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ITGA2B
integrin subunit alpha 2b
The ITGA2B gene encodes a crucial subunit of a protein complex vital for platelet aggregation and proper blood clot formation, with variants linked to inherited bleeding disorders. The ITGA2B gene provides instructions for the alphaIIb subunit of the integrin alphaIIb/beta3 receptor, which is found on the surface of platelets.
ITGA2B is located on the long (q) arm of chromosome 17, at band 17q21.31. Arm ratio per GRCh38 - banding schematic.
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Overview
The ITGA2B gene, also known as integrin subunit alpha 2b, is instrumental in the process of blood clotting. It provides the genetic blueprint for one part of a crucial receptor complex located on platelets, which are small cells in the blood vital for haemostasis. The ITGA2B gene's role in platelet function explains how certain variants cause inherited bleeding disorders.
What the gene does
The ITGA2B gene codes for the alphaIIb subunit, which combines with the beta3 subunit (encoded by the ITGB3 gene) to form the integrin alphaIIb/beta3 receptor [PMID:16292398]. This receptor is abundantly present on the surface of platelets, with an estimated 80,000 to 100,000 copies per platelet. This receptor recognises fibrinogen molecules, enabling connections to form between neighbouring platelets during clot assembly. When platelets connect through this receptor, they aggregate into clusters that become the foundation of a clot, stemming blood loss at injury sites [PMID:11985955]. The receptor also interacts with other proteins within the extracellular matrix and on platelets, contributing to effective clot formation and wound healing.
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Chromosome location
The ITGA2B gene is situated on chromosome 17 at position q21.31. This specific genomic location indicates where the gene resides within the human genome. It is categorised as an autosomal recessive gene in carrier screening contexts.
Protein structure
The ITGA2B protein, also known as alphaIIb, is composed of 1039 amino acids. Its structure includes several key repeats known as FG-GAP domains. These are specifically located at FG-GAP 1 (amino acids 35-96), FG-GAP 2 (amino acids 110-173), FG-GAP 3 (amino acids 187-238), FG-GAP 4 (amino acids 251-305), FG-GAP 5 (amino acids 306-371), FG-GAP 6 (amino acids 373-432), and FG-GAP 7 (amino acids 435-496). Additionally, a GFFKR motif is present at amino acids 1022-1026, which is typically involved in regulatory interactions.
Key variants
Variants within the ITGA2B gene can alter the production or function of the alphaIIb subunit. These genetic changes can impair the formation of the functional integrin alphaIIb/beta3 receptor on platelets. Such alterations can significantly affect the ability of platelets to aggregate, leading to various bleeding disorders.
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.1423C>T | p.Gln475Ter | Pathogenic | ★★★☆ | Glanzmann thrombasthenia |
c.1654del | p.Val552fs | Pathogenic | ★★★☆ | Glanzmann thrombasthenia |
c.188+1G>A | - | Pathogenic | ★★★☆ | Glanzmann thrombasthenia |
c.2674del | p.Ile892fs | Pathogenic | ★★★☆ | Glanzmann thrombasthenia |
c.2822G>A | p.Trp941Ter | Pathogenic | ★★★☆ | Glanzmann thrombasthenia |
c.3001_3010dup | p.Val1004fs | Pathogenic | ★★★☆ | Glanzmann thrombasthenia |
c.480del | p.Cys161fs | Pathogenic | ★★★☆ | Glanzmann thrombasthenia |
c.575-2A>T | - | Pathogenic | ★★★☆ | Glanzmann thrombasthenia |
c.605T>G | p.Phe202Cys | Pathogenic | ★★★☆ | Glanzmann thrombasthenia |
c.963del | p.His322fs | Pathogenic | ★★★☆ | Glanzmann thrombasthenia |
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 ITGA2B gene are primarily associated with Glanzmann thrombasthenia [PMID:24810672]. This is a rare, inherited bleeding disorder characterised by defective platelet aggregation. At least 200 different variants in ITGA2B have been identified as causes of Glanzmann thrombasthenia. Individuals with Glanzmann thrombasthenia may experience symptoms such as easy bruising, nosebleeds, and prolonged bleeding after injury or surgery, due to the impaired function of their platelets.
Inheritance pattern
Conditions caused by pathogenic ITGA2B 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 ITGA2B gene is included in several NHS England Genomic Medicine Service approved panels for inherited conditions. It is part of the 'Bleeding and platelet disorders' panel (R90), which has a green status, indicating it is routinely tested. It is also found on the 'Inherited bleeding disorders' panel, also with a green status.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the ITGA2B gene?
The ITGA2B gene provides instructions for making the alphaIIb subunit of the integrin alphaIIb/beta3 receptor, which is essential for platelet aggregation and blood clot formation.
Which condition is primarily associated with ITGA2B gene variants?
Variants in the ITGA2B gene are primarily associated with Glanzmann thrombasthenia, a rare inherited bleeding disorder characterised by impaired platelet function.
How does the ITGA2B protein contribute to blood clotting?
The ITGA2B protein forms part of a receptor on platelets that binds to fibrinogen, helping platelets stick together. This aggregation is a crucial step in forming a stable blood clot to stop bleeding.
References
- Nurden AT, Pillois X, Fiore M. Expanding the Mutation Spectrum Affecting αIIbβ3 Integrin in Glanzmann Thrombasthenia: Screening of the ITGA2B and ITGB3 Genes in a Large International Cohort. Human mutation. 2015. PMID: 25728920
- Kunishima S, Kashiwagi H, Otsu M. Heterozygous ITGA2B R995W mutation inducing constitutive activation of the αIIbβ3 receptor affects proplatelet formation and causes congenital macrothrombocytopenia. Blood. 2011. PMID: 21454453
- Nurden AT, Fiore M, Nurden P. Glanzmann thrombasthenia: a review of ITGA2B and ITGB3 defects with emphasis on variants, phenotypic variability, and mouse models. Blood. 2011. PMID: 21917754
- Nurden AT, Pillois X, Fiore M. Glanzmann thrombasthenia-like syndromes associated with Macrothrombocytopenias and mutations in the genes encoding the αIIbβ3 integrin. Seminars in thrombosis and hemostasis. 2011. PMID: 22102273
- Pillitteri D, Pilgrimm AK, Kirchmaier CM. Novel Mutations in the GPIIb and GPIIIa Genes in Glanzmann Thrombasthenia. Transfusion medicine and hemotherapy : offizielles Organ der Deutschen Gesellschaft fur Transfusionsmedizin und Immunhamatologie. 2010. PMID: 21113249