2.1. Loeys-Dietz syndrome

More than 35 mutations in the TGFBR1 gene have been found to cause Loeys-Dietz syndrome type I. 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. The TGFBR1 gene mutations that cause Loeys-Dietz syndrome are present in one copy of the gene in each cell. Most of these mutations change single protein building blocks (amino acids) in TGF-β receptor type 1, 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 1 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 I.

2.2. Other cancers

More than 10 mutations in the TGFBR1 gene have been found to increase the risk of developing a form of skin cancer called multiple self-healing squamous epithelioma (MSSE). This condition, also known as Ferguson-Smith disease, is characterized by the formation of multiple invasive skin tumors that grow uncontrollably for a few weeks, but then suddenly shrink and die off, leaving a noncancerous scar.

People with MSSE have a mutation in one copy of the TGFBR1 gene in each cell. An additional mutation in the second copy of the TGFBR1 gene is needed for tumors to form in MSSE. The second mutation, which is called a somatic mutation, is found only in the tumor cells and is not inherited. Unlike TGFBR1 gene mutations that cause Loeys-Dietz syndrome type I (described above), the mutations that cause MSSE prevent the production of any protein at all. A complete lack of functional receptor in certain cells results in a total loss of TGF-β pathway signaling and severely reduced tumor suppression, allowing the skin cancers to form. The mechanism responsible for the spontaneous healing of the multiple skin tumors in MSSE is unknown.