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…

• HH
  Howard Hughes Medical Institute
• AH
  American Heart Association
• SC
  Sarnoff Cardiovascular Research Foundation
• DF
  Deutsche Forschungsgemeinschaft

  Award: SFB 1002 TPB3
• FL
  Fondation Leducq
• NI
  National Institutes of Health

  Awards: HL125807, HL007374, HL115553, HG005550, EB017103