RAF1

The RAF1 gene provides instructions for making a protein that is part of a signaling pathway called the RAS/MAPK pathway, which transmits chemical signals from outside the cell to the cell's nucleus. RAS/MAPK signaling helps control 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).

The RAF1 gene belongs to a class of genes known as oncogenes. When mutated, oncogenes have the potential to cause normal cells to become cancerous.

multiple lentigines syndrome - caused by mutations in the RAF1 gene

At least two mutations in the RAF1 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 protein building blocks (amino acids) in the RAF1 protein. One mutation replaces the amino acid serine with the amino acid leucine at position 257 in the RAF1 protein (written Ser257Leu or S257L). The other mutation replaces the amino acid leucine with the amino acid valine at position 613 in the RAF1 protein (written Leu613Val or L613V).

The known RAF1 gene changes that cause multiple lentigines syndrome are believed to abnormally activate the RAF1 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 RAF1 gene

More than 10 mutations causing Noonan syndrome have been identified in the RAF1 gene. These mutations change single amino acids in the RAF1 protein. These changes interrupt the normal processes of the RAF1 protein, causing problems with cell division, apoptosis, cell differentiation, and cell migration. Researchers believe that this disruption in normal cell processes plays a role in the signs and symptoms of Noonan syndrome, specifically cardiac abnormalities. It has been noted that people with Noonan syndrome caused by a RAF1 gene mutation have a greater incidence of heart defects than other people with Noonan syndrome, specifically a condition called hypertrophic cardiomyopathy, which is a thickening of the heart muscle that forces the heart to work harder to pump blood.

cancers - increased risk from variations of the RAF1 gene

Some 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. Somatic mutations in the RAF1 gene are involved in the development of several types of cancer. These mutations lead to a RAF1 protein that is always active and can direct cells to grow and divide uncontrollably. Studies suggest that RAF1 gene mutations may be found in ovarian, lung, and colorectal cancers. Somatic mutations in the RAF1 gene are a rare cause of cancer.

For reasons that are unclear, inherited mutations in the RAF1 gene do not appear to increase the risk of cancer in people with multiple lentigines syndrome or Noonan syndrome.