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ITGB3
integrin subunit beta 3
The ITGB3 gene provides instructions for producing the beta3 subunit of the integrin αIIbβ3 protein, essential for normal platelet function and effective blood clot formation. ITGB3 plays a critical role in haemostasis by contributing to 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 encodes the integrin subunit beta 3. This protein is a vital component of the integrin αIIbβ3 receptor, which is predominantly expressed on the surface of platelets. Platelets are small blood cells crucial for initiating and regulating blood clotting processes throughout the body.
What the gene does
The ITGB3 gene provides instructions for the beta3 subunit, which then associates with the alphaIIb subunit (from the ITGA2B gene) to form the integrin αIIbβ3 receptor. Platelets typically display between 80,000 and 100,000 copies of this receptor on their surface. During the process of blood clot formation, integrin αIIbβ3 binds to fibrinogen, a protein that acts as a bridge between adjacent platelets. This binding facilitates platelet aggregation, which is essential for forming a stable blood clot to seal damaged blood vessels and prevent blood loss. The integrin αIIbβ3 receptor also interacts with other proteins on platelets, within the bloodstream, and in the extracellular matrix, further supporting effective clot formation and wound healing.
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Chromosome location
The ITGB3 gene is situated on chromosome 17 at position 17q21.32. This chromosomal location defines the specific region where the gene resides within the human genome.
Protein structure
The ITGB3 protein consists of 788 amino acids and features several distinct domains and regions. Key structural elements include the PSI domain (amino acids 30-76) and the VWFA domain (amino acids 135-377). Specific regions involved in binding various molecules include the area involved in CX3CL1-, NRG1-, FGF1- and IGF1-binding (amino acids 203-210) and a dedicated CX3CL1-binding region (amino acids 293-313). The protein also contains multiple I-EGF domains, namely I-EGF 1 (amino acids 463-498), I-EGF 2 (amino acids 499-548), I-EGF 3 (amino acids 549-585), and I-EGF 4 (amino acids 586-625). A LIR motif is located towards the C-terminus (amino acids 777-783).
Key variants
Variants within the ITGB3 gene can affect the structure and function of the integrin beta 3 protein. These genetic changes may impact the protein's ability to combine with other subunits or bind to its targets, thereby influencing platelet function and blood clot formation. Such variants are typically inherited in an autosomal recessive manner, meaning an individual must inherit two copies of the altered gene to exhibit 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.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-characterised condition is Glanzmann thrombasthenia, a rare autosomal recessive bleeding disorder. Individuals with Glanzmann thrombasthenia may experience symptoms such as frequent nosebleeds (epistaxis) and bleeding from the gums. Over 130 ITGB3 gene variants have been identified as causes of Glanzmann thrombasthenia, affecting the production or activity of the beta3 subunit and disrupting functional integrin αIIbβ3. Other conditions associated with ITGB3 variants include osteopetrosis and platelet-type bleeding disorder 16, which shares similar symptoms with Glanzmann thrombasthenia.
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 England Genomic Medicine Service national test panels. It is part of the Bleeding and platelet disorders panel (R90), the COVID-19 research panel, and the Inherited bleeding disorders panel, all of which are categorised as 'green' in PanelApp, indicating they are clinically actionable and routinely tested.
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 making the beta3 subunit of the integrin αIIbβ3 receptor. This receptor is found on platelets and is crucial for platelet aggregation and the formation of stable blood clots, which prevent excessive bleeding.
What is Glanzmann thrombasthenia?
Glanzmann thrombasthenia is a rare inherited bleeding disorder caused by pathogenic variants in the ITGB3 gene. It results in a deficiency or dysfunction of the integrin αIIbβ3 receptor on platelets, impairing their ability to aggregate and form proper blood clots.
How is Glanzmann thrombasthenia inherited?
Glanzmann thrombasthenia is typically inherited in an autosomal recessive manner. This means an individual must inherit two altered copies of the ITGB3 gene, one from each parent, to develop the condition. Individuals with only one altered copy are usually carriers and do not show symptoms.
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