MYH7-Mutation Associated Allelic Imbalance in Familial Hypertrophic Cardiomyopathy: Molecular Mechanisms and Correlation with Disease Prognosis

Abstract

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 β-myosin heavy chain (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 and myocardium of genotyped and clinically well-characterized FHC-patients with different MYH7-mutations. We demonstrated an unequal allelic mRNA expression for each mutation analysed. The ratios of the mutated mRNA ranged from 29% to 66% in a mutation-specific manner. They were comparable in myocardium and soleus muscle and, importantly, were essentially the same at the protein level. 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 that mutation V606M disrupts an exonic splicing enhancer site. Additionally, for the mutation R723G severe changes in the mRNA secondary structure were predicted. Alternative splicing variants of the V606-allele and a structure-related increased stability of the R723G-allele thus may provide potential factors inducing altered levels of mutated MYH7-mRNA.