TGFBR2

The TGFBR2 gene provides instructions for making a protein called transforming growth factor-beta (TGF-β) receptor type 2. This receptor transmits signals from the cell surface into the cell through a process called signal transduction. Through this type of signaling, the environment outside the cell affects activities inside the cell such as stimulation of cell growth and division.

To carry out its signaling function, the TGF-β receptor type 2 spans the cell membrane, so that one end of the protein projects from the outer surface of the cell (the extracellular domain) and the other end remains inside the cell (the intracellular domain). A protein called TGF-β attaches (binds) to the extracellular domain of the TGF-β receptor type 2, which turns on (activates) the receptor and allows it to bind to a similar receptor on the cell surface. The formation of this TGF-β receptor complex triggers signal transduction by activating other proteins in this signaling pathway.

Signals triggered through the TGF-β receptor complex prompt various responses by the cell. One such response is to inhibit cell growth and division. Based on this action, the TGF-β receptor type 2 is sometimes called a tumor suppressor. Tumor suppressors keep cells from growing and dividing too fast or in an uncontrolled way. TGF-β receptor type 2 signaling also helps control the process by which cells mature to carry out special functions (differentiation), and plays a role in the formation of the extracellular matrix, which is an intricate lattice that forms in the spaces between cells and provides structural support to tissues.

Loeys-Dietz syndrome - caused by mutations in the TGFBR2 gene

More than 70 mutations in the TGFBR2 gene have been found to cause Loeys-Dietz syndrome types I and II. Loeys-Dietz syndrome is a disorder that affects the connective tissue, which gives structure and support to blood vessels, skeleton, and other parts of the body. Most TGFBR2 gene mutations that cause Loeys-Dietz syndrome change single protein building blocks (amino acids) in the TGF-β receptor type 2, resulting in a nonfunctional receptor protein. Although the receptor proteins are nonfunctional, cell signaling still occurs at an even greater frequency than normal, indicating that other, unknown mechanisms compensate for the lack of receptor activity. As a result, the signaling pathway is overactive, which disrupts development of connective tissue and various body systems and leads to the varied signs and symptoms of Loeys-Dietz syndrome types I and II.

cancers - increased risk from variations of the TGFBR2 gene

Some TGFBR2 gene mutations are acquired during a person's lifetime and are present only in certain cells. These changes are called somatic mutations and are not inherited. People with somatic mutations in the TGFBR2 gene appear to have an increased risk of developing various cancers. Somatic TGFBR2 gene mutations probably disrupt the signaling process that helps regulate cell division. Unchecked cell division can lead to the formation of tumors, particularly when TGFBR2 gene mutations occur in the colon, rectum, and esophagus. It is estimated that 30 percent of cancerous (malignant) colon tumors have TGFBR2 gene mutations in their cells.

familial thoracic aortic aneurysm and dissection - increased risk from variations of the TGFBR2 gene

At least two TGFBR2 gene mutations have been identified in people with familial thoracic aortic aneurysm and dissection (familial TAAD). This disorder involves problems with the aorta, which is the large blood vessel that distributes blood from the heart to the rest of the body. The aorta can weaken and stretch, causing a bulge in the blood vessel wall (an aneurysm). Stretching of the aorta may also lead to a sudden tearing of the layers in the aorta wall (aortic dissection). Aortic aneurysm and dissection can be life threatening.

The two TGFBR2 gene mutations that have been identified in people with familial TAAD change an amino acid at a particular point (known as position 460) in the TGF-β receptor type 2. These mutations replace the amino acid arginine with the amino acids cysteine or histidine (written as Arg460Cys or Arg460His, respectively). A change in this amino acid alters the receptor's structure, which disturbs signal transduction. The disturbed signaling can impair cell growth and development. It is not known how these changes result in the specific aortic abnormalities associated with familial TAAD.