Key result
A premature truncation mutation in troponin T alters and destabilizes troponin binding to the thin filament, affecting transitions that regulate myosin binding and cardiac muscle contraction.
Premature truncation of troponin T causes hypertrophic cardiomyopathy by destabilizing troponin binding to the thin filament and disrupting the regulation of muscle contraction.
No change to HCM care from this animal model; leaves open human validation of troponin destabilization mechanisms.
Familial hypertrophic cardiomyopathy (FHC) is caused by missense or premature truncation mutations in proteins of the cardiac contractile apparatus. Mutant proteins are incorporated into the thin filament or thick filament and eventually produce cardiomyopathy. However, it has been unclear how the several, genetically identified defects in protein structure translate into impaired protein and muscle function. We have studied the basis of FHC caused by premature truncation of the most frequently implicated thin filament target, troponin T. Electron microscope observations showed that the thin filament undergoes normal structural changes in response to Ca(2+) binding. On the other hand, solution studies showed that the mutation alters and destabilizes troponin binding to the thin filament to different extents in different regulatory states, thereby affecting the transitions among states that regulate myosin binding and muscle contraction. Development of hypertrophic cardiomyopathy can thus be traced to a defect in the primary mechanism controlling cardiac contraction, switching between different conformations of the thin filament.
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Burhop et al. (2001) studied Familial hypertrophic cardiomyopathy. Premature truncation mutation of troponin T was evaluated on Thin filament function and structure. A premature truncation mutation in troponin T alters and destabilizes troponin binding to the thin filament, affecting transitions that regulate myosin binding and cardiac muscle contraction.
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