SMAD4

The SMAD4 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. The SMAD proteins bind to the SMAD4 protein and form a protein complex, which then moves to the cell nucleus. In the nucleus, the SMAD protein complex binds to specific areas of DNA where it controls the activity of particular genes and regulates cell growth and division (proliferation).

By controlling gene activity and regulating cell proliferation, the SMAD4 protein serves both as a transcription factor and as a tumor suppressor. Transcription factors help control the activity of particular genes, and tumor suppressors keep cells from growing and dividing too fast or in an uncontrolled way.

hereditary hemorrhagic telangiectasia - caused by mutations in the SMAD4 gene

At least 5 mutations in the SMAD4 gene have been found to cause juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome. People with this disorder have the blood vessel problems associated with hereditary hemorrhagic telangiectasia and an increased risk of developing intestinal growths (polyps) at an early age; the polyps may become cancerous.

SMAD4 mutations affect the signaling pathway of TGF-β proteins. Disruption of this pathway may interfere with both the tumor suppressor function of SMAD4 and the appropriate development of the boundaries between veins and arteries, resulting in the signs and symptoms of juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome.

juvenile polyposis syndrome - caused by mutations in the SMAD4 gene

More than 60 mutations in the SMAD4 gene have been found to cause juvenile polyposis syndrome. One mutation that has been found in multiple affected individuals deletes four DNA building blocks (nucleotides) in a region of the SMAD4 gene called exon 9 (written as 1244_1247delACAG). This mutation is thought to cause a more aggressive form of juvenile polyposis syndrome characterized by numerous polyps throughout the gastrointestinal tract and a greater risk for cancer development.

Most SMAD4 gene mutations that cause juvenile polyposis syndrome result in the production of an abnormally short, nonfunctional protein. A lack of functional SMAD4 protein prevents binding to other SMAD proteins and interferes with the transmission of chemical signals from the cell surface to the nucleus. The SMAD protein complex is not activated and cannot be transported to the nucleus, where it is needed to regulate cell proliferation and the activity of certain genes. This unregulated cell growth can lead to polyp formation in people with juvenile polyposis syndrome.

cancers - increased risk from variations of the SMAD4 gene

People with mutations in the SMAD4 gene appear to have an increased risk of developing various cancers. Some of these gene mutations are inherited, while others are acquired during a person's lifetime. Such acquired (somatic) mutations are present only in certain cells. Cells with mutations in the SMAD4 gene, whether inherited or somatic, may proliferate out of control and result in a tumor, often in the colon or pancreas.