Exploration of pathomechanisms triggered by a single-nucleotide polymorphism in titin's I-band: the cardiomyopathy-linked mutation T2580I
Author
Bogomolovas, Julius
Fleming, Jennifer R.
Anderson, Brian R.
Williams, Rhys
Lange, Stephan

Simon, Bernd

Khan, Muzamil M.

Rudolf, Rüdiger

Franke, Barbara
Bullard, Belinda
Rigden, Daniel J.

Granzier, Henk
Labeit, Siegfried

Mayans, Olga

Affiliation
Univ Arizona, Dept Cellular & Mol MedUniv Arizona, Sarver Mol Cardiovasc Res Program
Issue Date
2016-09-28Keywords
cardiomyopathymissense single-nucleotide polymorphism
titin protein structure
transgenic muscle
transgenic mouse model
Metadata
Show full item recordPublisher
ROYAL SOCCitation
Exploration of pathomechanisms triggered by a single-nucleotide polymorphism in titin's I-band: the cardiomyopathy-linked mutation T2580I 2016, 6 (9):160114 Open BiologyJournal
Open BiologyRights
© 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
2046-2441Version
Final published versionSponsors
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]ae974a485f413a2113503eed53cd6c53
10.1098/rsob.160114