BRAF

The BRAF gene provides instructions for making a protein that helps transmit chemical signals from outside the cell to the cell's nucleus. This protein is part of a signaling pathway known as the RAS/MAPK pathway, which helps control several important cell functions. Specifically, the RAS/MAPK pathway regulates the growth and division (proliferation) of cells, the process by which cells mature to carry out specific functions (differentiation), cell movement (migration), and the self-destruction of cells (apoptosis). Chemical signaling through this pathway is essential for normal development before birth.

The BRAF gene belongs to a class of genes known as oncogenes. When mutated, oncogenes have the potential to cause normal cells to become cancerous.

cardiofaciocutaneous syndrome - caused by mutations in the BRAF gene

Mutations in the BRAF gene are the most common cause of cardiofaciocutaneous syndrome. At least 36 BRAF mutations have been identified in people with this disorder. These mutations change single protein building blocks (amino acids) in the BRAF protein. Almost all of these genetic changes abnormally activate the protein, which disrupts the tightly regulated RAS/MAPK signaling pathway in cells throughout the body. The altered signaling interferes with the normal development of many organs and tissues, resulting in the characteristic features of cardiofaciocutaneous syndrome.

multiple lentigines syndrome - caused by mutations in the BRAF gene

At least two mutations in the BRAF gene have been found to cause multiple lentigines syndrome (formerly called LEOPARD syndrome). This condition is characterized by multiple brown skin spots (lentigines), heart defects, short stature, genital abnormalities, hearing loss, and distinctive facial features. These mutations change single amino acids in the BRAF protein. One mutation replaces the amino acid threonine with the amino acid proline at position 241 in the BRAF protein (written as Thr241Pro or T241P). The other mutation replaces the amino acid leucine with the amino acid phenylalanine at position 245 in the BRAF protein (written as Leu245Phe or L245F).

The known BRAF gene changes that cause multiple lentigines syndrome are believed to abnormally activate the BRAF protein, which disrupts the regulation of the RAS/MAPK signaling pathway that controls cell functions such as growth and division. This misregulation can result in the various features of multiple lentigines syndrome.

Noonan syndrome - caused by mutations in the BRAF gene

At least four BRAF gene mutations have been found to cause Noonan syndrome. These mutations change single amino acids in the BRAF protein. The resulting protein is continuously active, rather than switching on and off in response to cell signals. This increase in protein activity disrupts the regulation of the RAS/MAPK signaling pathway, which controls cell functions such as growth and division. This misregulation can result in the heart defects, growth problems, skeletal abnormalities and other features of Noonan syndrome.

cancers - associated with the BRAF gene

Some gene mutations are acquired during a person's lifetime and are present only in certain cells. These changes, which are called somatic mutations, are not inherited. Somatic mutations in the BRAF gene are common in several types of cancer. Normally, the BRAF protein is switched on and off in response to signals that control cell growth and development. Somatic mutations cause the BRAF protein to be continuously active and to transmit messages to the nucleus even in the absence of these chemical signals. The overactive protein may contribute to the growth of cancers by allowing abnormal cells to grow and divide uncontrollably.

The most common BRAF gene mutation found in human cancers replaces the amino acid valine with the amino acid glutamic acid at position 600 in the BRAF protein (written as Val600Glu or V600E). This mutation has frequently been found in an aggressive form of skin cancer called melanoma as well as in noncancerous skin growths called nevi. It has also been identified in cancers of the colon and rectum, ovary, and thyroid gland. Several other somatic mutations in the BRAF gene have also been associated with cancer.

For reasons that are unclear, inherited mutations in the BRAF gene do not appear to increase the risk of cancer in people with cardiofaciocutaneous syndrome, multiple lentigines syndrome, or Noonan syndrome.

Langerhans cell histiocytosis - associated with the BRAF gene

Somatic mutations in the BRAF gene, most frequently the V600E mutation (described above), have been identified in some individuals with Langerhans cell histiocytosis. This disorder causes an abnormal accumulation of immune cells called Langerhans cells in multiple tissues and organs, which often leads to the formation of tumors called granulomas. However, Langerhans cell histiocytosis is usually not considered a form of cancer.

The BRAF gene mutations, which are found only in the abnormal Langerhans cells, cause the BRAF protein to be continuously active. The overactive protein may contribute to the development of Langerhans cell histiocytosis by allowing the Langerhans cells to grow and divide uncontrollably.

other disorders - associated with the BRAF gene

At least one somatic mutation in the BRAF gene, the V600E mutation (described above), has been identified in some people with Erdheim-Chester disease. This rare condition is characterized by the abnormal accumulation of immune system cells called histiocytes in many of the body's tissues; it is classified as a form of non-Langerhans cell histiocytosis. The disease most commonly affects the bones, causing bone thickening and pain, but the accumulation of histocytes can also cause signs and symptoms affecting the brain, eyes, lungs, liver, kidneys, and other organs.

The V600E mutation causes the BRAF protein to be continuously active, which may allow histiocytes to grow and divide uncontrollably. However, it is unclear how this mutation is related to Erdheim-Chester disease.