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Exploration of pathomechanisms triggered by a single-nucleotide polymorphism in titin's I-band: the cardiomyopathy-linked mutation T2580I
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)
,
RĂ¼diger
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
Diamond Keywords: Cardiovascular Disease
Subject Areas:
Biology and Bio-materials
Instruments:
I02-Macromolecular Crystallography
,
I04-Macromolecular Crystallography
,
I24-Microfocus Macromolecular Crystallography
Added On:
21/04/2017 13:29
Documents:
160114.full.pdf
Discipline Tags:
Non-Communicable Diseases
Health & Wellbeing
Genetics
Structural biology
Life Sciences & Biotech
Technical Tags:
Diffraction
Macromolecular Crystallography (MX)