Creation of a transgenic animal model of hypertrophic cardiomyopathy caused by cardiac troponin T mutation.

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[Purpose] Previous finding suggest that myocardial hypertrophy seen in patients with hypertrophic cardiomyopathy (HCM) caused by β-myosin heavy chain mutation is a compensatory mechanism for depressed myocyte contraction. Although the patients with HCM caused by the cardiac TnT (TnT) mutations are typically associated with an incomplete disease penetrance and mild to moderate cardiac hypertrophy, their prognosis is though to poor. It remains unknown whether a mode of pathogenesis for TnT mutation is similar to that for myosin heavy chain mutation. To clarify this question, two truncated cardiac TnTs produced by a splice donor site mutation in intron 15 and three missense mutations (Phe110lle, Glu244Asp and Arg278Cys) were constructed. [methods] Human cardiac TnT cDNA was cloned by RT-PCR, then above mutations were inserted into this cDNA using PCR based procedure. Those mutants were expressed in E. coli and partially (50%-55%) exchanged into rabbit permeabilized cardiac muscle fibers. [Results] The muscle fibers exchanged with the splice donor site mutations conferred a lower cooperativity, while the fibers exchanged with missense mutations did not affects the cooperativity, compared to wild type TnT. Glu244Asp mutation augmented both a CaィイD12+ィエD1 sensitivity and a maximum force-generating capability, whereas Arg278Cys mutation showed the higher CaィイD12+ィエD1 sensitivity without any effects on the maximum force. In contrast, Phe110lle showed marked increase in CaィイD12+ィエD1 -activated maximum force without CaィイD12+ィエD1 sensitizing effect. [Conclusions] There results indicate that a hypercontractility may be a common feature of the cardiac muscle expressing mutant troponin T. Moreover, it is also suggest that cardiac hypertrophy in patients with hypertrophic cardiomyopathy caused by troponin T mutation is not a consequence of depressed cardiac function.