Identifizierung von Mutationen im Desmin-Gen bei Patienten mit dilatativer Kardiomyopathie

Dilated cardiomyopathy (DCM) is one of the most frequent non-ischaemic heart diseases, resulting in systolic heart failure and cardiac death. Mutations in proteins expressed in the myocardium appear to account for approximately one-third or more of all cases, and in the majority of familiar cases, mutations in cytoskeletal proteins have been identified as the genetic origin of the disease. The intermediate filament protein desmin, which is localized in sarcomeric distribution in cardiomyocytes, is believed to be responsible for up to 2% of all cases of familial DCM. Pathogenic mutations in the desmin gene have been associated with a broad range of clinical symptoms affecting myocardial, smooth and skeletal muscles, giving rise to a disease entity commonly called desminopathy. In this genetic study, a total study cohort of 235 patients diagnosed as suffering from DCM was tested for the presence of point mutations and/or single nucleotide polymorphisms (SNPs) within the human desmin gene. Single-strand conformation polymorphism analysis (SSCP) and denaturing gradient-gel electrophoresis (DGGE) were used as genetic screening procedures to identify disease-associated desmin mutations. The results from this study demonstrated the presence of the synonymous single nucleotide polymorphism p.L136L in six study participants and, in addition, the low pathogenic p.A213V mutation in two patients. The latter missense mutation resulted in a substitution of a critical amino acid residue in the 1B domain of desmin. The p.A213V mutation was noticed for its low penetrance, since it was also detected in non-affected, healthy family members from one of the index patients. Thus, the p.A213V mutation seems to have a modifying impact on the phenotype of the disease, rather than constituting an obligatory pathological factor for developing the disease. In addition, we show that the applied PCR-based screening procedures applied here are in general useful methods in identifying disease-associated mutations in a cytoskeletal protein such as desmin.