A deletion mutation ΔK210 in cardiac troponin T (cTnT) was recently found to cause familial dilated cardiomyopathy (DCM). To explore the effect of this mutation on cardiac muscle contraction under physiological conditions, we determined the Ca 2+ -activated force generation in permeabilized rabbit cardiac muscle fibers into which the mutant and wild-type cTnTs were incorporated by using our TnT exchange technique. The free Ca 2+ concentrations required for the force generation were higher in the mutant cTnT-exchanged fibers than in the wild-type cTnT-exchanged ones, with no statistically significant differences in maximal force-generating capability and cooperativity. Exchanging the mutant cTnT into isolated cardiac myofibrils also increased the free Ca 2+ concentrations required for the activation of ATPase. In contrast, a deletion mutation ΔE160 in cTnT that causes familial hypertrophic cardiomyopathy (HCM) decreased the free Ca 2+ concentrations required for force generation, just as in the case of the other HCM-causing mutations in cTnT. The results indicate that cTnT mutations found in the two distinct forms of cardiomyopathy (i.e., HCM and DCM) change the Ca 2+ sensitivity of cardiac muscle contraction in opposite directions. The present study strongly suggests that Ca 2+ desensitization of force generation in sarcomere is a primary mechanism for the pathogenesis of DCM associated with the deletion mutation ΔK210 in cTnT.

Morimoto, S., Lu, Q.-W., Harada, K., Takahashi-Yanaga, F., Minakami, R., Ohta, M., Sasaguri, T., & Ohtsuki, I. (2002). Ca 2+ -desensitizing effect of a deletion mutation ΔK210 in cardiac troponin T that causes familial dilated cardiomyopathy. Proceedings of the National Academy of Sciences, 99(2), 913–918.