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

Science. 2015 Aug 28;349(6251):982-6. doi: 10.1126/science.aaa5458.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Agonists / pharmacology
  • Cardiomyopathy, Dilated / genetics*
  • Cardiomyopathy, Dilated / pathology
  • Cardiomyopathy, Dilated / physiopathology*
  • Cells, Cultured
  • Connectin / chemistry
  • Connectin / genetics*
  • Connectin / physiology*
  • Heart Rate
  • Humans
  • Induced Pluripotent Stem Cells / physiology*
  • Isoproterenol / pharmacology
  • Mutant Proteins / chemistry
  • Mutant Proteins / physiology
  • Mutation, Missense*
  • Myocardial Contraction
  • Myocytes, Cardiac / physiology*
  • RNA / genetics
  • RNA / metabolism
  • Sarcomeres / physiology*
  • Sarcomeres / ultrastructure
  • Sequence Analysis, RNA
  • Signal Transduction
  • Stress, Physiological


  • Adrenergic beta-Agonists
  • Connectin
  • Mutant Proteins
  • TTN protein, human
  • RNA
  • Isoproterenol