Proteomic and Gene Expression in Hereditary Disorders of Connective Tissue

National Institute On Aging

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Abstract

Hereditary disorders of connective tissue, such as Ehlers Danlos (EDS), Loeyz-Dietz, Marfan, Stickler, Fibromuscular Dysplasia (FMD), Vascular EDS (VEDS), and Familial Aneurysm syndromes are genetically and clinically heterogeneous. While many of the causative genes are known, many others are not. Many affected families may have mutations in unique genes that may be impractical to identify with usual methodologies. [unreadable] [unreadable] The goal of this project is to develop a comprehensive gene expression and a complementary protein profiling approach utilizing samples collected from affected patients through an IRP-approved protocol (2003-086). The hypothesis is that conditions that share a similar phenotype in terms of complications, regardless of the underlying gene mutation, the expression and proteomic profiles wil turn out to similar and amenable to treatment utilizing the same targets. For example, Loeyz-Dietz syndrome is caused by mutations in TGFbetaR1&2, which are cell surface receptors, and Marfan syndrome is caused by mutations in FBN1, a structural extracellular matrix protein. Despite different causative mutations, both syndromes lead to derangements of the TGFbeta pathway, have phenotypic similarities, and are amenable to treatment by losartan at angiotensin receptor blocker, and a modulator of TGFbeta expression. [unreadable] [unreadable] We are utilizing whole genome expression arrays, RT-PCR 2-D protein electrophoresis, mass spectroscopy, western blot and immunochemistry approaches to investigate the consequences of known mutations in VEDS patients, and comparing the profiles patients without such mutations but with similar phenotypic features, such as those seen in FMD and Familial Aneurysm syndromes. Initial results show that the Bone Morphogenic Protein pathway may be altered in VEDS and in a recently identified COL5A1 haploinsufficient Familial Aneurysm syndrome, but not in FMD. By contrast, the TGFB pathway is altered in FMD, but not in VEDS. This is envisioned as a long term project given that more than 300 unique patient fibroblast lines from connective tissue patients are being studied in the lab.