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

Bogomolovas, Julius; Fleming, Jennifer R.; Anderson, Brian R.; Williams, Rhys; Lange, Stephan; Simon, Bernd; Khan, Muzamil M. 1; Rudolf, Rüdiger 1; Franke, Barbara; Bullard, Belinda; Rigden, Daniel J.; Granzier, Henk; Labeit, Siegfried; Mayans, Olga
1 Institut für Toxikologie und Genetik (ITG), Karlsruher Institut für Technologie (KIT)


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. ... mehr

Volltext §
DOI: 10.5445/IR/1000061646
DOI: 10.1098/rsob.160114
Zitationen: 16
Web of Science
Zitationen: 15
Zitationen: 18
Cover der Publikation
Zugehörige Institution(en) am KIT Institut für Toxikologie und Genetik (ITG)
Publikationstyp Zeitschriftenaufsatz
Publikationsjahr 2016
Sprache Englisch
Identifikator ISSN: 2046-2441
KITopen-ID: 1000061646
HGF-Programm 47.01.01 (POF III, LK 01) Biol.Netzwerke u.Synth.Regulat. ITG+ITC
Erschienen in Open biology
Verlag The Royal Society
Band 6
Heft 9
Seiten 160114
Vorab online veröffentlicht am 01.09.2016
Schlagwörter cardiomyopathy,, missense single-nucleotide polymorphism,, titin protein structure,, transgenic muscle,, transgenic mouse model
Nachgewiesen in Scopus
Web of Science
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