Lessons learned from the intersection of two frequent monogenic disorders : the Marfan syndrome and autosomal dominant polycystic kidney disease
Faculty of Medicine and Health Sciences
Proceedings of the Belgian Royal Academies of Medicine. - Brussels, 2012, currens
, p. 179-197
University of Antwerp
Aortic aneurysms, which lead to aortic dissections and ruptures if left untreated, are among the most life threatening forms of cardiovascular disease. Thoracic aortic aneurysm is a prominent clinical feature of several hereditary connective tissue disorders, including Marfan syndrome (MFS). MFS is caused by mutations in FBN1, which encodes fibrillin-1, an important extracellular matrix protein. Through the study of MFS mouse models and diseases related to MFS, it became clear that dysregulated TGF-β signaling contributes significantly to the pathogenesis of thoracic aortic aneurysms. Thoracic aortic and other aneurysms do also occur in autosomal dominant polycystic kidney disease (ADPKD). Mutations in PKD1 or PKD2 are responsible for ADPKD. The function of the polycystins, the proteins encoded by these two genes, is not clear yet, but an upregulation of TGF-β signaling has also been suggested as a pathogenetic mechanism. Although the main manifestation of ADPKD consists of renal cysts, a clear cardiovascular involvement with aneurysm formation has been demonstrated. Vice versa, kidney cysts have been observed in MFS. This clinical overlap suggests a mechanistic link between ADPKD and MFS. This link provides interesting opportunities for investigations on the pathogenic mechanisms of both diseases, more in particular the mechanisms leading to formation of thoracic aortic aneurysms.