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

DOI: 10.1098/rsob.160114

Authors: Julijus Bogomolovas (University of Liverpool) , Jennifer R. Fleming (University of Konstanz; University of Liverpool) , Brian R. Anderson (University of Arizona) , Rhys Williams (University of Liverpool) , Stephan Lange (University of California San Diego) , Bernd Simon (European Molecular Biology Laboratory) , Muzamil M. Khan (Karlsruhe Institute of Technology; Mannheim University of Applied Sciences) , Rüdiger Rudolf (Mannheim University of Applied Sciences; Karlsruhe Institute of Technology) , Barbara Franke (University of Konstanz) , Belinda Bullard (University of York) , Daniel J. Rigden (University of Liverpool) , Henk Granzier (University of Arizona) , Siegfried Labeit (Medical Faculty Mannheim) , Olga Mayans (University of Liverpool; University of Konstanz)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Open Biology , VOL 6

State: Published (Approved)
Published: September 2016
Diamond Proposal Number(s): 7146

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.

Journal Keywords: cardiomyopathy; missense single-nucleotide; polymorphism; titin protein structure; transgenic muscle; transgenic mouse model

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I02-Macromolecular Crystallography , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Documents:
160114.full.pdf