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HRAS
HRas proto-oncogene, GTPase
The HRAS gene encodes the H-Ras protein, a key regulator of cell growth, division, and differentiation, involved in signal transduction pathways that influence cellular behaviour. The HRAS gene is a proto-oncogene that plays a vital role in cell signalling, controlling processes like cell proliferation, differentiation, and programmed cell death.
HRAS is located on the short (p) arm of chromosome 11, at band 11p15.5. Arm ratio per GRCh38 - banding schematic.
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Overview
The HRAS gene, also known as Harvey rat sarcoma viral oncogene homologue, contains the genetic blueprint for the H-Ras protein. This protein is a member of the Ras family of GTPases, which operate as molecular switches in various cellular processes. HRAS is categorised as a proto-oncogene, meaning that specific alterations can transform it into an oncogene, potentially contributing to cancer development. Its role in signal transduction is fundamental for governing cell division, growth, and specialisation, making it integral to normal physiological functions and implicated in disease when dysregulated. Through these mechanisms, HRAS coordinates essential cellular regulatory networks that maintain tissue homeostasis under normal conditions.
What the gene does
The H-Ras protein acts as a small GTPase, central to numerous intracellular signalling pathways. Its primary role involves coordinating communication between extracellular signals and the cell's nucleus, thereby orchestrating critical cellular responses such as growth and division. The protein functions like a molecular switch, transitioning between an active state when bound to guanosine triphosphate (GTP) and an inactive state when bound to guanosine diphosphate (GDP). When active and GTP-bound, H-Ras transmits signals that encourage cell proliferation and survival. The protein then self-inactivates by converting GTP molecules into GDP through its enzymatic activity. This precise ON/OFF switching mechanism is vital for maintaining tight control over cell behaviour. Beyond cell multiplication, H-Ras also influences cell differentiation, which is the developmental pathway through which cells acquire specialised roles, and apoptosis, the controlled process of programmed cell death. Proper H-Ras function is therefore critical for preventing uncontrolled cellular expansion and maintaining tissue balance.
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Chromosome location
The HRAS gene is situated on chromosome 11, specifically at position 11p15.5. This location indicates it is found on the short (p) arm of chromosome 11, within region 1, band 5, sub-band 5. The precise mapping on the chromosome aids in understanding its genetic neighbourhood and potential interactions with other genes in the vicinity.
Protein structure
The H-Ras protein consists of 189 amino acids. Key functional regions within the protein dictate its regulatory capabilities. These include the Effector region, spanning amino acids 32-40, which is crucial for interacting with downstream signalling molecules. Another important segment is the Hypervariable region, located between amino acids 166-185, which contributes to its membrane localisation and specificity in signalling pathways.
Key variants
Variants in the HRAS gene can influence protein function, leading to various health implications. These alterations often involve single amino acid substitutions within critical regions of the H-Ras protein, impacting its ability to switch between active and inactive states. Most pathogenic variants in HRAS result in a constitutively active protein that continuously transmits growth-promoting signals, even in the absence of external stimuli. The specific variant type and its location within the gene can dictate the severity and specific clinical manifestations observed. Research indicates that more than 15 different genetic changes in HRAS have been documented in individuals diagnosed with Costello syndrome, affecting critical regions of the encoded protein.
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.173C>T | p.Thr58Ile | Pathogenic | ★★★☆ | Costello syndrome |
c.34G>A | p.Gly12Ser | Pathogenic | ★★★☆ | Myopathy, congenital, with excess of muscle spindles |
c.350A>G | p.Lys117Arg | Pathogenic | ★★★☆ | Costello syndrome |
c.37G>T | p.Gly13Cys | Pathogenic | ★★★☆ | Costello syndrome |
c.179G>A | p.Gly60Asp | Pathogenic | ★★☆☆ | not provided |
c.179G>T | p.Gly60Val | Pathogenic | ★★☆☆ | not provided |
c.181C>A | p.Gln61Lys | Pathogenic/Likely pathogenic | ★★☆☆ | Thyroid cancer, nonmedullary, 2 |
c.187G>A | p.Glu63Lys | Pathogenic | ★★☆☆ | Myopathy, congenital, with excess of muscle spindles |
c.197_217dup | p.Met72_Arg73insProMetArgAspGlnTyrMet | Pathogenic/Likely pathogenic | ★★☆☆ | HRAS-related disorder |
c.175G>A | p.Ala59Thr | Likely pathogenic | ★★★☆ | Costello syndrome |
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
Pathogenic variants in the HRAS gene are associated with a spectrum of conditions, most notably Costello syndrome, an inherited disorder affecting multiple body systems. These variants are also implicated in other conditions such as Linear sebaceous naevus syndrome, which typically manifests as overgrowths of skin cells. The nature of the HRAS variant often determines the specific condition or increased disease risk.
Inheritance pattern
Conditions caused by pathogenic HRAS 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 HRAS gene is included in several NHS England Genomic Medicine Service national genomic test directories, reflecting its clinical significance. It is listed as 'green' on panels such as Adult solid tumours cancer susceptibility, Childhood solid tumours, and Foetal anomalies (R21), amongst others. This indicates that HRAS is considered a gene for which there is strong evidence for association with the indicated conditions, and testing may be routinely offered.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Maintaining a generally healthy lifestyle is important for overall well-being, though there is no conclusive evidence that specific lifestyle choices can prevent conditions directly caused by HRAS gene variants. A balanced diet rich in fruits and vegetables, regular physical activity, and avoiding smoking are widely recommended for the general population to reduce cancer risk. However, these general health recommendations do not directly mitigate the effects of inherited genetic changes in HRAS.
Supplement considerations
There is no scientific evidence to suggest that any specific supplements can prevent or treat conditions associated with HRAS gene variants. While some supplements are marketed for general health benefits, individuals should consult with a healthcare professional before taking any supplements, particularly if they have a diagnosed genetic condition.
Frequently asked questions
What is the primary function of the HRAS gene?
The HRAS gene provides instructions for the H-Ras protein, a GTPase that acts as a molecular switch in cell signalling pathways. It regulates crucial cellular processes such as cell growth, division, and differentiation by relaying signals from outside the cell to the nucleus.
What medical conditions are associated with HRAS gene variants?
Variants in the HRAS gene are primarily associated with Costello syndrome, a rare genetic disorder affecting multiple body systems. They are also implicated in Linear sebaceous naevus syndrome and can increase the risk for certain cancers.
Is HRAS considered an oncogene?
Yes, HRAS is classified as a proto-oncogene. This means that while it plays a vital role in normal cell function, specific pathogenic variants can transform it into an oncogene, potentially leading to uncontrolled cell growth and contributing to cancer development.
How does the H-Ras protein function as a molecular switch?
The H-Ras protein cycles between an active state, when bound to GTP, and an inactive state, when bound to GDP. This ON/OFF mechanism allows it to precisely control the transmission of signals that regulate cell proliferation, differentiation, and apoptosis.
Can lifestyle changes prevent conditions associated with HRAS variants?
There is no definitive evidence that specific lifestyle changes can prevent conditions caused by HRAS gene variants. However, a generally healthy lifestyle, including a balanced diet and regular exercise, is recommended for overall well-being.
References
- Levinsohn JL, Tian LC, Boyden LM. Whole-exome sequencing reveals somatic mutations in HRAS and KRAS, which cause nevus sebaceus. The Journal of investigative dermatology. 2013. PMID: 23096712
- Hafner C, Toll A, Gantner S. Keratinocytic epidermal nevi are associated with mosaic RAS mutations. Journal of medical genetics. 2012. PMID: 22499344
- Groesser L, Herschberger E, Ruetten A. Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome. Nature genetics. 2012. PMID: 22683711
- Gripp KW, Innes AM, Axelrad ME. Costello syndrome associated with novel germline HRAS mutations: an attenuated phenotype? American journal of medical genetics. Part A. 2008. PMID: 18247425
- Rauen KA. HRAS and the Costello syndrome. Clinical genetics. 2007. PMID: 17250658
- Gripp KW, Lin AE, Stabley DL. HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation. American journal of medical genetics. Part A. 2006. PMID: 16329078
- Estep AL, Tidyman WE, Teitell MA. HRAS mutations in Costello syndrome: detection of constitutional activating mutations in codon 12 and 13 and loss of wild-type allele in malignancy. American journal of medical genetics. Part A. 2006. PMID: 16372351
- Kerr B, Delrue MA, Sigaudy S. Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases. Journal of medical genetics. 2006. PMID: 16443854
- Sol-Church K, Stabley DL, Nicholson L. Paternal bias in parental origin of HRAS mutations in Costello syndrome. Human mutation. 2006. PMID: 16835863
- Gripp KW, Stabley DL, Nicholson L. Somatic mosaicism for an HRAS mutation causes Costello syndrome. American journal of medical genetics. Part A. 2006. PMID: 16969868
- Giehl K. Oncogenic Ras in tumour progression and metastasis. Biological chemistry. 2005. PMID: 15843165
- Aoki Y, Niihori T, Kawame H. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nature genetics. 2005. PMID: 16170316
- Wolff EM, Liang G, Jones PA. Mechanisms of Disease: genetic and epigenetic alterations that drive bladder cancer. Nature clinical practice. Urology. 2005. PMID: 16474624
- Colicelli J. Human RAS superfamily proteins and related GTPases. Science's STKE : signal transduction knowledge environment. 2004. PMID: 15367757
- Oxford G, Theodorescu D. The role of Ras superfamily proteins in bladder cancer progression. The Journal of urology. 2003. PMID: 14532839