07.04 Loeys-Dietz Syndrome (LDS): In Vitro Studies of Skin Fibroblasts Showing Differences Between Mutations in the TGFBR1 and TGFBR2 Genes

LDS is a newly described condition caused by mutations in the genes encoding transforming growth factor-beta (TGF-B) receptors 1 and 2. The condition is associated with vascular tortuousity and formation and rupture of arterial aneurysms. Skin fibroblasts were cultured from 3 patients with confirmed LDS. All 3 cases had typical phenotypic features including a dilated aortic root and tortuous aortic arch and branches. DNA analysis revealed in case 1 a missense mutation of TGFBR1 gene (c.722C>T), in case 2 a missense mutation of TGFBR1 (c.1460G>A) and in case 3 a missense mutation of TGFBR2 (c.1583G>A). In vitro studies of skin fibroblasts from these patients indicated that both patients carrying mutations of TGFBR1 demonstrated a significant deficiency in the net expression of elastin and fibrillin genes (assessed by RT-PCR) and did not deposit elastic fibers in primary cultures. In contrast, they produced normal levels of auxiliary components of elastic fibers (fibulins 1, 2 and 5) and deposited normal collagen fibers. Interestingly, fibroblasts derived from patients with mutation of TGFBR2 genes produced normal components of elastic fibers, but displayed intracellular retention of collagen type 1 and had significantly lower deposition of mature collagen fibers. Our findings indicate that the clinical manifestations associated with TGFBR1 and 2 mutations, although similar, are caused by different mechanisms.