Please use this identifier to cite or link to this item: https://doi.org/10.1038/ng.3719
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dc.titleTitin-truncating variants affect heart function in disease cohorts and the general population
dc.contributor.authorSchafer S.
dc.contributor.authorDe Marvao A.
dc.contributor.authorAdami E.
dc.contributor.authorFiedler L.R.
dc.contributor.authorNg B.
dc.contributor.authorKhin E.
dc.contributor.authorRackham O.J.L.
dc.contributor.authorVan Heesch S.
dc.contributor.authorPua C.J.
dc.contributor.authorKui M.
dc.contributor.authorWalsh R.
dc.contributor.authorTayal U.
dc.contributor.authorPrasad S.K.
dc.contributor.authorDawes T.J.W.
dc.contributor.authorKo N.S.J.
dc.contributor.authorSim D.
dc.contributor.authorChan L.L.H.
dc.contributor.authorChin C.W.L.
dc.contributor.authorMazzarotto F.
dc.contributor.authorBarton P.J.
dc.contributor.authorKreuchwig F.
dc.contributor.authorDe Kleijn D.P.V.
dc.contributor.authorTotman T.
dc.contributor.authorBiffi C.
dc.contributor.authorTee N.
dc.contributor.authorRueckert D.
dc.contributor.authorSchneider V.
dc.contributor.authorFaber A.
dc.contributor.authorRegitz-Zagrosek V.
dc.contributor.authorSeidman J.G.
dc.contributor.authorSeidman C.E.
dc.contributor.authorLinke W.A.
dc.contributor.authorKovalik J.-P.
dc.contributor.authorO'Regan D.
dc.contributor.authorWare J.S.
dc.contributor.authorHubner N.
dc.contributor.authorCook S.A.
dc.date.accessioned2019-01-08T09:08:21Z
dc.date.available2019-01-08T09:08:21Z
dc.date.issued2017
dc.identifier.citationSchafer S., De Marvao A., Adami E., Fiedler L.R., Ng B., Khin E., Rackham O.J.L., Van Heesch S., Pua C.J., Kui M., Walsh R., Tayal U., Prasad S.K., Dawes T.J.W., Ko N.S.J., Sim D., Chan L.L.H., Chin C.W.L., Mazzarotto F., Barton P.J., Kreuchwig F., De Kleijn D.P.V., Totman T., Biffi C., Tee N., Rueckert D., Schneider V., Faber A., Regitz-Zagrosek V., Seidman J.G., Seidman C.E., Linke W.A., Kovalik J.-P., O'Regan D., Ware J.S., Hubner N., Cook S.A. (2017). Titin-truncating variants affect heart function in disease cohorts and the general population. Nature Genetics 49 (1) : 46-53. ScholarBank@NUS Repository. https://doi.org/10.1038/ng.3719
dc.identifier.issn10614036
dc.identifier.urihttp://scholarbank.nus.edu.sg/handle/10635/150642
dc.description.abstractTitin-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. 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. © 2017 Nature America, Inc., part of Springer Nature. All rights reserved.
dc.publisherNature Publishing Group
dc.sourceScopus
dc.typeArticle
dc.contributor.departmentDUKE-NUS MEDICAL SCHOOL
dc.description.doi10.1038/ng.3719
dc.description.sourcetitleNature Genetics
dc.description.volume49
dc.description.issue1
dc.description.page46-53
dc.description.codenNGENE
dc.grant.idHHMI
dc.grant.idCIRG13nov024
dc.grant.idTP1
dc.grant.idSFB1002
dc.grant.idDH
dc.grant.idDH
dc.grant.id107469/Z/15/Z
dc.grant.id092854/Z/10/Z
dc.grant.id087183/Z/08/Z
dc.grant.idWT095908
dc.grant.idALTF 186-2015
dc.grant.fundingagencyHoward Hughes Medical Institute
dc.grant.fundingagencyNMRC, National Medical Research Council
dc.grant.fundingagencyDFG, Deutsche Forschungsgemeinschaft
dc.grant.fundingagencyDFG, Deutsche Forschungsgemeinschaft
dc.grant.fundingagencyDepartment of Health
dc.grant.fundingagencyDepartment of Health
dc.grant.fundingagencyWellcome Trust
dc.grant.fundingagencyWellcome Trust
dc.grant.fundingagencyWellcome Trust
dc.grant.fundingagencyWellcome Trust
dc.grant.fundingagencyEMBO
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