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Dilated cardiomyopathy is a primary disorder of the cardiac muscle. The structural alterations of the cardiac muscle lead to heart failure which results in death in almost every second case within two years after diagnosis. Therefore DCM is one of the most common causes of heart failure and the most common indication for cardiac transplantation. Due to linkage analysis and the analysis of candidate genes of families with DCM, mutations in more than 20 genes were discovered by now. One of these genes is the ankyrin-repeat-domain-1 gene (ANKRD1) which encodes for the cardiac-ankyrin-repeat protein (CARP). On the basis of genetic and functional analysis of CARP mutations the hypothesis for a possible role of CARP being responsible for causing DCM was confirmed. To date, genetic variants in CARP account for approximately two percent of all DCM cases.
In this thesis the ANKRD1 was examined for further genetic alterations that could specify the impact of the gene on the pathogenesis of DCM. A systematic mutation analysis with the ANKRD1 gene in 161 DCM patients was accomplished. The genomic DNA was extracted from whole blood and the nine exons of the gene were amplified by PCR. Subsequently the single-strand-conformation-polymorphism analysis (SSCP) was performed. In case of a mobility-shift of a single-stranded DNA fragment the particular exon was sequenced. A silent mutation in exon 2, one unknown polymorphism in exon 1 and six known polymorphisms were identified. It remains uncertain whether the silent mutation has an impact on the pathogenesis of DCM. Further experiments would have to be performed to investigate possible negative effects regarding the functional integrity and expression of CARP due to the nucleotid substitution. One unknown polymorphism in exon 1 was identified in 1.2% of the analyzed cohort. 202 healthy control subjects were also tested for this polymorphism which occured in 1.0 % of the cases. Because of the non-significant result it can be assumed that the polymorphism in exon 1 is not causing the disease. The prevalences of the identified polymorphisms in intron 4, 7 and 9 are already known.
Taken together this thesis could not confirm the published prevalences of mutations in the ANKRD1 gene, which according to the literature occured in approximately two percent of the DCM cases. The results indicate that mutations in ANKRD1 can be only responsible for a minority of DCM patients. This finding underlines that DCM is genetically a heterogenous disease. Further systematic screenings in DCM are necessary for an early diagnosis and optimal treatment.