| Autor: |
McAfee, Quentin, Chen, Christina Yingxian, Yang, Yifan, Caporizzo, Matthew A., Morley, Michael, Babu, Apoorva, Jeong, Sunhye, Brandimarto, Jeffrey, Bedi Jr, Kenneth C., Flam, Emily, Cesare, Joseph, Cappola, Thomas P., Margulies, Kenneth, Prosser, Benjamin, Arany, Zolt |
| Předmět: |
|
| Zdroj: |
Science Translational Medicine; 11/3/2021, Vol. 13 Issue 618, p1-11, 11p |
| Abstrakt: |
Tracking titin in dilated cardiomyopathy: Truncating variants in TTN, the gene encoding the titin protein, underlie 15 to 25% of cases of nonischemic dilated cardiomyopathy (DCM), but whether the disease is caused by haploinsufficiency or the presence of truncated titin proteins is not yet clear. Here, using tissues from the hearts of patients with DCM and TTN-truncating variants as well as human induced pluripotent stem cells differentiated into cardiomyocytes, Fomin et al. and McAfee et al. identified both the presence of truncated titin proteins and less-abundant full-length titin protein. These findings suggest that the presence of truncated titin proteins as "poison peptides" and titin haploinsufficiency both contribute to the pathogenesis of disease and should support the investigation of targeted therapies to treat DCM caused by TTN-truncating variants. Truncating variants in TTN (TTNtvs) are the most common known cause of nonischemic dilated cardiomyopathy (DCM), but how TTNtvs cause disease has remained controversial. Efforts to detect truncated titin proteins in affected human DCM hearts have failed, suggesting that disease is caused by haploinsufficiency, but reduced amounts of titin protein have not yet been demonstrated. Here, we leveraged a collection of 184 explanted posttransplant DCM hearts to show, using specialized electrophoretic gels, Western blotting, allelic phasing, and unbiased proteomics, that truncated titin proteins can quantitatively be detected in human DCM hearts. The sizes of truncated proteins corresponded to that predicted by their respective TTNtvs; the truncated proteins were encoded by the TTNtv-bearing allele; and no degradation fragments from protein encoded by either allele were detectable. In parallel, full-length titin was less abundant in TTNtv+ than in TTNtv− DCM hearts. Disease severity or need for transplantation did not correlate with TTNtv location. Transcriptomic profiling revealed few differences in splicing or allelic imbalance of the TTN transcript between TTNtv+ and TTNtv− DCM hearts. Studies with isolated human adult cardiomyocytes revealed no defects in contractility in cells from TTNtv+ compared to TTNtv− DCM hearts. Together, these data demonstrate the presence of truncated titin protein in human TTNtv+ DCM, show reduced amounts of full-length titin protein in TTNtv+ DCM hearts, and support combined dominant-negative and haploinsufficiency contributions to disease. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
|
