Journal
NATURE GENETICS
Volume 49, Issue 1, Pages 46-53Publisher
NATURE RESEARCH
DOI: 10.1038/ng.3719
Keywords
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Categories
Funding
- MRC Clinical Sciences Centre, UK
- NIHR Biomedical Research Unit in Cardiovascular Disease at Royal Brompton
- Harefield NHS Foundation Trust and Imperial College London
- NIHR Imperial Biomedical Research Centre
- British Heart Foundation, UK [SP/10/10/28431, PG/12/27/29489]
- Wellcome Trust, UK [107469/Z/15/Z, 087183/Z/08/Z, 092854/Z/10/Z, WT095908]
- Wellcome Trust [100211/Z/12/Z, P43579_WMET]
- Fondation Leducq
- Tanoto Foundation
- CORDA
- National Institutes of Health [NHLBI 2R01HL080494]
- National Medical Research Council (NMRC) Singapore [CIRG13nov024, STaRl3nov002]
- SingHealth Duke-NUS Institute of Precision Medicine
- Rosetrees Trust
- Health Innovation Challenge Fund from the Wellcome Trust [HICF-R6-373]
- Department of Health, UK
- Howard Hughes Medical Institute
- European Union EURATRANS award [HEALTH-F4-2010-241504]
- Helmholtz Alliance ICEMED
- European Union FP7 [CardioNeT-ITN-289600]
- Deutsche Forschungsgemeinschaft [SFB1002, TPA08, Forschergruppe 1054 HU 1522/1-1, TP1]
- EMBO Long-Term Fellowship [ALTF 186-2015]
- Marie Curie Actions (LTECOFUND) [GA-2013-609409]
- UK Department of Health
- Wellcome Trust
- EPSRC [EP/K030523/1] Funding Source: UKRI
- MRC [MC_UP_1102/20, MC_UP_1102/19, MC_U120085815, MR/M003191/1] Funding Source: UKRI
- British Heart Foundation [FS/15/81/31817, SP/10/10/28431, PG/12/27/29489] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [EP/K030523/1] Funding Source: researchfish
- Medical Research Council [MR/M003191/1, MC_UP_1102/19, MC_U120085815, MC_UP_1102/20] Funding Source: researchfish
- Wellcome Trust [107469/Z/15/Z] Funding Source: researchfish
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL080494] Funding Source: NIH RePORTER
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Titin-truncating variants (TTNtv) commonly cause dilated cardiomyopathy (DCM). TTNtv are also encountered in similar to 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.
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