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ACVRL1
activin A receptor like type 1
The ACVRL1 gene provides instructions for a protein essential in blood vessel development and specialisation, particularly for arteries and veins. The ACVRL1 gene encodes the activin receptor-like kinase 1 protein, a cell surface receptor crucial for proper blood vessel formation.
ACVRL1 is located on the long (q) arm of chromosome 12, at band 12q13.13. Arm ratio per GRCh38 - banding schematic.
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Overview
The ACVRL1 gene, also known as activin A receptor like type 1, plays a critical role in human health by directing the production of a protein involved in the development of blood vessels. This protein is particularly abundant on the surface of cells that line developing arteries. It functions as a receptor, binding to specific proteins to initiate signalling pathways important for vascular differentiation and integrity.
Variations in the ACVRL1 gene are associated with inherited conditions that primarily affect the vascular system, such as hereditary haemorrhagic telangiectasia. Understanding the ACVRL1 gene's function is therefore key to comprehending the genetic basis of these conditions and potential therapeutic approaches.
What the gene does
The ACVRL1 gene provides instructions for producing activin receptor-like kinase 1, a protein located on the surface of cells. This protein acts as a receptor, specifically interacting with proteins from the transforming growth factor beta (TGF-beta) family. This interaction is likened to a "lock and key" mechanism, where the ACVRL1 protein is the lock and the TGF-beta protein is the key, triggering a cascade of intracellular signals.
This signalling pathway is vital for the development and specialisation of blood vessels. In particular, it influences the differentiation of new blood vessels into either arteries or veins. The protein's kinase activity, including regions like the GS domain and the larger protein kinase domain, is fundamental to transmitting these signals within the cell. Proper ACVRL1 function ensures the healthy formation and integrity of the circulatory system.
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Chromosome location
The ACVRL1 gene is situated on chromosome 12 at position 12q13.13. This specific location on the long arm of chromosome 12 houses the genetic blueprint for the activin receptor-like kinase 1 protein. The gene provides the instructions for a protein composed of 503 amino acids.
Protein structure
The ACVRL1 protein is 503 amino acids long and contains several distinct functional regions. A key region spanning amino acids 73-76 mediates specificity for the BMP ligand, influencing which signalling molecules the protein interacts with. The GS domain, located from amino acids 172-201, is involved in signal transduction. The largest functional component is the protein kinase domain, spanning amino acids 202-492, which is responsible for the protein's enzymatic activity, enabling it to phosphorylate other proteins and propagate cellular signals.
Key variants
Genetic variations, or variants, in the ACVRL1 gene can alter the function of the activin receptor-like kinase 1 protein. Many of these variants involve changes to single protein building blocks (amino acids) or lead to the production of an abnormally short, non-functional protein. Such alterations can impair the protein's ability to properly regulate blood vessel development and differentiation.
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.1217G>A | p.Trp406Ter | Pathogenic | ★★★☆ | Telangiectasia, hereditary hemorrhagic, type 2 |
c.1232G>A | p.Arg411Gln | Pathogenic | ★★★☆ | Telangiectasia, hereditary hemorrhagic, type 2 |
c.1468C>T | p.Gln490Ter | Pathogenic | ★★★☆ | Pulmonary arterial hypertension related to hereditary hemorrhagic telangiectasia |
c.620del | p.Cys207fs | Pathogenic | ★★★☆ | Telangiectasia, hereditary hemorrhagic, type 2 |
c.706G>A | p.Glu236Lys | Pathogenic | ★★★☆ | Telangiectasia, hereditary hemorrhagic, type 2 |
c.998G>T | p.Ser333Ile | Pathogenic | ★★★☆ | not provided |
c.1121_1124dup | p.Tyr375Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Telangiectasia, hereditary hemorrhagic, type 2 |
c.1133C>T | p.Pro378Leu | Pathogenic/Likely pathogenic | ★★☆☆ | Telangiectasia, hereditary hemorrhagic, type 2 |
c.1150C>T | p.Gln384Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Telangiectasia, hereditary hemorrhagic, type 2 |
c.1198G>A | p.Ala400Thr | Pathogenic/Likely pathogenic | ★★☆☆ | Telangiectasia, hereditary hemorrhagic, type 2 |
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 ACVRL1 gene are primarily associated with hereditary haemorrhagic telangiectasia type 2. This condition is characterised by abnormal blood vessel formation, leading to fragile vessels that can rupture and bleed. Some variations in ACVRL1 have also been linked to an increased risk of developing cerebral arteriovenous malformations, particularly in individuals without other signs of hereditary haemorrhagic telangiectasia.
UK clinical status
The ACVRL1 gene is included in several NHS Genomic Medicine Service national test panels, indicating its recognised clinical significance within the UK. It is featured in green R-code panels for Bleeding and platelet disorders (R90), Cerebral vascular malformations (R336), Foetal anomalies (R21), Hereditary haemorrhagic telangiectasia (R186), Inherited bleeding disorders, Pulmonary arterial hypertension (R188), and Vascular skin disorders (R326). This inclusion highlights its importance in diagnosing and managing a range of conditions affecting the vascular system.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the ACVRL1 gene?
The ACVRL1 gene provides instructions for making a protein that acts as a receptor on cell surfaces. This receptor plays a critical role in the development and specialisation of blood vessels, particularly in determining whether new vessels become arteries or veins.
Which condition is most commonly associated with ACVRL1 gene variants?
Variants in the ACVRL1 gene are most commonly associated with hereditary haemorrhagic telangiectasia type 2. This is an inherited disorder characterised by malformations in blood vessels, which can lead to bleeding.
Where is the ACVRL1 gene located in the human genome?
The ACVRL1 gene is located on chromosome 12. Specifically, its position is at 12q13.13, which is on the long arm of chromosome 12.
References
- Letteboer TG, Zewald RA, Kamping EJ. Hereditary hemorrhagic telangiectasia: ENG and ALK-1 mutations in Dutch patients. Human genetics. 2005. PMID: 15517393
- Lebrin F, Deckers M, Bertolino P. TGF-beta receptor function in the endothelium. Cardiovascular research. 2005. PMID: 15664386
- Pawlikowska L, Tran MN, Achrol AS. Polymorphisms in transforming growth factor-beta-related genes ALK1 and ENG are associated with sporadic brain arteriovenous malformations. Stroke. 2005. PMID: 16179574
- Lesca G, Plauchu H, Coulet F. Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France. Human mutation. 2004. PMID: 15024723
- van den Driesche S, Mummery CL, Westermann CJ. Hereditary hemorrhagic telangiectasia: an update on transforming growth factor beta signaling in vasculogenesis and angiogenesis. Cardiovascular research. 2003. PMID: 12667943
- Azuma H. Genetic and molecular pathogenesis of hereditary hemorrhagic telangiectasia. The journal of medical investigation : JMI. 2000. PMID: 11019486