Familial Hypertrophic Cardiomyopathy (FHC) is an autosomal dominant disease of the heart. The severity of the disease ranges from mild cases to sudden cardiac death or progression to heart failure. 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 b-myosin heavy chain gene (MYH7).

To gain further insights into the mechanisms of FHC-progression in heterozygous patients we performed a comparative expression analysis of the wildtype and the mutated MYH7-allele. We have analyzed samples from Musculus soleus of genotyped and clinically well-characterized FHC-patients with different MYH7-mutations. We observed a mutation-specific unequal allelic mRNA expression for each mutation analysed ranging from 29% to 66%. At the protein level, these ratios were essentially the same. For two FHC-mutations we could additionally obtain material from the myocardium. MYH7 mRNA-expression analysis revealed that the fractions of mutated mRNA are mutation-specific and comparable in slow-twitch muscle and myocardium even in unrelated patients. Intriguingly, we observed a correlation between life expectancy and fraction of mutated mRNA or protein. Thus, the allelic imbalance may provide a novel factor underlying the progression of FHC.

Our results suggest that the allelic imbalance is induced by differential regulation of the mutated MYH7 mRNA-expression. Thus we aimed to identify molecular mechanisms that may account for the mutation-related different mRNA levels. Bioinformatical analysis revealed i.e. disruption in splicing enhancer sites and changes in the secondary mRNA-structure. These changes thus may provide potential factors inducing altered levels of mutated MYH7-mRNA.