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ADAMTS13
ADAM metallopeptidase with thrombospondin type 1 motif 13
The ADAMTS13 gene provides instructions for an enzyme crucial in regulating blood clotting by processing a large protein called von Willebrand factor. The ADAMTS13 gene encodes an enzyme that plays a vital role in preventing uncontrolled blood clot formation.
ADAMTS13 is located on the long (q) arm of chromosome 9, at band 9q34.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The ADAMTS13 gene, also known as ADAM metallopeptidase with thrombospondin type 1 motif 13, is instrumental in maintaining normal blood clotting processes. It produces an enzyme that specifically cleaves von Willebrand factor, a large protein involved in platelet adhesion and clot formation. This enzymatic activity is essential for preventing the spontaneous formation of blood clots throughout the body's circulation.
Inherited changes in the ADAMTS13 gene are associated with conditions that can affect blood clotting, such as Congenital TTP. Understanding the function of ADAMTS13 is key to comprehending the underlying mechanisms of these disorders.
What the gene does
The ADAMTS13 enzyme's primary function is to regulate blood clotting by processing von Willebrand factor (VWF). VWF is a large protein that helps platelets stick together and adhere to damaged blood vessel walls, forming initial blood clots to stop bleeding. Without proper regulation, VWF can lead to the formation of inappropriate blood clots.
The ADAMTS13 enzyme acts as a 'molecular scissors,' cutting VWF into smaller fragments. This cleavage prevents VWF from excessively promoting platelet aggregation and forming clots in the absence of injury. By carefully controlling VWF activity, ADAMTS13 ensures that blood clotting occurs only when necessary and does not obstruct normal blood flow.
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Chromosome location
The ADAMTS13 gene is located on chromosome 9, specifically at position 9q34.2. This chromosomal address indicates its precise place within the human genome.
Protein structure
The ADAMTS13 protein is composed of 1427 amino acids and features a complex domain architecture crucial for its enzymatic function. Key regions include a Disordered region (amino acids 51-70), followed by the catalytic Peptidase M12B domain (amino acids 80-286). A Disintegrin domain (amino acids 287-383) is present, along with multiple TSP type-1 domains: TSP type-1 1 (amino acids 384-439), TSP type-1 2 (amino acids 682-730), TSP type-1 3 (amino acids 742-805), TSP type-1 4 (amino acids 808-859), TSP type-1 5 (amino acids 896-950), TSP type-1 6 (amino acids 951-1011), TSP type-1 7 (amino acids 1012-1068), and TSP type-1 8 (amino acids 1072-1131). The protein also contains a Cysteine-rich region (amino acids 440-556) which includes a Cell attachment site (amino acids 498-500), a Spacer region (amino acids 556-685), and a CUB 1 domain (amino acids 1192-1298).
Key variants
Genetic variations within the ADAMTS13 gene can affect the enzyme's structure and function. These changes, often referred to as mutations or pathogenic variants, can impair the protein's ability to cleave von Willebrand factor effectively. Over 150 different pathogenic variants have been identified in individuals with inherited forms of associated conditions. As ADAMTS13 is inherited in an autosomal recessive manner, an individual must inherit two altered copies of the gene, one from each parent, to develop the associated condition.
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.1045C>T | p.Arg349Cys | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1058C>T | p.Pro353Leu | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1169G>A | p.Trp390Ter | Pathogenic | ★★☆☆ | Upshaw-Schulman syndrome |
c.1393_1394del | p.Ala465fs | Pathogenic/Likely pathogenic | ★★☆☆ | ADAMTS13-related disorder |
c.1456_1457del | p.Met486fs | Pathogenic | ★★☆☆ | ADAMTS13-related disorder |
c.1520G>A | p.Arg507Gln | Pathogenic | ★★☆☆ | not provided |
c.1787C>T | p.Ala596Val | Pathogenic | ★★☆☆ | not provided |
c.2050C>T | p.Gln684Ter | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.2074C>T | p.Arg692Cys | Pathogenic | ★★☆☆ | Upshaw-Schulman syndrome |
c.22dup | p.Ala8fs | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
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 ADAMTS13 gene are primarily associated with Congenital TTP, also known as Upshaw-Schulman syndrome. This condition is characterised by the formation of small blood clots throughout the body's small blood vessels, which can lead to serious health problems by blocking blood flow to vital organs such as the brain, kidneys, and heart. Symptoms can include low platelet count, red blood cell destruction, and neurological issues.
Inheritance pattern
Conditions caused by pathogenic ADAMTS13 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
ADAMTS13 is included in several NHS Genomic Medicine Service national test directories, reflecting its clinical significance within the UK. It is part of panels for Bleeding and platelet disorders (R90), Cytopenias and congenital anaemias, Inherited bleeding disorders, Thrombophilia with a likely monogenic cause (R97), and Vascular skin disorders (R326). These inclusions mean that genetic testing for variants in ADAMTS13 may be offered to eligible patients within the NHS.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the ADAMTS13 gene do?
The ADAMTS13 gene provides instructions for making an enzyme that regulates blood clotting. This enzyme cuts a large protein called von Willebrand factor into smaller pieces, preventing excessive blood clot formation in the circulation.
What condition is associated with changes in the ADAMTS13 gene?
Changes in the ADAMTS13 gene are primarily associated with Congenital Thrombotic Thrombocytopenic Purpura (TTP), also known as Upshaw-Schulman syndrome. This condition causes blood clots to form in small blood vessels throughout the body.
How is Congenital TTP inherited?
Congenital TTP is inherited in an autosomal recessive manner. This means an individual must inherit two pathogenic variants in the ADAMTS13 gene, one from each parent, to develop the condition. Individuals with only one pathogenic variant are typically carriers and do not show symptoms.
References
- Tsai HM. Thrombotic thrombocytopenic purpura and the atypical hemolytic uremic syndrome: an update. Hematology/oncology clinics of North America. 2013. PMID: 23714312
- Tsai HM. Is severe deficiency of ADAMTS-13 specific for thrombotic thrombocytopenic purpura? Yes. Journal of thrombosis and haemostasis : JTH. 2003. PMID: 12871390
- Levy GG, Nichols WC, Lian EC. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature. 2001. PMID: 11586351