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ITGA2B
integrin subunit alpha 2b
The ITGA2B gene provides instructions for a key component of a platelet receptor essential for proper blood clot formation, and variants in this gene are associated with bleeding disorders. The ITGA2B gene encodes the alphaIIb subunit, which combines with the beta3 subunit (from the ITGB3 gene) to form the integrin alphaIIb/beta3 receptor on 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, or integrin subunit alpha 2b, plays a vital role in haemostasis, the body's process of stopping bleeding. It provides the genetic blueprint for one part of a crucial receptor found on the surface of platelets, which are small blood cells involved in clotting. This receptor facilitates the binding of platelets to other cells and proteins, forming a stable plug at sites of injury.
What the gene does
The ITGA2B gene instructs the cell to produce the alphaIIb subunit of the integrin alphaIIb/beta3 receptor. This receptor is highly abundant on the surface of platelets, with an estimated 80,000 to 100,000 copies per platelet. The alphaIIb subunit partners with the beta3 subunit, encoded by the ITGB3 gene, to create the functional integrin alphaIIb/beta3 complex. During blood clot formation, this integrin receptor binds to fibrinogen and other proteins, enabling platelets to stick together and form a cohesive clot. This aggregation and cohesion are fundamental for sealing damaged blood vessels and preventing excessive blood loss. Beyond clot formation, integrin alphaIIb/beta3 also interacts with proteins in the extracellular matrix, contributing to wound healing.
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Chromosome location
The ITGA2B gene is situated on chromosome 17, specifically at position 17q21.31. This chromosomal location indicates where the gene can be found within the human genome.
Protein structure
The ITGA2B protein, comprising 1039 amino acids, features several distinct structural elements. It includes seven FG-GAP repeats: 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). Towards the C-terminus, a GFFKR motif is located at amino acids 1022-1026.
Key variants
Genetic variations, or variants, in the ITGA2B gene can alter the function or production of the alphaIIb subunit. These changes may impair the formation of the critical integrin alphaIIb/beta3 receptor or its ability to bind to other proteins, such as fibrinogen. The impact of these variants can range from reduced receptor activity to complete absence of functional receptors on platelet surfaces.
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 inherited bleeding disorders. The most well-known condition linked to ITGA2B is Glanzmann thrombasthenia, an autosomal recessive disorder characterised by impaired platelet aggregation. This can lead to symptoms such as easy bruising, frequent nosebleeds, gum bleeding, and prolonged bleeding after injury or surgery. ITGA2B variants can also cause other rare bleeding disorders like platelet-type bleeding disorder 16, presenting with similar but potentially less severe symptoms than Glanzmann thrombasthenia.
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 recognised within the NHS Genomic Medicine Service due to its clinical significance. It is included on the Bleeding and platelet disorders panel (R90) and the Inherited bleeding disorders panel, both of which are classified as 'green', indicating they are routinely evaluated for diagnostic purposes in the UK.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the ITGA2B gene?
The ITGA2B gene provides instructions for making the alphaIIb subunit of the integrin alphaIIb/beta3 receptor, which is crucial for platelets to aggregate and form blood clots.
What condition is most commonly associated with ITGA2B gene variants?
The condition most commonly associated with pathogenic variants in the ITGA2B gene is Glanzmann thrombasthenia, a rare inherited bleeding disorder.
How does ITGA2B relate to blood clotting?
The protein produced by ITGA2B, as part of the integrin alphaIIb/beta3 receptor, enables platelets to bind to fibrinogen and each other, a process essential for the formation of stable blood clots 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