Bogomolovas, Julius Fleming, Jennifer Anderson, Brian R. Williams, Rhys Lange, Stephan Simon, Bernd Khan, Muzamil M. Rudolf, RĂ¼diger Franke, Barbara Bullard, Belinda Rigden, Daniel J. Granzier, Henk Labeit, Siegfried Mayans, Olga Supplementary Material from Exploration of pathomechanisms triggered by a single-nucleotide polymorphism in titin's I-band: the cardiomyopathy-linked mutation T2580I Missense single-nucleotide polymorphisms (mSNP) 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 <i>in vivo</i> 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. cardiomyopathy;missense single-nucleotide polymorphism;titin protein structure;transgenic muscle;transgenic mouse model 2016-09-21
    https://rs.figshare.com/articles/journal_contribution/Supplementary_Material_from_Exploration_of_pathomechanisms_triggered_by_a_single-nucleotide_polymorphism_in_titin_s_I-band_the_cardiomyopathy-linked_mutation_T2580I/3843228
10.6084/m9.figshare.3843228.v1