Research Report 2010 - MDC

Ludwig ThierfelderStructure of the GroupGroup LeaderProf. Dr. Ludwig ThierfelderScientistsDr. Florian BlaschkeDr. Jörg DrenckhahnDr. Brenda Gerull*Dr. Michael Gramlich*Dr. Arnd HeuserDr. Susanne Probst*Dr. Sabine KlaassenDr. Bertold StrukCardiovascular Molecular GeneticsMolecular genetics of cardiomyopathies, regeneration of the embryonic heart andelucidation of the molecular pathology/genetics of vascular lesions are the majortopics of our research group. A number of cardiomyopathy causing mutations have beenidentified by our research group and the molecular pathology of those mutations iscurrently under investigation. The capacity of the embryonic heart to regenerate fromgenetic damage is based on a complex mechanism of compensatory proliferation, inhibitionof apoptosis, and adaptation of various signaling pathways. Liver X receptor agonists arepotential targets for the treatment of metabolic, inflammatory and cardiovascular diseasesand negatively interfere with cytokine-induced nuclear receptor corepressor dissociationfrom the C-reactive protein promoter, thus maintaining this gene in a repressed state.Genetics of cardiomyopathiesBrenda Gerull, Sabine Klaassen, Arnd Heuser,Michael GramlichArrhythmogenic right ventricular cardiomyopathy(ARVC) is an inherited heart disease predominantlyaffecting the right ventricle and a prevalent cause ofventricular arrhythmias and sudden death, especially inyoung adults. Genetically, heterozygous loss-of-functionmutations in desmosomal proteins (desmocollin2,desmoglein2, plakoglobin, desmoplakin, andplakophilin2) have been mainly associated with ARVC.We have described mutations in plakophilin2 (PKP2)and desmocollin2 (DSC2) as a cause of autosomal dominantARVC. PKP2 mutations account for a significantproportion of ARVC cases (10-45%). PKP2 and DSC2 arecomponents of the desmosomal intercellular junctioncomplex (see figure 1) known to be essential for maintainingtissue integrity and increasingly implicated incell signaling. While the involvement of multipledesmosomal protein genes has led to speculationregarding the sensitivity of myocardium to mechanicaldisruption, the pathogenic mechanisms leading toARVC in humans are largely unknown. We currently tryto elucidate the genetic and molecular mechanisms ofvarious human PKP2 mutations and their consequencesin the pathology of the intercellular junction complexusing cell culture experiments and transgenic mousemodels. Furthermore, we investigate different knockoutmodels of desmosomal components to define theadhesive and signaling contributions of thesel proteinsin the maintenance of cardiac tissue.Left ventricular noncompaction of the myocardium(LVNC) has recently been recognized as a distinct primarycardiomyopathy with a genetic etiology. LVNC ischaracterized by a unique congenital cardiac morphology,consisting of numerous, excessively prominentventricular trabeculations and deep intertrabecularrecesses. The heterogeneity of the clinical featuresincludes progressive deterioration in cardiac functionresulting in congestive heart failure, arrhythmias,thrombembolic events, and sudden cardiac death. Thedisorder is assumed to result from an intrauterinearrest in the process of compaction of the developingmyocardium. We found mutations in genes encodingsarcomere proteins in a significant proportion of LVNCpatients. Heterozygous mutations in genes encoding –myosin heavy chain (MYH7), -cardiac actin (ACTC), andcardiac troponin T (TNNT2) account for 17% of cases ofisolated LVNC in adult patients. As hypertrophic cardiomyopathy(HCM) and dilated cardiomyopathy42 Cardiovascular and Metabolic Disease Research