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RASA1
RAS p21 protein activator 1
The RASA1 gene encodes a protein crucial for regulating the RAS/MAPK signalling pathway and plays a vital role in the normal development of the vascular system. The RASA1 gene provides instructions for the p120-RasGAP protein, which acts as a negative regulator of the RAS/MAPK signalling pathway, helping to switch off signals involved in cell growth, division, and differentiation.
RASA1 is located on the long (q) arm of chromosome 5, at band 5q14.3. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 5 in the library →Overview
The RASA1 gene, also known as RAS p21 protein activator 1, is integral to cellular communication and vascular development. It produces a protein called p120-RasGAP, which is a key regulator of the RAS/MAPK signalling pathway. This pathway controls many fundamental cellular processes, including growth, proliferation, and differentiation.
Disruptions in the RASA1 gene's function are associated with several inherited conditions, primarily those affecting the vascular system. Understanding the role of RASA1 is important for comprehending the genetic basis of these conditions.
What the gene does
The protein encoded by the RASA1 gene, p120-RasGAP, acts as a negative regulator within the RAS/MAPK signalling pathway. This pathway is responsible for transmitting signals from outside the cell to the nucleus, influencing critical cell functions such as growth, division, and maturation. By turning off these signals when they are not needed, p120-RasGAP helps maintain proper cellular control.
While its precise mechanisms are still being explored, p120-RasGAP is considered vital for the normal development and maintenance of the vascular system, which comprises arteries, veins, and capillaries responsible for blood circulation throughout the body. Abnormalities in this protein can lead to improper regulation of cell signalling, particularly in vascular tissues.
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Chromosome location
The RASA1 gene is located on chromosome 5, specifically at position 5q14.3. This genomic address indicates its precise position on the long arm of chromosome 5, providing a clear reference point for genetic studies and diagnostic purposes.
Protein structure
The RASA1 protein, which has a length of 1047 amino acids, contains several distinct functional domains. These include two SH2 domains, SH2 1 (amino acids 181-272) and SH2 2 (amino acids 351-441), involved in protein-protein interactions. An SH3 domain (amino acids 279-341) is also present, typically mediating interactions with proline-rich motifs. Further domains include a PH domain (amino acids 474-577) and a C2 domain (amino acids 577-690), both often involved in membrane targeting and signal transduction. A crucial Ras-GAP domain (amino acids 764-974) is responsible for its GTPase-activating protein function, enabling it to regulate RAS proteins.
Key variants
Genetic changes within the RASA1 gene can lead to alterations in the p120-RasGAP protein's structure or function. These variants can result in a loss of the protein's ability to properly regulate the RAS/MAPK signalling pathway, or impair its role in vascular development. The specific impact of a variant can vary, influencing the type and severity of associated 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.1052G>A | p.Trp351Ter | Pathogenic | ★★☆☆ | Capillary malformation-arteriovenous malformation syndrome |
c.1192C>T | p.Arg398Ter | Pathogenic | ★★☆☆ | Capillary malformation-arteriovenous malformation syndrome |
c.1201del | p.Ile401fs | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1222C>T | p.Gln408Ter | Pathogenic | ★★☆☆ | Capillary malformation-arteriovenous malformation syndrome |
c.1231del | p.Met411fs | Pathogenic/Likely pathogenic | ★★☆☆ | Capillary malformation-arteriovenous malformation syndrome |
c.1248T>G | p.Tyr416Ter | Pathogenic | ★★☆☆ | not provided |
c.1279C>T | p.Arg427Ter | Pathogenic | ★★☆☆ | not provided |
c.13_37del | p.Glu5fs | Pathogenic/Likely pathogenic | ★★☆☆ | Capillary malformation-arteriovenous malformation syndrome |
c.1358_1359del | p.Thr453fs | Pathogenic/Likely pathogenic | ★★☆☆ | Capillary malformation-arteriovenous malformation syndrome |
c.1534C>T | p.Arg512Ter | Pathogenic | ★★☆☆ | not specified |
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 RASA1 gene are primarily associated with conditions affecting the vascular system, including Capillary malformation-AVM syndrome. This condition is characterised by various abnormalities of the vascular system. Individuals with RASA1 mutations may also present with other complex vascular anomalies, highlighting the gene's critical role in vascular development.
Inheritance pattern
Conditions caused by pathogenic RASA1 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 RASA1 gene is included in several NHS Genomic Medicine Service national test panels. These panels cover a range of conditions where RASA1 variants are clinically relevant, such as Cerebral vascular malformations, Foetal anomalies, Foetal hydrops, Hereditary haemorrhagic telangiectasia, Mosaic skin disorders - Deep sequencing, Primary lymphoedema, Segmental overgrowth disorders - Deep sequencing, and Vascular skin disorders. This inclusion indicates its recognised importance in diagnosing these inherited conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the RASA1 gene?
The RASA1 gene provides instructions for making the p120-RasGAP protein, which negatively regulates the RAS/MAPK signalling pathway. This regulation is crucial for controlling cell growth, division, and differentiation, and is also essential for the normal development of the vascular system.
What conditions are associated with RASA1 gene variants?
Variants in the RASA1 gene are primarily associated with Capillary malformation-AVM syndrome, a condition characterised by abnormalities of the vascular system. It can also be linked to other vascular anomalies.
How is the RASA1 gene relevant to NHS clinical testing?
The RASA1 gene is included in several NHS Genomic Medicine Service national test panels for conditions such as Cerebral vascular malformations, Foetal anomalies, Primary lymphoedema, and various vascular skin disorders, demonstrating its clinical significance in the UK.
References
- Revencu N, Boon LM, Mulliken JB. Parkes Weber syndrome, vein of Galen aneurysmal malformation, and other fast-flow vascular anomalies are caused by RASA1 mutations. Human mutation. 2008. PMID: 18446851
- Boon LM, Mulliken JB, Vikkula M. RASA1: variable phenotype with capillary and arteriovenous malformations. Current opinion in genetics & development. 2005. PMID: 15917201
- Eerola I, Boon LM, Mulliken JB. Capillary malformation-arteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations. American journal of human genetics. 2003. PMID: 14639529
- Kulkarni SV, Gish G, van der Geer P. Role of p120 Ras-GAP in directed cell movement. The Journal of cell biology. 2000. PMID: 10769036
- Adam MP, Bick S, Mirzaa GM. Capillary Malformation-Arteriovenous Malformation Syndrome. 1993. PMID: 21348050
- Friedman E, Gejman PV, Martin GA. Nonsense mutations in the C-terminal SH2 region of the GTPase activating protein (GAP) gene in human tumours. Nature genetics. 1993. PMID: 8275088