SMAD3

The SMAD3 gene provides instructions for making a protein involved in transmitting chemical signals from the cell surface to the nucleus. This signaling pathway, called the transforming growth factor beta (TGF-β) pathway, allows the environment outside the cell to affect how the cell produces other proteins. The signaling process begins when a TGF-β protein attaches (binds) to a receptor on the cell surface, which activates a group of related SMAD proteins (including the SMAD3 protein). These SMAD proteins bind together to form a protein complex, which then moves to the cell nucleus. In the nucleus, the SMAD protein complex binds to specific areas of DNA to control the activity of particular genes and regulate cell proliferation.

By controlling gene activity and regulating cell proliferation, the SMAD3 protein serves both as a transcription factor and as a tumor suppressor. Transcription factors help control when particular genes are turned on or off, and tumor suppressors keep cells from growing and dividing too fast or in an uncontrolled way.

Loeys-Dietz syndrome - caused by mutations in the SMAD3 gene

At least eight mutations in the SMAD3 gene have been found to cause Loeys-Dietz syndrome type III. This a disorder that affects the connective tissue, which gives structure and support to blood vessels, the skeleton, and many other parts of the body. Some of these mutations 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. However, the SMAD protein complex is overactive, indicating that other, unknown mechanisms compensate for the lack of SMAD3 protein. This overactivity leads to dysregulated cell proliferation and gene activation, specifically affecting blood vessel and cartilage development, causing the abnormalities typical of Loeys-Dietz syndrome type III.

Genetics Home Reference provides information about familial thoracic aortic aneurysm and dissection, which is also associated with changes in the SMAD3 gene.