Marfan syndrome and related disorders 2011

Author: B. Loeys
Submitted: Monday 5th of September 2011 02:10:39 PM
Submitted by: egf
Educational levels: qc1, qc2, qc3


The recent study of different connective tissue diseases and their homologous mouse models have dramatically altered our understanding of their pathogenesis. A major breakthrough was realized with the study of mouse model of Marfan syndrome (MFS). The study of emphysema development in a fibrillin-1 deficient Marfan mouse model pinpointed altered TGFbeta signaling as the culprit in the pathogenesis. The role of TGFbeta pathway was also proven in the study of aortic walls of fibrillin-1 mouse models. This central role of TGFbeta in aortic aneurysm formation was confirmed by the identification mutations in the TGFBR1/2 genes (transforming growth factor beta receptor 1 or 2) as the cause of a new aortic aneurysm syndrome (Loeys-Dietz syndrome, LDS). This syndrome is characterized by the triad of hypertelorism, cleft palate/bifid uvula and widespread aneurismal disease with arterial tortuosity. Increased TGFbeta activity was demonstrated in aortic walls of both LDS and MFS patients. Interestingly, in another rare autosomal recessive connective tissue disorder, the arterial tortuosity syndrome, caused by deficiency of a glucose transporter, GLUT10 and also complicated with arterial aneurysms, we also showed TGFbeta upregulation in vascular smooth muscle cells. It is notable in this context that mice lacking the extracellular protein fibulin-5 have fragmented elastin and tortuous elongated aorta, but do not develop aortic aneurysms or dissections. This is also confirmed by our observations in patients with FBLN5-mutations, generating the hypothesis that fibulin-5 deficiency does not lead to altered TGFbeta activity and, hence, do not progress to aneurismal changes. By contrast, in our experience patients with fibulin-4 deficiency have a marked vascular phenotype with arterial tortuosity and aneurysms. Similarly mutant mice that have lost the related fibulin-4 gene show a striking aortic rupture phenotype and perinatal lethality. We confirmed altered TGFbeta signaling in aortic wall tissues of fibulin-4 deficient patients. Finally, perhaps most intriguingly we identified domain specific FBN1 mutations as the molecular cause of a congenital form of scleroderma, stiff skin syndrome (SSS). We demonstrated that altered cell-matrix interactions in SSS accompany excessive microfibrillar deposition, impaired elastogenesis, and increased TGF concentration and signaling in the dermis. As such, these human diseases and different mouse models have offered the opportunity to unravel the complex interaction between aortic integrity and extracellular matrix regulation of TGFbeta activity. There is increasing evidence indicating that misregulation of TGFbeta signaling owing to defects in extracellular proteins is centrally important to the development of aortic aneurysms. This view has now replaced the previous idea that aortic aneurysms were simply due to a structural deficiency of the elastin matrix in the aorta. Moreover, this new view offers excellent targets for therapeutic interventions.


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B. Loeys. Marfan syndrome and related disorders 2011. EUROGENE portal. September 2011. online:


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