Do missense mutations Phe110Ile and Glu244Asp in human cardiac troponin T alter force generation and Ca(2+) sensitivity in skinned cardiac muscle fibers?
The Glu244Asp mutation increases Ca2+ sensitivity, supporting the hypothesis that increased Ca2+ sensitivity drives the pathogenesis of poor-prognosis hypertrophic cardiomyopathy caused by troponin T mutations.
The functional effects of two missense mutations in human cardiac troponin T, Phe110Ile and Glu244Asp, associated with familial hypertrophic cardiomyopathy were examined by exchanging the bacterially expressed and purified mutant troponin T into rabbit cardiac skinned muscle fibers. Both mutations significantly increased the maximum force without affecting the cooperativity. The Glu244Asp mutation also increased the Ca(2+) sensitivity of the force generation, as in the case of other mutations associated with a poor prognosis. On the other hand, the Phe110Ile mutation, associated with a favorable prognosis, had no effect on the Ca(2+) sensitivity. The results strongly support the hypothesis that increased Ca(2+) sensitivity is responsible for the pathogenesis of hypertrophic cardiomyopathy with a poor prognosis caused by mutations in troponin T.
Nakaura et al. (Wed,) studied this question.
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