Transforming Growth Factor β Signaling Perturbation in the Loeys-Dietz Syndrome

The transforming growth factor beta (TGF beta) superfamily consists of multipotential secreting cytokines that mediate many key events in normal cellular growth and development, including differentiation, proliferation, motility, organization and death. TGF beta s act as ligand for 3 classes of cell surface receptors, the transmembrane serine-threonine kinase receptors, TGF beta receptor type I (TGF beta RI) and type 2 (TGF beta RII), and TGF beta RIII receptors which include an ubiquitous extracellular beta-glycan and the membrane glycoprotein endoglin (CD105). Binding of TGF beta s to their receptors initiates diverse cellular responses resulting in the phosphorilation of Smad proteins, which then translocate to the nucleus and regulate the transcription of target genes. Perturbation of TGF beta signaling has been implicated in various human disorders including cancer, fibrosis and auto-immune diseases. Recently, mutations in TGF beta R1 and TGF beta R2 genes have been found in association with a continuum of clinical features with widespread vascular involvement. The extreme of clinical severity is represented by the Loeys-Dietz syndrome (LDS), an autosomal dominant disorder characterized by hypertelorism, bifid uvula, and/or cleft palate, and aggressive arteriopathy causing arterial tortuosity as well as life-threatening complications such as vascular aneurysms and dissections. Elastin disarray, loss of elastic fibre architecture and increased collagen expression in the arterial wall are the pathologic hallmark of LDS. In the present review article we will provide details on the activation of TGF beta cascade, on the clinical features of LDS, as well as on the mechanisms of TGF beta signaling perturbation leading to this condition and the potential role of the antagonism of TGF beta activity in disease management.