P1.01 Treatment with Dexamethasone Reverses Impared Elastogenesis and Collagenogenesis in Cultures of Fibroblasts from Patients with Loeys-Dietz Syndrome (LDS)

LDS is an autosomal dominant condition caused by mutations in the TGFBR1 and TGFBR2 genes. The condition is associated with vascular tortuousity and formation and rupture of arterial aneurysms. Recent successful use of losartan in the Marfan mouse model has raised hope for medical treatment of LDS. Here we report a promising in vitro response in dexamethasone-treated cultured fibroblasts from three LDS patients. All 3 cases had typical phenotypic features includinga 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 with TGFBR1 mutations demonstrated a significant deficiency in the expression of elastin and fibrillin genes (RT-PCR). In contrast, they deposited normal collagen fibres. Fibroblasts derived from the patient with a TGFBR2 mutation produced normal elastic fibers, but displayed intracellular retention of collagen type 1 and significantly lower deposition of mature collagen fibers. Addition of 10-5M of dexamethasone to cultured fibroblasts restored normal elastogenesis in cultures of fibroblasts with mutations of TGFBR1 gene and normalized collagen fiber production in fibroblasts carrying TGFBR2 gene mutation. Further studies are needed to establish whether dexamethasone can have a therapeutic effect in patients with LDS. Prenatal treatment of affected fetuses may prevent or ameliorate the clinical manifestations of this disorder.