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Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease

Official URL:https://doi.org/10.1126/scitranslmed.3010134
PubMed:View item in PubMed
Creators Name:Roberts, A.M. and Ware, J.S. and Herman, D.S. and Schafer, S. and Baksi, J. and Bick, A.G. and Buchan, R.J. and Walsh, R. and John, S. and Wilkinson, S. and Mazzarotto, F. and Felkin, L.E. and Gong, S. and MacArthur, J.A.L. and Cunningham, F. and Flannick, J. and Gabriel, S.B. and Altshuler, D.M. and Macdonald, P.S. and Heinig, M. and Keogh, A.M. and Hayward, C.S. and Banner, N.R. and Pennell, D.J. and O'Regan, D.P. and San, T.R. and de Marvao, A. and Dawes, T.J.W. and Gulati, A. and Birks, E.J. and Yacoub, M.H. and Radke, M. and Gotthardt, M. and Wilson, J.G. and O'Donnell, C.J. and Prasad, S.K. and Barton, P.J.R. and Fatkin, D. and Hubner, N. and Seidman, J.G. and Seidman, C.E. and Cook, S.A.
Journal Title:Science Translational Medicine
Journal Abbreviation:Sci Transl Med
Volume:7
Number:270
Page Range:270ra6
Date:14 January 2015
Keywords:Alleles, Cohort Studies, Connectin, Dilated Cardiomyopathy, Exons, Genetic Transcription, Genetic Variation, Healthy Volunteers, Heart, Heart Failure, Immunoglobulins, Mutation, Protein Isoforms
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.
ISSN:1946-6234
Publisher:American Association for the Advancement of Science (U.S.A.)
Item Type:Article

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