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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Hinson, JT; Chopra, A; Nafissi, N; Polacheck, WJ; Benson, CC; Swist, S; Gorham, J; Yang, L; Schafer, S; Sheng, CC; Haghighi, A; Homsy, J; Hubner, N; Church, G; Cook, SA; Linke, WA; Chen, CS; Seidman, JG; Seidman, CE

Published Date

  • August 2015

Published In

Volume / Issue

  • 349 / 6251

Start / End Page

  • 982 - 986

PubMed ID

  • 26315439

Pubmed Central ID

  • PMC4618316

Electronic International Standard Serial Number (EISSN)

  • 1095-9203

International Standard Serial Number (ISSN)

  • 0036-8075

Digital Object Identifier (DOI)

  • 10.1126/science.aaa5458


  • eng