The "final common pathway" hypothesis and inherited cardiovascular disease- The role of cytoskeletal proteins in dilated cardiomyopathy

The genetic basis of a number of inherited cardiovascular diseases has been elucidated over the last few years, including the long QT syndromes, hyper trophic cardiomyopathy and dilated cardiomyopathy. While genetic heterogene ity has been demonstrated in most of these diseases, a pattern has emerged, specifically that genes encoding proteins with similar functions or involv ed in the same pathway are responsible for a particular disease or syndrome . Based on this observation we proposed the "final common pathway" hypothes is. In the case of the arrhythmogenic disorders, the long QT syndromes and Brugada syndrome, mutations have been described in a number of ion channel proteins. including cardiac potassium (KVLQT1, HERG and minK) and sodium (S CN5A) channels. Thus, using the "final common pathway" hypothesis we have p roposed these diseases to be "ion channelopathies". Hypertrophic cardiomyop athy appears to be a disease of the sarcomere ("sarcomyopathy") since all t he disease-causing mutations have been identified in the gene encoding many of the sarcomeric proteins, including beta-myosin heavy chain, alpha-tropo myosin, troponin I and troponin T as well as in actin, close to the beta-my osin heavy chain binding site. The genes responsible for familial dilated c ardiomyopathy have been less well characterized. For X-linked dilated cardi omyopathy, mutations in the dystrophin and G4.5 genes have been reported. I n addition, mutations in actin (close to the dystrophin binding domain) and desmin, a component of the intermediate filaments, have been reported. How ever, the genes at a further 6 loci associated with autosomal dominant dila ted cardiomyopathy (associated with conduction disease in 2 cases) remain u nidentified. Due to the mutations in dystrophin, actin and desmin, we have proposed that dilated cardiomyopathy is a "cytoskeletalopathy", and we are currently inv estigating the involvement of these genes in patients.