On this page
RAF1
Raf-1 proto-oncogene, serine/threonine kinase
The RAF1 gene provides instructions for a protein that is a key component of the RAS/MAPK signalling pathway, regulating fundamental cellular processes such as growth, division, and differentiation. RAF1 is a proto-oncogene that plays a critical role in transmitting signals from outside the cell to the nucleus, influencing cell proliferation and development.
RAF1 is located on the short (p) arm of chromosome 3, at band 3p25.2. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 3 in the library →Available at Jeen Health
Clinical tests that include this
Overview
The RAF1 gene, also known as Raf-1 proto-oncogene, serine/threonine kinase, is fundamental for cellular communication and regulation. It encodes a protein that acts as a kinase, adding phosphate groups to other proteins, which is a common method for activating or deactivating proteins within a cell. This gene is classified as an oncogene, meaning that when it undergoes certain changes, it has the potential to contribute to the development of cancer [PMID:17989269].
Signalling pathways involving RAF1 are essential for healthy human development and maintaining tissue homeostasis. Disturbances in these pathways, often due to variants in genes like RAF1, can lead to a range of developmental disorders and oncogenic processes. Understanding the RAF1 gene's function and its associated variants is therefore crucial for diagnosing and researching these conditions.
What the gene does
The RAF1 gene specifies the production of the Raf-1 protein, an important part of the RAS/MAPK (mitogen-activated protein kinase) signalling pathway. This pathway is responsible for relaying chemical signals from the cell's exterior to its nucleus, influencing a wide array of vital cellular activities [PMID:17989269]. These activities include cell growth, proliferation (division), differentiation (the process by which cells mature into specialised types), cell movement, and programmed cell death (apoptosis).
The Raf-1 protein acts as a serine/threonine kinase, an enzyme that phosphorylates (adds a phosphate group to) serine and threonine amino acid residues on target proteins. This phosphorylation cascade ultimately transmits signals downstream within the cell. As a proto-oncogene, the RAF1 gene, particularly its protein product, is tightly regulated. When somatic mutations occur in RAF1, they can lead to a continuously active Raf-1 protein, which can then promote uncontrolled cell growth and division, a hallmark of cancer development.
Video: Genetics 101
Chromosome location
The RAF1 gene is located on chromosome 3, specifically at position 3p25.2. Chromosomes are highly organised structures found within cells, containing a person's genetic material. The 'p' arm of the chromosome refers to the shorter arm, while 'q' refers to the longer arm. The numbers and decimals that follow indicate the precise band location on that arm.
This genomic address ensures that the RAF1 gene is consistently found at the same place across individuals, facilitating genetic studies and diagnostic efforts. Its specific placement within the human genome underscores its foundational role in biology.
Protein structure
The Raf-1 protein is composed of 648 amino acids and features several distinct functional domains critical for its activity within the RAS/MAPK pathway. At the N-terminal end, from amino acids 56-131, is the RBD (Ras Binding Domain), which facilitates interaction with activated RAS proteins, initiating the signalling cascade. Following this is the Phorbol-ester/DAG-type (Zinc finger) domain, spanning amino acids 138-184, involved in membrane localisation and activation through specific lipid binding.
A Disordered region, from amino acids 220-334, provides flexibility that may be important for protein-protein interactions or conformational changes. Further downstream, an Interaction with PEBP1/RKIP region (amino acids 331-349) mediates its interaction with protein kinase inhibitor proteins. The central catalytic activity resides within the Protein kinase domain, located from amino acids 349-609, which is responsible for the serine/threonine kinase activity that propagates the cellular signal.
Key variants
Variants in the RAF1 gene can range from single nucleotide changes to larger genomic alterations, each potentially impacting the function of the Raf-1 protein. Such variants may lead to a protein that is either hyperactive, deficient, or otherwise altered in its regulatory role within cellular signalling pathways. The clinical consequences of RAF1 variants depend heavily on their specific nature and location, influencing protein stability, enzyme activity, or interaction with other cellular components.
Inherited variants are passed down through families and can predispose individuals to certain conditions. Somatic variants, on the other hand, arise during a person's lifetime within specific cells and are often associated with cancer development, where the altered RAF1 protein can drive uncontrolled cellular proliferation. The study of these diverse RAF1 variants is vital for understanding associated health conditions.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1082G>C | p.Gly361Ala | Pathogenic | ★★★☆ | RASopathy |
c.1472C>T | p.Thr491Ile | Pathogenic | ★★★☆ | RASopathy |
c.1837C>G | p.Leu613Val | Pathogenic | ★★★☆ | RASopathy |
c.770C>T | p.Ser257Leu | Pathogenic | ★★★☆ | Noonan syndrome |
c.775T>A | p.Ser259Thr | Pathogenic | ★★★☆ | RASopathy |
c.775T>G | p.Ser259Ala | Pathogenic | ★★★☆ | RASopathy |
c.776C>A | p.Ser259Tyr | Pathogenic | ★★★☆ | RASopathy |
c.781C>T | p.Pro261Ser | Pathogenic | ★★★☆ | Noonan syndrome |
c.782C>A | p.Pro261His | Pathogenic/Likely pathogenic | ★★☆☆ | Cardiovascular phenotype |
c.786T>G | p.Asn262Lys | Pathogenic | ★★☆☆ | RASopathy |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in the RAF1 gene are linked to a spectrum of inherited conditions, predominantly affecting development. Noonan syndrome, an autosomal dominant disorder, is one such condition frequently associated with RAF1 variants. Over 25 different mutations in the RAF1 gene have been found to cause Noonan syndrome, which is characterised by distinct facial features, short stature, heart defects, bleeding issues, and skeletal abnormalities [PMID:17989269]. Additionally, RAF1 variants can lead to Noonan syndrome with multiple lentigines, previously known as LEOPARD syndrome, which presents with similar features along with numerous brown skin spots [PMID:15849767].
Beyond inherited conditions, somatic mutations in RAF1 are also implicated in the development of various cancers, including bladder cancer. In these cases, the gene's oncogenic potential is realised, driving uncontrolled cell growth and proliferation.
Inheritance pattern
Conditions caused by pathogenic RAF1 variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
In the UK, the RAF1 gene is actively assessed across several NHS national genomic testing panels, reflecting its established association with a range of inherited and acquired conditions. It holds 'green' status for numerous panels, indicating its clinical validity for diagnostic testing within these contexts. These include panels for Adult solid tumours cancer susceptibility and Childhood solid tumours, highlighting its relevance in oncological genomics. Furthermore, RAF1 is assessed for use in panels relating to Foetal anomalies, Intellectual disability (R29), Monogenic short stature (R453), and Paediatric or syndromic cardiomyopathy (R135). Its inclusion in the RASopathies panel acknowledges its role in this group of developmental disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Research suggests that generally maintaining a healthy lifestyle may support overall well-being, particularly for individuals with genetic predispositions. For the general population, practices such as a balanced diet rich in fruits and vegetables, regular physical activity, and avoiding smoking are associated with reduced risks for various health concerns. While these broad recommendations are beneficial for health, there is no conclusive evidence indicating that specific lifestyle modifications can prevent the onset or progression of conditions directly linked to RAF1 gene variants.
Supplement considerations
At present, there is no conclusive scientific evidence to suggest that specific dietary supplements can prevent, treat, or mitigate the effects of conditions associated with RAF1 gene variants. Individuals considering any supplements should consult with a healthcare professional. A healthcare provider can offer personalised advice, assess potential interactions with existing medications, and ensure that any decisions regarding supplementation are appropriate for an individual's specific health needs.
Frequently asked questions
What is the primary function of the RAF1 gene?
The RAF1 gene provides instructions for making the Raf-1 protein, a key component of the RAS/MAPK signalling pathway. This pathway transmits signals within cells to control growth, division, differentiation, and programmed cell death.
How is the RAF1 gene associated with cancer?
The RAF1 gene is a proto-oncogene. When certain somatic mutations occur, the Raf-1 protein can become overactive, leading to uncontrolled cell growth and division, which contributes to the development of various cancers.
What is Noonan syndrome, and how does RAF1 relate to it?
Noonan syndrome is an inherited developmental disorder characterised by distinctive facial features, short stature, and heart defects. Specific inherited variants in the RAF1 gene are known to cause Noonan syndrome through altered protein function [PMID:17989269].
Is RAF1 involved in other conditions besides Noonan syndrome?
Yes, beyond Noonan syndrome, RAF1 variants can lead to Noonan syndrome with multiple lentigines. Somatic mutations in RAF1 are also implicated in the development of certain cancers, including bladder cancer.
Can lifestyle changes or supplements influence RAF1-related conditions?
While a generally healthy lifestyle is beneficial for overall well-being, there is no definitive evidence that specific lifestyle changes or dietary supplements can prevent or treat conditions directly caused by RAF1 gene variants. Always consult a healthcare professional for personalised advice.
References
- Hopper RK, Feinstein JA, Manning MA. Neonatal pulmonary arterial hypertension and Noonan syndrome: two fatal cases with a specific RAF1 mutation. American journal of medical genetics. Part A. 2015. PMID: 25706034
- Kobayashi T, Aoki Y, Niihori T. Molecular and clinical analysis of RAF1 in Noonan syndrome and related disorders: dephosphorylation of serine 259 as the essential mechanism for mutant activation. Human mutation. 2010. PMID: 20052757
- Romano AA, Allanson JE, Dahlgren J. Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics. 2010. PMID: 20876176
- Yokoyama T, Takano K, Yoshida A. DA-Raf1, a competent intrinsic dominant-negative antagonist of the Ras-ERK pathway, is required for myogenic differentiation. The Journal of cell biology. 2007. PMID: 17535970
- Razzaque MA, Nishizawa T, Komoike Y. Germline gain-of-function mutations in RAF1 cause Noonan syndrome. Nature genetics. 2007. PMID: 17603482
- Pandit B, Sarkozy A, Pennacchio LA. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nature genetics. 2007. PMID: 17603483
- McPhillips F, Mullen P, MacLeod KG. Raf-1 is the predominant Raf isoform that mediates growth factor-stimulated growth in ovarian cancer cells. Carcinogenesis. 2006. PMID: 16332724
- Mhawech-Fauceglia P, Cheney RT, Schwaller J. Genetic alterations in urothelial bladder carcinoma: an updated review. Cancer. 2006. PMID: 16470587