The Role of Cardiac Troponin T Quantity and Function in Cardiac Development and Dilated Cardiomyopathy

DSpace/Manakin Repository

The Role of Cardiac Troponin T Quantity and Function in Cardiac Development and Dilated Cardiomyopathy

Citable link to this page

. . . . . .

Title: The Role of Cardiac Troponin T Quantity and Function in Cardiac Development and Dilated Cardiomyopathy
Author: Ahmad, Ferhaan; Banerjee, Sanjay K.; Lage, Michele L.; Huang, Xueyin N.; Saba, Samir; Rager, Jennifer; Janczewski, Andrzej M.; Tobita, Kimimasa; Tinney, Joseph P.; Moskowitz, Ivan P.; Keller, Bradley B.; Mathier, Michael A.; Shroff, Sanjeev G.; Smith, Stephen H.; Conner, David Atwater; Perez-Atayde, Antonio Rafael; Seidman, Christine Edry; Seidman, Jonathan G.

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

Citation: Ahmad, Ferhaan, Sanjay K. Banerjee, Michele L. Lage, Xueyin N. Huang, Stephen H. Smith, Samir Saba, Jennifer Rager, et al. 2008. The Role of cardiac troponin T quantity and function in cardiac development and dilated cardiomyopathy. PLoS ONE 3(7): e2642.
Full Text & Related Files:
Abstract: Background: Hypertrophic (HCM) and dilated (DCM) cardiomyopathies result from sarcomeric protein mutations, including cardiac troponin T (cTnT, TNNT2). We determined whether TNNT2 mutations cause cardiomyopathies by altering cTnT function or quantity; whether the severity of DCM is related to the ratio of mutant to wildtype cTnT; whether Ca2+ desensitization occurs in DCM; and whether absence of cTnT impairs early embryonic cardiogenesis. Methods and Findings: We ablated Tnnt2 to produce heterozygous Tnnt2+/− mice, and crossbreeding produced homozygous null Tnnt2−/− embryos. We also generated transgenic mice overexpressing wildtype (TGWT) or DCM mutant (TGK210Δ) Tnnt2. Crossbreeding produced mice lacking one allele of Tnnt2, but carrying wildtype (Tnnt2+/−/TGWT) or mutant (Tnnt2+/−/TGK210Δ) transgenes. Tnnt2+/− mice relative to wildtype had significantly reduced transcript (0.82±0.06[SD] vs. 1.00±0.12 arbitrary units; p = 0.025), but not protein (1.01±0.20 vs. 1.00±0.13 arbitrary units; p = 0.44). Tnnt2+/− mice had normal hearts (histology, mass, left ventricular end diastolic diameter [LVEDD], fractional shortening [FS]). Moreover, whereas Tnnt2+/−/TGK210Δ mice had severe DCM, TGK210Δ mice had only mild DCM (FS 18±4 vs. 29±7%; p<0.01). The difference in severity of DCM may be attributable to a greater ratio of mutant to wildtype Tnnt2 transcript in Tnnt2+/−/TGK210Δ relative to TGK210Δ mice (2.42±0.08, p = 0.03). Tnnt2+/−/TGK210Δ muscle showed Ca2+ desensitization (pCa50 = 5.34±0.08 vs. 5.58±0.03 at sarcomere length 1.9 µm, p<0.01), but no difference in maximum force generation. Day 9.5 Tnnt2−/− embryos had normally looped hearts, but thin ventricular walls, large pericardial effusions, noncontractile hearts, and severely disorganized sarcomeres. Conclusions: Absence of one Tnnt2 allele leads to a mild deficit in transcript but not protein, leading to a normal cardiac phenotype. DCM results from abnormal function of a mutant protein, which is associated with myocyte Ca2+ desensitization. The severity of DCM depends on the ratio of mutant to wildtype Tnnt2 transcript. cTnT is essential for sarcomere formation, but normal embryonic heart looping occurs without contractile activity.
Published Version: doi:10.1371/journal.pone.0002642
Other Sources:
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at
Citable link to this page:

Show full Dublin Core record

This item appears in the following Collection(s)


Search DASH

Advanced Search