Sebastian Schafer 1 2 , Antonio de Marvao 3 , Eleonora Adami 4 , Lorna R Fiedler 2 , Benjamin Ng 1 , Ester Khin 2 , Owen J L Rackham 2 , Sebastiaan van Heesch 4 , Chee J Pua 1 , Miao Kui 2 , Roddy Walsh 5 , Upasana Tayal 5 , Sanjay K Prasad 5 , Timothy J W Dawes 3 , Nicole S J Ko 2 , David Sim 1 , Laura L H Chan 1 , Calvin W L Chin 1 2 , Francesco Mazzarotto 5 , Paul J Barton 5 , Franziska Kreuchwig 4 , Dominique P V de Kleijn 6 7 , Teresa Totman 6 , Carlo Biffi 3 , Nicole Tee 1 , Daniel Rueckert 8 , Valentin Schneider 4 , Allison Faber 4 , Vera Regitz-Zagrosek 9 10 , Jonathan G Seidman 11 , Christine E Seidman 11 12 13 , Wolfgang A Linke 14 15 , Jean-Paul Kovalik 2 , Declan O'Regan 3 , James S Ware 3 5 , Norbert Hubner 4 10 16 , Stuart A Cook 1 2 5
1 National Heart Centre Singapore, Singapore.
2 Duke-National University of Singapore, Singapore.
3 Cardiovascular and Metabolic Disorders Program, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, London, UK.
4 Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
5 National Heart and Lung Institute and NIHR Royal Brompton Cardiovascular BRU, Imperial College London, London, UK.
6 Department of Surgery, National University of Singapore, Singapore.
7 Departments of Cardiology and Vascular Surgery, University Medical Center, Utrecht, the Netherlands.
9 Institute of Gender in Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany.
10 DZHK (German Centre for Cardiovascular Research), partner site Berlin, Berlin, Germany.
12 Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
14 Department of Cardiovascular Physiology, Ruhr University Bochum, Bochum, Germany.
15 DZHK (German Centre for Cardiovascular Research), partner site Goettingen, Goettingen, Germany.
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.
Ttn protein, rat
P43579_WMET/WT_/Wellcome Trust/United Kingdom