Marfan syndrome and related disorders: from gene to medicine.

Author: B. Loeys
Submitted: Sunday 12th of September 2010 07:43:03 AM
Submitted by: egf
Educational levels: expert, qc3

Abstract

Aortic aneurysms are an important cause of mortality in the western world. Monogenic disorders such as the Marfan syndrome (MFS) are an important genetic model for the pathogenesis of aortic aneurysm. In the MFS, progressive dilatation of the aortic root leads to aortic aneurysm and dissection, often associated with precocious death. Early pathogenetic models for MFS focused upon structural weakness of the tissues imposed by microfibrillar deficiency. However, recent studies of transgenic mouse models have challenged this model and demonstrated a central role for the upregulation of the TGFbeta signaling pathway. The discovery of a new aortic aneurysm syndrome, the Loeys-Dietz syndrome (LDS), confirmed the importance of the cytokine TGFbeta in aneurysm pathogenesis. The main distinguishing features between LDS and MFS include the presence of hypertelorism, cleft palate/bifid uvula and arterial tortuosity. LDS is caused by mutations in the genes encoding the receptors for TGFbeta (TGFBR1/2). This insight helped to elucidate the pathogenesis of other rare autosomal recessive connective tissue disorders, arterial tortuosity syndrome (ATS) and autosomal recessive cutis laxa (ARCL). ATS is caused by mutations in the SLC2A10 gene, coding for GLUT10, a member of the glucose transporter family. In analogy to LDS, we demonstrated an upregulation of TGFbeta in ATS and ARCL. Finally, all these insights have also lead to new therapeutic insights. In transgenic mouse models it was shown that losartan, an angiotensin II type 1 receptor with known inhibiting effects on TGFbeta, rescues the aortic phenotype. If these promising results are confirmed in human trials, losartan might have beneficial effects in the treatment of more common non-hereditary aortic aneurysms.

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B. Loeys. Marfan syndrome and related disorders: from gene to medicine.. EUROGENE portal. September 2010. online: http://eurogene.open.ac.uk/content/marfan-syndrome-and-related-disorders-gene-medicine

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