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Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease.
Publication available at: | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4560092/ |
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Title: | Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease. |
Authors: | Roberts, AM Ware, JS Herman, DS Schafer, S Baksi, J Bick, AG Buchan, RJ Walsh, R John, S Wilkinson, S Mazzarotto, F Felkin, LE Gong, S L MacArthur, JA Cunningham, F Flannick, J Gabriel, SB Altshuler, DM Macdonald, PS Heinig, M Keogh, AM Hayward, CS Banner, NR Pennell, DJ O'Regan, DP San, TR De Marvao, A W Dawes, TJ Gulati, A Birks, EJ Yacoub, MH Radke, M Gotthardt, M Wilson, JG O'Donnell, CJ Prasad, SK Barton, PJ Fatkin, D Hubner, N Seidman, JG Seidman, CE Cook, SA |
Item Type: | Journal Article |
Abstract: | The recent discovery of heterozygous human mutations that truncate full-length titin (TTN, an abundant structural, sensory, and signaling filament in muscle) as a common cause of end-stage dilated cardiomyopathy (DCM) promises new prospects for improving heart failure management. However, realization of this opportunity has been hindered by the burden of TTN-truncating variants (TTNtv) in the general population and uncertainty about their consequences in health or disease. To elucidate the effects of TTNtv, we coupled TTN gene sequencing with cardiac phenotyping in 5267 individuals across the spectrum of cardiac physiology and integrated these data with RNA and protein analyses of human heart tissues. We report diversity of TTN isoform expression in the heart, define the relative inclusion of TTN exons in different isoforms (using the TTN transcript annotations available at http://cardiodb.org/titin), and demonstrate that these data, coupled with the position of the TTNtv, provide a robust strategy to discriminate pathogenic from benign TTNtv. We show that TTNtv is the most common genetic cause of DCM in ambulant patients in the community, identify clinically important manifestations of TTNtv-positive DCM, and define the penetrance and outcomes of TTNtv in the general population. By integrating genetic, transcriptome, and protein analyses, we provide evidence for a length-dependent mechanism of disease. These data inform diagnostic criteria and management strategies for TTNtv-positive DCM patients and for TTNtv that are identified as incidental findings. |
Issue Date: | 14-Jan-2015 |
Date of Acceptance: | 25-Nov-2014 |
URI: | http://hdl.handle.net/10044/1/85882 |
DOI: | 10.1126/scitranslmed.3010134 |
ISSN: | 1946-6234 |
Publisher: | American Association for the Advancement of Science |
Start Page: | 270ra6 |
End Page: | 270ra6 |
Journal / Book Title: | Science Translational Medicine |
Volume: | 7 |
Issue: | 270 |
Copyright Statement: | © 2015, American Association for the Advancement of Science. |
Sponsor/Funder: | British Heart Foundation British Heart Foundation Heart Research UK Commission of the European Communities British Heart Foundation British Heart Foundation |
Funder's Grant Number: | PG/09/074/27961 PG/12/27/29489 RG2596/11/13 289600 SP/10/10/28431 FS/13/13/29819 |
Keywords: | Science & Technology Life Sciences & Biomedicine Cell Biology Medicine, Research & Experimental Research & Experimental Medicine CARDIOVASCULAR MAGNETIC-RESONANCE FAMILIAL DILATED CARDIOMYOPATHY HEART-FAILURE PROGNOSTIC VALUE RISK-FACTORS POPULATION VARIANTS MUTATIONS SEQUENCE GENES Adolescent Adult Aged Alleles Cardiomyopathy, Dilated Cohort Studies Connectin Exons Genetic Variation Healthy Volunteers Heart Heart Failure Humans Immunoglobulins Middle Aged Mutation Protein Isoforms Transcription, Genetic Young Adult Heart Humans Cardiomyopathy, Dilated Immunoglobulins Protein Isoforms Cohort Studies Transcription, Genetic Mutation Alleles Exons Adolescent Adult Aged Middle Aged Heart Failure Genetic Variation Young Adult Healthy Volunteers Connectin 06 Biological Sciences 11 Medical and Health Sciences |
Publication Status: | Published |
Conference Place: | United States |
Open Access location: | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4560092/ |
Appears in Collections: | Imaging Sciences Department of Medicine (up to 2019) |