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


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 β-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.

DOI: 10.1126/science.aaa5458

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@article{Hinson2015HEARTDT, title={HEART DISEASE. Titin mutations in iPS cells define sarcomere insufficiency as a cause of dilated cardiomyopathy.}, author={J Travis Hinson and Anant Chopra and Navid Nafissi and William J Polacheck and Craig C. Benson and Sandra Swist and Joshua M Gorham and Luhan Yang and Sebastian Schafer and Calvin C. Sheng and Alireza Shourangiz Haghighi and Jason Homsy and Norbert Hubner and George M Church and Stuart A. Cook and Wolfgang A Linke and Christopher S. Chen and Jonathan G Seidman and Christine E Seidman}, journal={Science}, year={2015}, volume={349 6251}, pages={982-6} }