Helmholtz Gemeinschaft

Search
Browse
Statistics
Feeds

Titin-truncating variants affect heart function in disease cohorts and the general population

Official URL:https://doi.org/10.1038/ng.3719
PubMed:View item in PubMed
Creators Name:Schafer, S. and de Marvao, A. and Adami, E. and Fiedler, L.R. and Ng, B. and Khin, E. and Rackham, O.J.L. and van Heesch, S. and Pua, C.J. and Kui, M. and Walsh, R. and Tayal, U. and Prasad, S.K. and Dawes, T.J.W. and Ko, N.S.J. and Sim, D. and Chan, L.L.H. and Chin, C.W.L. and Mazzarotto, F. and Barton, P.J. and Kreuchwig, F. and de Kleijn, D.P.V. and Totman, T. and Biffi, C. and Tee, N. and Rueckert, D. and Schneider, V. and Faber, A. and Regitz-Zagrosek, V. and Seidman, J.G. and Seidman, C.E. and Linke, W.A. and Kovalik, J.P. and O'Regan, D. and Ware, J.S. and Hubner, N. and Cook, S.A.
Journal Title:Nature Genetics
Journal Abbreviation:Nat Genet
Volume:49
Number:1
Page Range:46-53
Date:January 2017
Abstract: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.
ISSN:1061-4036
Publisher:Nature Publishing Group (U.S.A.)
Item Type:Article

Repository Staff Only: item control page

Open Access
MDC Library