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.
Health Conditions Related to Genetic Changes
More than 25 mutations causing Noonan syndrome have been identified in the RAF1 gene. Noonan syndrome is characterized by mildly unusual facial characteristics, short stature, heart defects, bleeding problems, skeletal malformations, and many other signs and symptoms. The RAF1 gene mutations change single protein building blocks (amino acids) in the RAF1 protein. These changes increase protein activity and disrupt the regulation of the RAS/MAPK signaling pathway 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.More About This Health Condition
Noonan syndrome with multiple lentigines
At least two mutations in the RAF1 gene have been found to cause Noonan syndrome with multiple lentigines (formerly called LEOPARD syndrome). This condition is characterized by multiple brown skin spots (lentigines), heart defects, short stature, a sunken or protruding chest, and distinctive facial features. The RAF1 gene mutations change single amino acids in the RAF1 protein: One mutation replaces the amino acid serine with the amino acid leucine at position 257 (written Ser257Leu or S257L) and the other mutation replaces the amino acid leucine with the amino acid valine at position 613 (written Leu613Val or L613V).
The RAF1 gene changes that cause Noonan syndrome with multiple lentigines 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 Noonan syndrome with multiple lentigines.More About This Health Condition
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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 Noonan syndrome with multiple lentigines or Noonan syndrome.
Other Names for This Gene
- Oncogene RAF1
- raf proto-oncogene serine/threonine protein kinase
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
- Hopper RK, Feinstein JA, Manning MA, Benitz W, Hudgins L. Neonatal pulmonary arterial hypertension and Noonan syndrome: two fatal cases with a specific RAF1 mutation. Am J Med Genet A. 2015 Apr;167A(4):882-5. doi: 10.1002/ajmg.a.37024. Epub 2015 Feb 23. Citation on PubMed
- Kobayashi T, Aoki Y, Niihori T, Cavé H, Verloes A, Okamoto N, Kawame H, Fujiwara I, Takada F, Ohata T, Sakazume S, Ando T, Nakagawa N, Lapunzina P, Meneses AG, Gillessen-Kaesbach G, Wieczorek D, Kurosawa K, Mizuno S, Ohashi H, David A, Philip N, Guliyeva A, Narumi Y, Kure S, Tsuchiya S, Matsubara Y. Molecular and clinical analysis of RAF1 in Noonan syndrome and related disorders: dephosphorylation of serine 259 as the essential mechanism for mutant activation. Hum Mutat. 2010 Mar;31(3):284-94. doi: 10.1002/humu.21187. Citation on PubMed
- McPhillips F, Mullen P, MacLeod KG, Sewell JM, Monia BP, Cameron DA, Smyth JF, Langdon SP. Raf-1 is the predominant Raf isoform that mediates growth factor-stimulated growth in ovarian cancer cells. Carcinogenesis. 2006 Apr;27(4):729-39. Epub 2005 Dec 6. Citation on PubMed
- Mhawech-Fauceglia P, Cheney RT, Schwaller J. Genetic alterations in urothelial bladder carcinoma: an updated review. Cancer. 2006 Mar 15;106(6):1205-16. Review. Citation on PubMed
- Pandit B, Sarkozy A, Pennacchio LA, Carta C, Oishi K, Martinelli S, Pogna EA, Schackwitz W, Ustaszewska A, Landstrom A, Bos JM, Ommen SR, Esposito G, Lepri F, Faul C, Mundel P, López Siguero JP, Tenconi R, Selicorni A, Rossi C, Mazzanti L, Torrente I, Marino B, Digilio MC, Zampino G, Ackerman MJ, Dallapiccola B, Tartaglia M, Gelb BD. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet. 2007 Aug;39(8):1007-12. Epub 2007 Jul 1. Citation on PubMed
- Razzaque MA, Nishizawa T, Komoike Y, Yagi H, Furutani M, Amo R, Kamisago M, Momma K, Katayama H, Nakagawa M, Fujiwara Y, Matsushima M, Mizuno K, Tokuyama M, Hirota H, Muneuchi J, Higashinakagawa T, Matsuoka R. Germline gain-of-function mutations in RAF1 cause Noonan syndrome. Nat Genet. 2007 Aug;39(8):1013-7. Epub 2007 Jul 1. Citation on PubMed
- Romano AA, Allanson JE, Dahlgren J, Gelb BD, Hall B, Pierpont ME, Roberts AE, Robinson W, Takemoto CM, Noonan JA. Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics. 2010 Oct;126(4):746-59. doi: 10.1542/peds.2009-3207. Epub 2010 Sep 27. Review. Citation on PubMed
- Yokoyama T, Takano K, Yoshida A, Katada F, Sun P, Takenawa T, Andoh T, Endo T. DA-Raf1, a competent intrinsic dominant-negative antagonist of the Ras-ERK pathway, is required for myogenic differentiation. J Cell Biol. 2007 Jun 4;177(5):781-93. Epub 2007 May 29. Citation on PubMed or Free article on PubMed Central