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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 von Willebrand factor, preventing excessive clot formation. ADAMTS13 encodes an enzyme that cleaves von Willebrand factor, a protein involved in initiating 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, fully known as ADAM metallopeptidase with thrombospondin type 1 motif 13, plays a critical role in the human body's intricate blood clotting system. It provides the genetic blueprint for an enzyme responsible for controlling the size and activity of a key clotting protein. Proper function of the ADAMTS13 enzyme is essential for maintaining a healthy balance between preventing bleeding and avoiding inappropriate clot formation within blood vessels.
What the gene does
The ADAMTS13 enzyme functions as a specific protease, meaning it cuts other proteins. Its primary target is von Willebrand factor (vWF), a large protein essential for the initial stages of blood clotting. When a blood vessel is injured, vWF helps platelets stick together and adhere to the vessel wall, forming a temporary plug. Without ADAMTS13, vWF can exist in unusually large forms that are overly adhesive, leading to uncontrolled platelet clumping and the formation of unwanted blood clots in the circulation. The ADAMTS13 enzyme specifically cleaves these large vWF molecules into smaller, less active fragments. This processing prevents vWF from excessively recruiting platelets, thereby regulating clot formation and maintaining normal blood flow throughout the body. Dysfunction of this enzyme can lead to serious health consequences due to widespread microvascular clotting.
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Chromosome location
The ADAMTS13 gene is located on chromosome 9. Specifically, its chromosomal address is 9q34.2, which refers to band 2 on the long (q) arm of chromosome 9. This location places it among numerous other genes on this chromosome that contribute to a wide array of biological functions.
Protein structure
The ADAMTS13 protein is a large enzyme composed of 1427 amino acids. It features a complex modular structure with several distinct functional regions. Key domains include a Disordered region (amino acids 51-70), followed by the catalytic Peptidase M12B domain (amino acids 80-286), which is responsible for cleaving von Willebrand factor. Downstream of this is a Disintegrin domain (amino acids 287-383), and multiple Thrombospondin type-1 (TSP type-1) domains, such as TSP type-1 1 (amino acids 384-439), TSP type-1 2 (amino acids 682-730), and further TSP type-1 domains up to TSP type-1 8 (amino acids 1072-1131). Other important features include a Cysteine-rich region (amino acids 440-556) containing a Cell attachment site motif (amino acids 498-500), a Spacer region (amino acids 556-685), and finally, a CUB 1 domain (amino acids 1192-1298) towards the C-terminus.
Key variants
Variations within the ADAMTS13 gene can alter the protein's structure and function. These changes, known as genetic variants, can range from single nucleotide substitutions to larger deletions or insertions. Pathogenic variants typically lead to a reduction or complete loss of the ADAMTS13 enzyme's activity, which in turn affects its ability to properly process von Willebrand factor. The impact of a specific variant on enzyme function can vary, influencing the severity and onset 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.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 is an inherited disorder characterised by the recurrent formation of small blood clots throughout the body's microvasculature. These clots can impede blood flow to vital organs, potentially leading to a range of symptoms and complications. The condition is inherited in an autosomal recessive manner, meaning an individual must inherit two copies of a pathogenic variant (one from each parent) to be affected.
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
The ADAMTS13 gene is recognised within the UK's NHS Genomic Medicine Service. It is listed as 'green' on several NHS Genomic Test Directories (PanelApp), indicating strong evidence for its association with specific conditions. These include 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). This inclusion highlights its clinical significance in the diagnosis and management of these conditions within the NHS.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main role of the ADAMTS13 gene?
The ADAMTS13 gene provides instructions for making an enzyme that regulates blood clotting. It specifically cuts large von Willebrand factor proteins into smaller pieces, which prevents excessive platelet clumping and inappropriate blood clot formation.
What happens if the ADAMTS13 enzyme does not work correctly?
If the ADAMTS13 enzyme is not functional or is deficient, large von Willebrand factor molecules accumulate. This can lead to the formation of small blood clots in small blood vessels, which can restrict blood flow to organs and cause serious health problems, as seen in conditions like Congenital TTP.
How is Congenital TTP inherited?
Congenital TTP, associated with ADAMTS13 variants, is inherited in an autosomal recessive manner. This means that an individual must inherit two altered copies of the ADAMTS13 gene, one from each parent, to develop the condition. Individuals with only one altered copy 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