Clin Res Cardiol 101, Suppl 1, April 2012

P989 - Allelic imbalance of several Familial Hypertrophic Cardiomyopathy-mutations in the ß-myosin is associated with disease prognosis
J. Montag1, S. Tripathi1, A.-L. Weber1, I. Schultz1, E. Becker1, B. Borchert1, F. Navarro-Lopez2, A. Francino2, A. Perrot3, C. Özcelik4, W. McKenna5, K. J. Osterziel6, B. Brenner1, T. Kraft7
1Institut für Molekular- und Zellphysiologie OE4210, Medizinische Hochschule Hannover, Hannover; 2Molecular Cardiology, University of Barcelona Hospital Clinic, Barcelona, Spanien; 3Experimental & Clinical Research Center(ECRC), Charité - Universitätsmedizin Berlin, Campus Charité Buch, Berlin; 4CC13, Medizinische Klinik m. S. Kardiologie, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin; 5The Heart Hospital, University College London NHS Foundation Trust, London, Großbritannien; 6Kardiol. Gemeinschaftspraxis, Amberg; 7Molekular- und Zellphysiologie, Medizinische Hochschule Hannover, Hannover;
Familial Hypertrophic Cardiomyopathy (FHC) is the most common inherited disease of the heart and is transmitted autosomal dominantly. 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. Among these, 30-40% of the patients are affected by missense mutations in one allele of the ß-myosin heavy chain (MYH7). The pathomechanisms underlying disease progression are still unknown.
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 G584R, V606M, R719W, R723G, I736T, and G741R MYH7-mutations. We demonstrated an unequal allelic mRNA expression for the mutations. Interestingly, the ratios of the mutated mRNA were specific for the mutations and 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 severe changes in the mRNA secondary structure for the mutation R723G. Thus a structure-related increased stability of the R723G-allele thus may provide a potential factor inducing altered levels of mutated MYH7-mRNA.
Clin Res Cardiol 101, Suppl 1, April 2012
Zitierung mit Vortrags- oder Posternummer s.o.
DOI 10.1007/s00392-012-1100-6