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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 Ko, NSJ 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 RD410 SP/10/10/28431 289600 11 CVD-01 FS/13/54/30642 RDB02 79560 EP/K030523/1 PG/12/27/29489 HICF-R6-373 HICF-R6-373 107469/Z/15/Z MR/M003191/1 |
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 |