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

DSpace/Manakin Repository

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

Citable link to this page

 

 
Title: Titin mutations in iPS cells define sarcomere insufficiency as a cause of dilated cardiomyopathy
Author: Hinson, John Travis; Chopra, Anant; Nafissi, N.; Polacheck, William; Benson, Craig Carlyle; Swist, S.; Gorham, Joshua McClean; Yang, Luhan; Schafer, S.; Sheng, Calvin Chen; Haghighi, Alireza; Homsy, Jason George; Hubner, N.; Church, George McDonald; Cook, S. A.; Linke, Wolfgang; Chen, Christopher; Seidman, Jonathan G.; Seidman, Christine Edry

Note: Order does not necessarily reflect citation order of authors.

Citation: Hinson, J. T., A. Chopra, N. Nafissi, W. J. Polacheck, C. C. Benson, S. Swist, J. Gorham, et al. 2015. “Titin Mutations in iPS Cells Define Sarcomere Insufficiency as a Cause of Dilated Cardiomyopathy.” Science 349 (6251) (August 27): 982–986. doi:10.1126/science.aaa5458.
Full Text & Related Files:
Abstract: 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.
Published Version: doi:10.1126/science.aaa5458
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:33896200
Downloads of this work:

Show full Dublin Core record

This item appears in the following Collection(s)

 
 

Search DASH


Advanced Search
 
 

Submitters