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The role of cardiac troponin T quantity and function in cardiac development and dilated cardiomyopathy

Ahmad, F and Banerjee, SK and Lage, ML and Huang, XN and Smith, SH and Saba, S and Rager, J and Conner, DA and Janczewski, AM and Tobita, K and Tinney, JP and Moskowitz, IP and Perez-Atayde, AR and Keller, BB and Mathier, MA and Shroff, SG and Seidman, CE and Seidman, JG (2008) The role of cardiac troponin T quantity and function in cardiac development and dilated cardiomyopathy. PLoS ONE, 3 (7).

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Abstract

Background: Hypertrophic (HCM) and dilated (DCM) cardiomyopathies results 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. © 2008 Ahmad et al.


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Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Ahmad, F
Banerjee, SK
Lage, ML
Huang, XN
Smith, SHshs46@pitt.eduSHS46
Saba, Ssfs3@pitt.eduSFS3
Rager, J
Conner, DA
Janczewski, AM
Tobita, Kkit3@pitt.eduKIT3
Tinney, JP
Moskowitz, IP
Perez-Atayde, AR
Keller, BB
Mathier, MAmam44@pitt.eduMAM44
Shroff, SGsshroff@pitt.eduSSHROFF
Seidman, CE
Seidman, JG
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorSchwartz, ArnoldUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 9 July 2008
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 3
Number: 7
DOI or Unique Handle: 10.1371/journal.pone.0002642
Schools and Programs: Graduate School of Public Health > Human Genetics
Swanson School of Engineering > Bioengineering
Refereed: Yes
PubMed ID: 18612386
Date Deposited: 18 Jul 2012 20:26
Last Modified: 03 Feb 2019 01:55
URI: http://d-scholarship.pitt.edu/id/eprint/12981

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