Illustrated here is an example of our collaborative work using a transgenic mouse model of human familial hypertrophic cardiomyopathy (FHC). The Arg403Gln (R403Q) missense mutation in the b-myosin heavy chain is one of the most lethal and, consequently, one of the most studied inherited diseases of the heart. Results from one study using the Seidman R403Q/+ mouse (Blanchard et al., Circ. Res. 84(4), 475-483, 1999) suggest that the point mutation in the myosin motor protein alters the affinity of myosin for actin, such that cooperative activation of the thin filament and tension development is promoted at submaximal calcium concentration, while rate of work production and power output is depressed in the organized filament lattice. The direct but variable effect of the mutation (facilitating or debilitating, depending on the level of activation), together with variable patterns of fibrosis and myofibrillar disorder secondary to the mutation, undoubtedly contributes to the diversity of clinical symptoms observed in FHC.
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