Titin-truncating variants affect heart function in disease cohorts and the general population
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Open Access
- 21 November 2016
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Genetics
- Vol. 49 (1), 46-53
- https://doi.org/10.1038/ng.3719
Abstract
Stuart Cook and colleagues study the role of TTN (titin)-truncating variants using a combination of heart physiology experiments in rats and genomic analysis in humans. Their data show that TTN variants are associated with a range of cardiac phenotypes in healthy individuals and in patients with dilated cardiomyopathy. 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
This publication has 73 references indexed in Scilit:
- TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusionsGenome Biology, 2013
- Muscle-Specific Deletion of Carnitine Acetyltransferase Compromises Glucose Tolerance and Metabolic FlexibilityCell Metabolism, 2012
- RBM20, a gene for hereditary cardiomyopathy, regulates titin splicingNature Medicine, 2012
- Fast gapped-read alignment with Bowtie 2Nature Methods, 2012
- Truncations of Titin Causing Dilated CardiomyopathyNew England Journal of Medicine, 2012
- Stress-induced dilated cardiomyopathy in a knock-in mouse model mimicking human titin-based diseaseJournal of Molecular and Cellular Cardiology, 2009
- Genome-wide association study of blood pressure and hypertensionNature Genetics, 2009
- Genome-wide association study identifies eight loci associated with blood pressureNature Genetics, 2009
- Genome-Wide Analysis in Vivo of Translation with Nucleotide Resolution Using Ribosome ProfilingScience, 2009
- KEGG: Kyoto Encyclopedia of Genes and GenomesNucleic Acids Research, 2000