verlag
URL: https://doi.org/10.1007/s00401-019-02034-8
DOI: 10.1007/s00401-019-02034-8
PubMed id: 31218456
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