Exploration of pathomechanisms triggered by a single-nucleotide polymorphism in titin's I-band: the cardiomyopathy-linked mutation T2580I.
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.
Department of Integrative Pathophysiology, Medical Faculty Mannheim, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany Institute of Integrative Biology, University of Liverpool, Crown Street, Liverpool, L69 7ZB, UK.
Julius
http://orcid.org/0000-0001-8344-1909
J
Bogomolovas
Institute of Integrative Biology, University of Liverpool, Crown Street, Liverpool, L69 7ZB, UK Department of Biology, University of Konstanz, 78457 Konstanz, Germany.
Jennifer R
JR
Fleming
Department of Cellular and Molecular Medicine and Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, AZ 85724, USA.
Brian R
BR
Anderson
Institute of Integrative Biology, University of Liverpool, Crown Street, Liverpool, L69 7ZB, UK Department of Biology, University of Konstanz, 78457 Konstanz, Germany.
Rhys
R
Williams
School of Medicine, University of California San Diego, 9500 Gilman Drive, MC-0613C, La Jolla, CA 92093, USA.
Stephan
http://orcid.org/0000-0001-9361-6602
S
Lange
European Molecular Biology Laboratory, Structural and Computational Biology Unit, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
Bernd
http://orcid.org/0000-0003-0164-5516
B
Simon
Institute of Molecular and Cell Biology, Mannheim University of Applied Sciences, Paul-Wittsackstraße 110, 68163 Mannheim, Germany Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany.
Muzamil M
http://orcid.org/0000-0002-8188-0251
MM
Khan
Institute of Molecular and Cell Biology, Mannheim University of Applied Sciences, Paul-Wittsackstraße 110, 68163 Mannheim, Germany Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany.
Rüdiger
http://orcid.org/0000-0002-0833-1053
R
Rudolf
Department of Biology, University of Konstanz, 78457 Konstanz, Germany.
Barbara
B
Franke
Department of Biology, University of York, York YO10 5DD, UK.
Belinda
B
Bullard
Institute of Integrative Biology, University of Liverpool, Crown Street, Liverpool, L69 7ZB, UK.
Daniel J
http://orcid.org/0000-0002-7565-8937
DJ
Rigden
Department of Cellular and Molecular Medicine and Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, AZ 85724, USA.
Henk
H
Granzier
Department of Integrative Pathophysiology, Medical Faculty Mannheim, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany labeit@medma.de.
Siegfried
http://orcid.org/0000-0002-9009-210X
S
Labeit
Institute of Integrative Biology, University of Liverpool, Crown Street, Liverpool, L69 7ZB, UK Department of Biology, University of Konstanz, 78457 Konstanz, Germany olga.mayans@uni-konstanz.de.
Olga
http://orcid.org/0000-0001-6876-8532
O
Mayans
cardiomyopathy; missense single-nucleotide polymorphism; titin protein structure; transgenic mouse model; transgenic muscle
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