SMAD3

At least 35 mutations in the SMAD3 gene have been found to cause Loeys-Dietz syndrome type III. This disorder affects connective tissue, which gives structure and support to blood vessels, the skeleton, and many other parts of the body. Loeys-Dietz syndrome type III is characterized by abnormal blood vessels, skeletal and joint deformities, and skin abnormalities. Some of the mutations that cause this disorder insert or delete small amounts of genetic material in the SMAD3 gene, while other mutations result in a change to single protein building blocks (amino acids) in the SMAD3 protein. These mutations lead to the production of a nonfunctional SMAD3 protein. Despite a reduction in SMAD3 function, the TGF-β pathway is overactive. Researchers speculate that the activity of other proteins in this signaling pathway is increased to compensate for the lack of SMAD3 activity; however, the exact mechanism responsible for the increase in signaling is unclear. The overactive signaling pathway leads to dysregulated cell proliferation and gene activation, specifically affecting blood vessel, cartilage, and skin development. These changes lead to the abnormalities typical of Loeys-Dietz syndrome type III.

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