Different Functional Properties of Troponin T Mutants that Cause Dilated Cardiomyopathy

The effects of Troponin T (TnT) mutants R141W and ΔK210, the only two currently known mutations in TnT that cause dilated cardiomyopathy(DCM) independent of familial hypertrophic cardiomyopathy (FHC), and TnT-K273E, a mutation that leads to a progression from FHC to DCM, were investigated. Studies on the Ca²⁺ sensitivity of force development in porcine cardiac fibers demonstrated that TnT-ΔK210 caused a significant decrease in Ca²⁺ sensitivity, whereas the TnT-R141W did not result in any change in Ca²⁺ sensitivity when compared with human cardiac wild-type TnT (HCWTnT). TnT-ΔK210 also caused a decrease in maximal force when compared with HCWTnT and TnT-R141W. In addition, the TnT-ΔK210 mutant decreased maximal ATPase activity in the presence of Ca²⁺. However, the TnT-K273E mutation caused a significant increase in Ca ²⁺ sensitivity but behaved similarly to HCWTnT in actomyosin activation assays. Inhibition of ATPase activity in reconstituted actin-activated myosin ATPase assays was similar for all three TnT mutants and HCWTnT. Additionally, circular dichroism studies suggest that the secondary structure of all three TnT mutants was similar to that of the HCWTnT. These results suggest that a rightward shift in Ca²⁺ sensitivity is not the only determinant for the phenotype of DCM.