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    Exploration of pathomechanisms triggered by a single-nucleotide polymorphism in titin's I-band: the cardiomyopathy-linked mutation T2580I

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    Author
    Bogomolovas, Julius cc
    Fleming, Jennifer R.
    Anderson, Brian R.
    Williams, Rhys
    Lange, Stephan cc
    Simon, Bernd cc
    Khan, Muzamil M. cc
    Rudolf, Rüdiger cc
    Franke, Barbara
    Bullard, Belinda
    Rigden, Daniel J. cc
    Granzier, Henk
    Labeit, Siegfried cc
    Mayans, Olga cc
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    Affiliation
    Univ Arizona, Dept Cellular & Mol Med
    Univ Arizona, Sarver Mol Cardiovasc Res Program
    Issue Date
    2016-09-28
    Keywords
    cardiomyopathy
    missense single-nucleotide polymorphism
    titin protein structure
    transgenic muscle
    transgenic mouse model
    
    Metadata
    Show full item record
    Publisher
    ROYAL SOC
    Citation
    Exploration of pathomechanisms triggered by a single-nucleotide polymorphism in titin's I-band: the cardiomyopathy-linked mutation T2580I 2016, 6 (9):160114 Open Biology
    Journal
    Open Biology
    Rights
    © 2016 The Authors. Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/.
    Collection Information
    This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.
    Abstract
    Missense single-nucleotide polymorphisms (mSNPs) in titin are emerging as a main causative factor of heart failure. However, distinguishing between benign and disease-causing mSNPs is a substantial challenge. Here, we research the question of whether a single mSNP in a generic domain of titin can affect heart function as a whole and, if so, how. For this, we studied the mSNP T2850I, seemingly linked to arrhythmogenic right ventricular cardiomyopathy (ARVC). We used structural biology, computational simulations and transgenic muscle in vivo methods to track the effect of the mutation from the molecular to the organismal level. The data show that the T2850I exchange is compatible with the domain three-dimensional fold, but that it strongly destabilizes it. Further, it induces a change in the conformational dynamics of the titin chain that alters its reactivity, causing the formation of aberrant interactions in the sarcomere. Echocardiography of knock-in mice indicated a mild diastolic dysfunction arising from increased myocardial stiffness. In conclusion, our data provide evidence that single mSNPs in titin's I-band can alter overall muscle behaviour. Our suggested mechanisms of disease are the development of non-native sarcomeric interactions and titin instability leading to a reduced I-band compliance. However, understanding the T2850I-induced ARVC pathology mechanistically remains a complex problem and will require a deeper understanding of the sarcomeric context of the titin region affected.
    Note
    No embargo.
    ISSN
    2046-2441
    DOI
    10.1098/rsob.160114
    Version
    Final published version
    Sponsors
    British Heart Foundation [PG/13/21/3007]; Leducq Foundation [TNE-13CVD04]; Hector Foundation; Biotechnology and Biological Sciences Research Council [BB/M00676X/1]; EU-MCSA-IRSES (SarcoSi); NIH [HL107744, HL128457, HL062881, HL118524]
    Additional Links
    http://rsob.royalsocietypublishing.org/lookup/doi/10.1098/rsob.160114
    ae974a485f413a2113503eed53cd6c53
    10.1098/rsob.160114
    Scopus Count
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    UA Faculty Publications

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