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

Tools

Item Type:	Article
Title:	Titin-truncating variants affect heart function in disease cohorts and the general population
Creators Name:	Schafer, 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. and Cook, S.A.
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.
Keywords:	Case-Control Studies, Cohort Studies, Connectin, Dilated Cardiomyopathy, Genetic Variation, Heart, High-Throughput Nucleotide Sequencing, Animals, Rats
Source:	Nature Genetics
ISSN:	1061-4036
Publisher:	Nature Publishing Group
Volume:	49
Number:	1
Page Range:	46-53
Date:	January 2017
Official Publication:	https://doi.org/10.1038/ng.3719
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

Repository Staff Only: item control page