TGFBR2

The TGFBR2 gene provides instructions for making a protein called transforming growth factor (TGF)-beta type II receptor. 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 division and growth.

To carry out its signaling function, the TGF-beta type II receptor 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). The extracellular domain of the TGF-beta type II receptor associates with a similar receptor to form a receptor complex. Growth factors called TGF-beta proteins attach to this receptor complex, which triggers signal transduction.

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

Marfan syndrome - caused by mutations in the TGFBR2 gene

Some researchers believe that a small percentage of Marfan syndrome cases are caused by mutations in the TGFBR2 gene. These cases are called Marfan syndrome type II. The category of Marfan syndrome type II is not universally accepted, however. Other researchers believe that TGFBR2 mutations cause a disorder that may have some Marfan-like features but is not Marfan syndrome.

Researchers have identified more than 10 mutations in the TGFBR2 gene that cause Marfan syndrome. Almost all the mutations change one of the protein building blocks (amino acids) used to make the TGF-beta type II receptor. Another type of mutation leads to a shortened version of this receptor. All of these mutations disrupt the signaling activity of the receptor, which probably disturbs the growth and development of cells and tissues. These disturbances lead to features of Marfan syndrome, such as skeletal abnormalities and heart problems.

cancers - increased risk from variations of the TGFBR2 gene

Some TGFBR2 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. TGFBR2 somatic mutations probably disrupt the signaling process that helps regulate cell division. Unchecked cell division can lead to the formation of tumors, particularly when TGFBR2 mutations occur in the colon, rectum, and esophagus. It is estimated that 30 percent of cancerous (malignant) colon tumors have TGFBR2 mutations in their cells.

other disorders - caused by mutations in the TGFBR2 gene

TGFBR2 mutations cause two disorders characterized by heart problems. One disorder, known as familial thoracic aortic aneurysm and dissection (TAAD), involves problems with the large blood vessel that distributes blood from the heart to the rest of the body (the aorta). 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. TGFBR2 mutations that cause TAAD change a protein building block (amino acid) at a particular point (known as position 460) in the TGF-beta type II receptor. These mutations replace the amino acid arginine with the amino acids cysteine or histidine (written as Arg460Cys or Arg460His, respectively). A change in amino acids alters the receptor's structure, which disturbs signal transduction. The disturbed signaling can impair cell growth and development.

Researchers have also identified several TGFBR2 mutations that cause a disorder called Loeys-Dietz syndrome (LDS). Loeys-Dietz syndrome is characterized by aortic aneurysms and dissections at a young age, arteries that twist and turn abnormally (arterial tortuosity), widely spaced eyes (hypertelorism), an unusually shaped uvula (the soft flap of tissue that hangs from the back of the mouth), and an opening in the roof of the mouth (cleft palate). People with this syndrome also have skeletal abnormalities such as an abnormal curvature of the spine (scoliosis) or unusually flexible joints. Almost all the TGFBR2 mutations that cause Loeys-Dietz syndrome change one of the amino acids used to make the TGF-beta type II receptor. The remaining mutations lead to a shortened version of the TGF-beta type II receptor. These TGFBR2 mutations appear to increase the signaling activity of the receptor. Researchers believe that the increased signaling disturbs the formation of elastic fibers in the extracellular matrix, which in turn disrupts the function of flexible structures such as blood vessels.