Titin-truncating variants affect heart function in disease cohorts and the general population
Schafer, Sebastian; De Marvao, Antonio; Adami, Eleonora; Fiedler, Lorna R.; Ng, Benjamin; Khin, Ester; Rackham, Owen J L; Van Heesch, Sebastiaan; Pua, Chee J.; Kui, Miao; Walsh, Roddy; Tayal, Upasana; Prasad, Sanjay K.; Dawes, Timothy J W; Ko, Nicole S J; Sim, David; Chan, Laura L H; Chin, Calvin W L; Mazzarotto, Francesco; Barton, Paul J.; Kreuchwig, Franziska; De Kleijn, Dominique P V; Totman, Teresa; Biffi, Carlo; Tee, Nicole; Rueckert, Daniel; Schneider, Valentin; Faber, Allison; Regitz-Zagrosek, Vera; Seidman, Jonathan G.; Seidman, Christine E.; Linke, Wolfgang A.; Kovalik, Jean Paul; O'Regan, Declan; Ware, James S.; Hubner, Norbert; Cook, Stuart A.
(2017) Nature Genetics, volume 49, issue 1, pp. 46 - 53
(Article)
Abstract
Titin-truncating variants (TTNtv) commonly cause dilated cardiomyopathy (DCM). TTNtv are also encountered in 1/41% 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.
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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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Keywords: Genetics, Journal Article, Comparative Study
ISSN: 1061-4036
Publisher: Nature Publishing Group
Note: Funding Information: The research was supported by the MRC Clinical Sciences Centre, UK, to J.S.W., S.A.C., A.d.M. and D.P.O'R., the NIHR Biomedical Research Unit in Cardiovascular Disease at Royal Brompton, the Harefield NHS Foundation Trust and Imperial College London to J.S.W. and S.A.C., the NIHR Imperial Biomedical Research Centre, British Heart Foundation, UK (SP/10/10/28431, PG/12/27/29489) to S.A.C., D.P.O'R. and C.B., the Wellcome Trust, UK (107469/Z/15/Z to J.S.W., 087183/Z/08/Z, 092854/Z/10/Z and WT095908), a Wellcome Trust Fellowship (100211/Z/12/Z and P43579-WMET to T.J.W.D.), Fondation Leducq to J.S.W., the Tanoto Foundation to S.A.C., CORDA, the National Institutes of Health (NHLBI 2R01HL080494 to J.G.S. and C.E.S.), the National Medical Research Council (NMRC) Singapore (CIRG13nov024 and STaR13nov002 to D.P.V.d.K.), the SingHealth Duke-NUS Institute of Precision Medicine, the Rosetrees Trust, the Health Innovation Challenge Fund (HICF-R6-373 to J.S.W.) funding from the Wellcome Trust and the Department of Health, UK, the Howard Hughes Medical Institute, the European Union EURATRANS award (HEALTH-F4-2010-241504 to N.H.), the Helmholtz Alliance ICEMED to N.H., European Union FP7 (CardioNeT-ITN-289600 to F.M.), Deutsche Forschungsgemeinschaft (SFB1002, TPA08 to W.A.L., Forschergruppe 1054 HU 1522/1-1 to N.H. and TP1 to V.R.-Z.), and an EMBO Long-Term Fellowship (ALTF 186-2015 to S.v.H.) and Marie Curie Actions (LTFCOFUND2013, GA-2013-609409 to S.v.H.). Publisher Copyright: © 2017 Nature America, Inc., part of Springer Nature. All rights reserved.
(Peer reviewed)