TGFBR2

At least nine 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 cause life-threatening internal bleeding.

The TGFBR2 gene mutations that cause familial TAAD disturb 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.

More than 100 mutations in the TGFBR2 gene have been found to cause Loeys-Dietz syndrome type II. Loeys-Dietz syndrome affects connective tissue, which gives structure and support to blood vessels, the skeleton, and other parts of the body. This type of Loeys-Dietz syndrome is characterized by blood vessel abnormalities and skeletal deformities. Most TGFBR2 gene mutations that cause Loeys-Dietz syndrome change single protein building blocks (amino acids) in TGF-β receptor type 2, resulting in a receptor with little or no function. Although the receptor has severely reduced function, TGF-β pathway signaling occurs at an even greater intensity than normal. Researchers speculate that the activity of other proteins in this signaling pathway is increased to compensate for the reduction in TGF-β receptor type 2 activity; however, the exact mechanism responsible for the increase in signaling is unclear. The overactive signaling pathway disrupts development of connective tissue and various body systems and leads to the varied signs and symptoms of Loeys-Dietz syndrome type II.

Some TGFBR2 gene mutations that cause Loeys-Dietz syndrome type II have also been found to cause familial TAAD (described above). Affected families can include some individuals with Loeys-Dietz syndrome and others with familial TAAD.

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.