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ITGB3
integrin subunit beta 3
The *ITGB3* gene provides instructions for producing the beta-3 subunit of integrin αIIbβ3, a protein essential for platelet aggregation and blood clot formation. The *ITGB3* gene is fundamental for haemostasis, encoding a crucial part of the integrin αIIbβ3 receptor found on platelets.
ITGB3 is located on the long (q) arm of chromosome 17, at band 17q21.32. Arm ratio per GRCh38 - banding schematic.
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Overview
The *ITGB3* gene, also known as integrin subunit beta 3, contains the genetic blueprint for the beta-3 subunit of the integrin αIIbβ3 protein. This protein is predominantly located on the surface of platelets, which are small blood cells vital for stopping bleeding.
Integrin αIIbβ3 is critical for platelet aggregation, a process where platelets stick together to form a clot. Defects in the *ITGB3* gene can lead to impaired platelet function, resulting in bleeding disorders such as Glanzmann thrombasthenia.
What the gene does
The protein encoded by *ITGB3* is the beta-3 subunit, which combines with the alpha-IIb subunit (from the *ITGA2B* gene) to form the integrin αIIbβ3 receptor. Each platelet typically carries between 80,000 and 100,000 copies of this receptor on its surface.
During blood clot formation, integrin αIIbβ3 binds to fibrinogen, a protein found in the blood. This binding enables adjacent platelets to cluster together, a process known as platelet cohesion, which is essential for creating a stable blood clot. Beyond fibrinogen, integrin αIIbβ3 can also interact with other proteins on platelets, within the bloodstream, and in the extracellular matrix, further supporting appropriate clot formation and wound healing.
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Chromosome location
The *ITGB3* gene is situated on chromosome 17 at band 17q21.32. This precise genomic address helps in identifying and studying the gene's location within the human genome. The gene is responsible for producing a protein that is 788 amino acids long.
Protein structure
The ITGB3 protein, 788 amino acids in length, features several distinct domains and regions that contribute to its function. These include the PSI domain (amino acids 30-76) and the VWFA domain (amino acids 135-377). Key regions involved in binding various molecules are also present, such as a segment involved in CX3CL1-, NRG1-, FGF1- and IGF1-binding (amino acids 203-210), and a specific CX3CL1-binding region (amino acids 293-313). Further structural elements include the I-EGF 1, 2, 3, and 4 domains (amino acids 463-498, 499-548, 549-585, and 586-625 respectively), and a LIR motif (amino acids 777-783).
Key variants
Variants in the *ITGB3* gene can alter the structure or function of the beta-3 subunit, potentially affecting integrin αIIbβ3 activity. These genetic changes can impair the protein's ability to facilitate platelet aggregation, which is critical for effective blood clot formation. The impact of a variant depends on its specific nature and location within the gene.
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.1053_1058del | p.Ile351_Gly353delinsMet | Pathogenic | ★★★☆ | Glanzmann thrombasthenia |
c.1431C>T | p.Gly477= | Pathogenic | ★★★☆ | Glanzmann thrombasthenia |
c.1476G>A | p.Trp492Ter | Pathogenic | ★★★☆ | Glanzmann thrombasthenia |
c.1552C>T | p.Gln518Ter | Pathogenic | ★★★☆ | Glanzmann thrombasthenia |
c.1616_1617del | p.Phe539fs | Pathogenic | ★★★☆ | Glanzmann thrombasthenia |
c.1788del | p.Ser596fs | Pathogenic | ★★★☆ | Glanzmann thrombasthenia |
c.1815C>T | p.Gly605= | Pathogenic | ★★★☆ | Glanzmann thrombasthenia |
c.1990G>T | p.Glu664Ter | Pathogenic | ★★★☆ | Glanzmann thrombasthenia |
c.602del | p.Asn201fs | Pathogenic | ★★★☆ | Glanzmann thrombasthenia |
c.792G>A | p.Trp264Ter | 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 *ITGB3* gene are primarily associated with inherited bleeding disorders. The most well-known condition is Glanzmann thrombasthenia, which is inherited in an autosomal recessive pattern. This disorder arises when both copies of the *ITGB3* gene carry variants that significantly reduce the production or activity of the beta-3 subunit, leading to dysfunctional integrin αIIbβ3 and impaired platelet aggregation.
Inheritance pattern
Conditions caused by pathogenic ITGB3 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 *ITGB3* gene is included in several NHS Genomic Medicine Service national test directories, indicating its clinical relevance within the UK. It is currently listed on the 'Bleeding and platelet disorders', 'COVID-19 research', and 'Inherited bleeding disorders' panels, all of which are categorised as 'green', signifying their clinical utility.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the ITGB3 gene?
The *ITGB3* gene provides instructions for producing the beta-3 subunit of the integrin αIIbβ3 protein, which is found on platelets. This protein is essential for platelet aggregation and the formation of stable blood clots to stop bleeding.
Which condition is primarily associated with ITGB3 gene variants?
The primary condition associated with pathogenic variants in the *ITGB3* gene is Glanzmann thrombasthenia. This is a rare autosomal recessive bleeding disorder characterised by impaired platelet function.
How does ITGB3 relate to blood clotting?
The ITGB3 protein forms part of the integrin αIIbβ3 receptor on platelets. This receptor binds to fibrinogen, allowing platelets to stick together and form a plug at the site of injury, which is a crucial step in blood clot formation.
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
- Kobayashi Y, Matsui H, Kanai A. Identification of the integrin β3 L718P mutation in a pedigree with autosomal dominant thrombocytopenia with anisocytosis. British journal of haematology. 2013. PMID: 23253071
- 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