Key result
Myosins carrying early onset HCM mutations showed no clear differences in steady-state and transient kinetic properties compared to late onset mutations, though both differed from wild type.
Why the study?
The specific mechanistic changes in beta-MyHC leading to HCM remain incompletely understood, and whether early-onset mutations cause more severe molecular functional changes than late-onset mutations was unknown.
Do β-MyHC mutations resulting in early onset HCM show more severe molecular changes in function compared to later onset mutations?
Do β-MyHC mutations resulting in early onset HCM show more severe molecular changes in function compared to later onset mutations?
Early and late onset HCM mutations in the β-cardiac myosin heavy chain exhibit similar molecular functional changes, which are distinct from those seen in DCM.
No greater myosin dysfunction with early- versus late-onset HCM mutations; leaves open mechanisms of onset timing.
Hypertrophic Cardiomyopathy (HCM) is a common genetic disorder that typically involves left ventricular hypertrophy and cardiac hypercontractility. Mutations in β cardiac myosin heavy chain ( β-MyHC ) are a major cause of HCM, but the specific mechanistic changes to myosin function that lead to the disease remain incompletely understood. Predicting the severity of any single β-MyHC mutation is hindered by a lack of detailed evaluation at the molecular level. In addition, since the cardiomyopathy can take 20 or more years to develop, the severity of the mutations must be somewhat subtle. We hypothesized that mutations which result in early onset disease may show more severe molecular changes in function compared to later onset mutations. In this work, we performed steady-state and transient kinetic analyses of myosins carrying 1 of 7 missense mutations in the motor domain. Of these 7, 4 have been identified in early onset cardiomyopathy screens. The derived parameters were used to model the ATP driven cross-bridge cycle. Contrary to our hypothesis, the results show no clear differences between early and late onset HCM mutations. Despite the lack of distinction between early and late onset HCM, the predicted occupancy of the force-holding actin.myosin.ADP complex at [Actin] = 3 K app along with the closely related Duty Ratio ( DR ; fraction of myosin in strongly attached force-holding states) and the measured ATPases all change in parallel (in both sign and degree of change) compared to wild type (WT) values. Six of the 7 HCM mutations are clearly distinct from a set of DCM mutations previously characterized.
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Vera et al. (2019) studied Hypertrophic Cardiomyopathy. Early onset HCM mutations vs. Late onset HCM mutations and wild type was evaluated on Steady-state and transient kinetic properties. Myosins carrying early onset HCM mutations showed no clear differences in steady-state and transient kinetic properties compared to late onset mutations, though both differed from wild type.
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