Familial Hypertrophic Cardiomyopathy (FHC) is the most common inherited disease of the heart and transmitted autosomal dominantly. FHC is mostly caused by mutations in genes encoding for sarcomeric proteins, 30-40% of the patients are affected by missense mutations in one allele of the ventricular myosin isoform, the ß-myosin heavy chain (ß-MyHC). Here we report the analysis of the ß-MyHC G741R-mutation in slow Musculus soleus fibers that also express the ventricular isoform of the myosin heavy chain.

Three FHC-patients from a Spanish family were identified to harbour the G741R mutation. The severity of the disease ranged from NYHA class II to IV, all patients provided a severe hypertrophy with interventricular septum thickness of 16-24 mm. Functional analysis of chemically permeabilized fibers of M. soleus showed higher calcium-sensitivity and also a slightly increased maximum force in the most severely affected patient. Fiber stiffness under relaxing conditions and in rigor, as well as in vitro gliding velocity of actin filaments on isolated myosin were unchanged. In previous studies we found that minor functional effects of ß-MyHC-mutations are often associated with a low expression of the mutated as compared to the wildtype allele (allelic imbalance). Expression revealed fractions of mutated ß-MyHC-mRNA and protein clearly below 50%. Interestingly, the least affected patient expressed the lowest level of mutated ß-MyHC.

We conclude that mutation G741R might trigger the cardiac FHC-phenotype by increasing calcium sensitivity and force of the myocytes. Further analysis has to reveal whether these changes are due to effects of the mutation on cross-bridge cycling kinetics. In summary with our previous findings we now can show that in FHC the calcium sensitivity can either be increased (this mutation), decreased (R719W, R723G), or remain unchanged (I726T, R453C). This argues against the current assumption that FHC-mutations generally increase calcium-sensitivity.