Titin-truncating variants affect heart function in disease cohorts and the general population
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...
| Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Formato: | Journal article |
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Springer Nature
2016
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| _version_ | 1826282652596961280 |
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| author | Schafer, S de Marvao, A Adami, E Fiedler, LR Ng, B Khin, E Rackham, OJL 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-P O'Regan, D Ware, JS Hubner, N Cook, SA |
| author_facet | Schafer, S de Marvao, A Adami, E Fiedler, LR Ng, B Khin, E Rackham, OJL 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-P O'Regan, D Ware, JS Hubner, N Cook, SA |
| author_sort | Schafer, S |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T00:47:05Z |
| format | Journal article |
| id | oxford-uuid:850f94c1-5ec3-4f49-94dc-dca625b4a9a6 |
| institution | University of Oxford |
| last_indexed | 2024-03-07T00:47:05Z |
| publishDate | 2016 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:850f94c1-5ec3-4f49-94dc-dca625b4a9a62022-03-26T21:55:07ZTitin-truncating variants affect heart function in disease cohorts and the general populationJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:850f94c1-5ec3-4f49-94dc-dca625b4a9a6Symplectic Elements at OxfordSpringer Nature2016Schafer, Sde Marvao, AAdami, EFiedler, LRNg, BKhin, ERackham, OJLvan Heesch, SPua, CJKui, MWalsh, RTayal, UPrasad, SKDawes, TJWKo, NSJSim, DChan, LLHChin, CWLMazzarotto, FBarton, PJKreuchwig, Fde Kleijn, DPVTotman, TBiffi, CTee, NRueckert, DSchneider, VFaber, ARegitz-Zagrosek, VSeidman, JGSeidman, CELinke, WAKovalik, J-PO'Regan, DWare, JSHubner, NCook, SATitin-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. |
| spellingShingle | Schafer, S de Marvao, A Adami, E Fiedler, LR Ng, B Khin, E Rackham, OJL 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-P O'Regan, D Ware, JS Hubner, N Cook, SA Titin-truncating variants affect heart function in disease cohorts and the general population |
| title | Titin-truncating variants affect heart function in disease cohorts and the general population |
| title_full | Titin-truncating variants affect heart function in disease cohorts and the general population |
| title_fullStr | Titin-truncating variants affect heart function in disease cohorts and the general population |
| title_full_unstemmed | Titin-truncating variants affect heart function in disease cohorts and the general population |
| title_short | Titin-truncating variants affect heart function in disease cohorts and the general population |
| title_sort | titin truncating variants affect heart function in disease cohorts and the general population |
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