The long-range decreases in dynamic stability due to these two single-site mutations suggest increases in flexibility that may weaken the ability of Tm to inhibit activity at low Ca(2+) concentrations for D175N and to a greater degree for E180G, which may contribute to differences in the severity of FHC.
In addition, because diastolic dysfunction in E180GTm mice is dependent on inotropic status, cardiovascular stress may play an important role in FHC pathogenesis.
FHC is caused by genetic mutations in several of the sarcomeric proteins, such as myosin heavy chain, troponin T, troponin I, alpha-tropomyosin, essential and regulatory light chains of myosin, and the cardiac myosin-binding protein C. FHC is genetically heterogeneous, and, therefore, it is associated with a very diverse clinical presentation in terms of altered cardiac structure and clinical manifestations.
Recently, mutations in genes of two thin filament regulatory proteins, cardiac troponin T(cTnT) and alpha-tropomyosin (alpha-Tm), have also been linked to FHC.
Mutations in five different loci cause FHC and 3 disease genes have been identified: beta cardiac myosin heavy chain, alpha tropomyosin and cardiac troponin T. Because these genes encode contractile proteins, other FHC loci are predicted also to encode sarcomere components.
Because alpha-tropomyosin and cardiac troponin T as well as beta myosin heavy chain mutations cause the same phenotype, we conclude that FHC is a disease of the sarcomere.