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Autor
Azad, Amar J 1 Bennett, Pauline 1 Broadway-Stringer, Sophie 1 Davies, Benjamin 1 Djinovic-Carugo, Kristina 1 Douglas, Gillian 1 Ehler, Elisabeth 1 Galatik, Frantisek 1 Gautel, Mathias 1 Gehmlich, Katja 1 Hooper, Charlotte 1 Jiang, He 1 Kalisch-Smith, Jacinta I 1 Reyat, Jasmeet S 1 Singer, Evie 1 Sparrow, Duncan B 1 Steeples, Violetta 1 Wadmore, Kirsty 1 Watkins, Hugh 1
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Pracoviště
Department of Physiology Anatomy and ... 1 Department of Physiology Faculty of S... 1 Department of Structural and Computat... 1 Division of Cardiovascular Medicine R... 1 European Molecular Biology Laboratory... 1 Institute of Cardiovascular Sciences ... 1 Randall Centre for Cell and Molecular... 1 School of Basic and Medical Bioscienc... 1 School of Cardiovascular and Metaboli... 1 Transgenic Core Wellcome Centre for H... 1
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Autor
Azad, Amar J 1 Bennett, Pauline 1 Broadway-Stringer, Sophie 1 Davies, Benjamin 1 Djinovic-Carugo, Kristina 1 Douglas, Gillian 1 Ehler, Elisabeth 1 Galatik, Frantisek 1 Gautel, Mathias 1 Gehmlich, Katja 1 Hooper, Charlotte 1 Jiang, He 1 Kalisch-Smith, Jacinta I 1 Reyat, Jasmeet S 1 Singer, Evie 1 Sparrow, Duncan B 1 Steeples, Violetta 1 Wadmore, Kirsty 1 Watkins, Hugh 1
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Pracoviště
Department of Physiology Anatomy and ... 1 Department of Physiology Faculty of S... 1 Department of Structural and Computat... 1 Division of Cardiovascular Medicine R... 1 European Molecular Biology Laboratory... 1 Institute of Cardiovascular Sciences ... 1 Randall Centre for Cell and Molecular... 1 School of Basic and Medical Bioscienc... 1 School of Cardiovascular and Metaboli... 1 Transgenic Core Wellcome Centre for H... 1
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Reyat, Jasmeet S OR 0000000332479186 Dotaz Zobrazit nápovědu
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Directory of Open Access Journals
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PubMed
36899856
DOI
10.3390/cells12050721
Knihovny.cz E-zdroje
Pathogenic variants in ACTN2, coding for alpha-actinin 2, are known to be rare causes of Hypertrophic Cardiomyopathy. However, little is known about the underlying disease mechanisms. Adult heterozygous mice carrying the Actn2 p.Met228Thr variant were phenotyped by echocardiography. For homozygous mice, viable E15.5 embryonic hearts were analysed by High Resolution Episcopic Microscopy and wholemount staining, complemented by unbiased proteomics, qPCR and Western blotting. Heterozygous Actn2 p.Met228Thr mice have no overt phenotype. Only mature males show molecular parameters indicative of cardiomyopathy. By contrast, the variant is embryonically lethal in the homozygous setting and E15.5 hearts show multiple morphological abnormalities. Molecular analyses, including unbiased proteomics, identified quantitative abnormalities in sarcomeric parameters, cell-cycle defects and mitochondrial dysfunction. The mutant alpha-actinin protein is found to be destabilised, associated with increased activity of the ubiquitin-proteasomal system. This missense variant in alpha-actinin renders the protein less stable. In response, the ubiquitin-proteasomal system is activated; a mechanism that has been implicated in cardiomyopathies previously. In parallel, a lack of functional alpha-actinin is thought to cause energetic defects through mitochondrial dysfunction. This seems, together with cell-cycle defects, the likely cause of the death of the embryos. The defects also have wide-ranging morphological consequences.
- MeSH
- aktinin metabolismus MeSH
- hypertrofická kardiomyopatie * MeSH
- kardiomyopatie * MeSH
- myši MeSH
- srdce MeSH
- ubikvitiny MeSH
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- práce podpořená grantem MeSH
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