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Titin mutations in iPS cells define sarcomere insufficiency as a cause of dilated cardiomyopathy

Item Type:Article
Title:Titin mutations in iPS cells define sarcomere insufficiency as a cause of dilated cardiomyopathy
Creators Name:Hinson, J.T. and Chopra, A. and Nafissi, N. and Polacheck, W.J. and Benson, C.C. and Swist, S. and Gorham, J. and Yang, L. and Schafer, S. and Sheng, C.C. and Haghighi, A. and Homsy, J. and Hubner, N. and Church, G. and Cook, S.A. and Linke, W.A. and Chen, C.S. and Seidman, J.G. and Seidman, C.E.
Abstract:Human mutations that truncate the massive sarcomere protein titin [TTN-truncating variants (TTNtvs)] are the most common genetic cause for dilated cardiomyopathy (DCM), a major cause of heart failure and premature death. Here we show that cardiac microtissues engineered from human induced pluripotent stem (iPS) cells are a powerful system for evaluating the pathogenicity of titin gene variants. We found that certain missense mutations, like TTNtvs, diminish contractile performance and are pathogenic. By combining functional analyses with RNA sequencing, we explain why truncations in the A-band domain of TTN cause DCM, whereas truncations in the I band are better tolerated. Finally, we demonstrate that mutant titin protein in iPS cell-derived cardiomyocytes results in sarcomere insufficiency, impaired responses to mechanical and {beta}-adrenergic stress, and attenuated growth factor and cell signaling activation. Our findings indicate that titin mutations cause DCM by disrupting critical linkages between sarcomerogenesis and adaptive remodeling.
Keywords:Adrenergic {beta}-Agonists, Cardiac Myocytes, Connectin, Cultured Cells, Dilated Cardiomyopathy, Heart Rate, Induced Pluripotent Stem Cells, Isoproterenol, Missense Mutation, Mutant Proteins, Myocardial Contraction, Physiological Stress, RNA, RNA Sequence Analysis, Sarcomeres, Signal Transduction
Publisher:American Association for the Advancement of Science
Page Range:982-986
Date:28 August 2015
Additional Information:Copyright © 2015 American Association for the Advancement of Science
Official Publication:https://doi.org/10.1126/science.aaa5458
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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