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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 Ca 2+  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 (TG WT ) or DCM mutant (TG K210Δ )  Tnnt2 . Crossbreeding produced mice lacking one allele of  Tnnt2 , but carrying wildtype ( Tnnt2   +/− /TG WT ) or mutant ( Tnnt2   +/− /TG K210Δ ) 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   +/− /TG K210Δ  mice had severe DCM, TG K210Δ  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   +/− /TG K210Δ  relative to TG K210Δ  mice (2.42±0.08,  p  = 0.03).  Tnnt2   +/− /TG K210Δ  muscle showed Ca 2+  desensitization (pCa 50  = 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 Ca 2+  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.

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