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Titin truncating variants affect heart function in disease cohorts and the general population

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Title: Titin truncating variants affect heart function in disease cohorts and the general population
Authors: Schafer, S
De Marvao, A
Adami, E
Fiedler, LR
Ng, B
Khin, E
Rackham, O
Van Heesch, S
Pua, CJ
Kui, M
Walsh, R
Tayal, U
Prasad, SK
Dawes, TJW
Sim, D
Chan, LLH
Chin, CWL
Mazzarotto, F
Barton, PJ
Kreuchwig, F
De Kleijn, DPV
Totman, T
Biffi, C
Tee, N
Rueckert, D
Schneider, V
Faber, A
Regitz-Zagrosek, V
Seidman, JG
Seidman, CE
Linke, WA
Kovalik, J
O'Regan, D
Ware, JS
Hubner, N
Cook, SA
Item Type: Journal Article
Abstract: Titin-truncating variants (TTNtv) commonly cause dilated cardiomyopathy (DCM). TTNtv are also encountered in ~1% of the general population, where they may be silent, perhaps reflecting allelic factors. To better understand TTNtv, we integrated TTN allelic series, cardiac imaging and genomic data in humans and studied rat models with disparate TTNtv. In patients with DCM, TTNtv throughout titin were significantly associated with DCM. Ribosomal profiling in rat showed the translational footprint of premature stop codons in Ttn, TTNtv-position-independent nonsense-mediated degradation of the mutant allele and a signature of perturbed cardiac metabolism. Heart physiology in rats with TTNtv was unremarkable at baseline but became impaired during cardiac stress. In healthy humans, machine-learning-based analysis of high-resolution cardiac imaging showed TTNtv to be associated with eccentric cardiac remodeling. These data show that TTNtv have molecular and physiological effects on the heart across species, with a continuum of expressivity in health and disease.
Issue Date: 21-Nov-2016
Date of Acceptance: 18-Oct-2016
URI: http://hdl.handle.net/10044/1/42638
DOI: https://dx.doi.org/10.1038/ng.3719
ISSN: 1546-1718
Publisher: Nature Publishing Group
Start Page: 46
End Page: 53
Journal / Book Title: Nature Genetics
Volume: 49
Copyright Statement: © 2016 Nature America, Inc., part of Springer Nature. All rights reserved.
Sponsor/Funder: British Heart Foundation
Imperial College Healthcare NHS Trust- BRC Funding
British Heart Foundation
Commission of the European Communities
Fondation Leducq
British Heart Foundation
National Institute for Health Research
Engineering & Physical Science Research Council (EPSRC)
British Heart Foundation
Wellcome Trust
Department of Health
Wellcome Trust
Medical Research Council
Funder's Grant Number: RE/08/002/23906
11 CVD-01
RDB02 79560
Keywords: Developmental Biology
11 Medical And Health Sciences
06 Biological Sciences
Publication Status: Published
Open Access location: http://rdcu.be/mP1y
Appears in Collections:Computing
Institute of Clinical Sciences
Faculty of Engineering