Journal
SCIENCE
Volume 349, Issue 6251, Pages 982-986Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aaa5458
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Funding
- LaDue Fellowship
- American Heart Association
- Sarnoff Foundation
- Leducq Foundation
- German Research Foundation [SFB 1002 TPB3]
- NIH [HG005550, EB017103, HL115553, HL007374, HL125807]
- NIHR Cardiovascular Biomedical Research Unit of Royal Brompton and Harefield NHS Foundation Trust
- RESBIO Technology Resource for Polymeric Biomaterials
- Howard Hughes Medical Institute
- Illumina, Inc.
- MRC [MC_U120085815] Funding Source: UKRI
- British Heart Foundation [SP/10/10/28431] Funding Source: researchfish
- Medical Research Council [MC_U120085815] Funding Source: researchfish
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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.
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