Alternative titles; symbols
HGNC Approved Gene Symbol: ITGA2
Cytogenetic location: 5q11.2 Genomic coordinates (GRCh38): 5:52,989,352-53,094,779 (from NCBI)
The ITGA2 gene encodes alpha-2 integrin, a membrane glycoprotein known as GP Ia, which is expressed in a variety of cell types, including megakaryocytes and platelets. In platelets, GP Ia forms a complex with GP IIa (ITGB1; 135630) and represents one of the collagen receptors on the cell surface (summary by Noris et al., 2006).
The protein was originally identified as a very late activation protein (VLA), a family of heterodimeric cell surface glycoproteins first identified on activated human T lymphocytes. VLAs were subsequently shown to be present on a wide variety of cell types including fibroblasts and platelets. Six forms, VLA1 to VLA6, have been identified, each consisting of a distinct alpha chain (numbered alpha-1 to alpha-6) associated with a common ITGB1 beta chain (VLA-beta). GP Ia represents the VLA-alpha-2 component of VLA2 (summary by Woods et al., 1989).
Takada and Hemler (1989) deduced the complete amino acid sequence of GP Ia from the nucleotide sequence in human lung fibroblasts. The mature polypeptide consists of 1,152 amino acids and contains a transmembrane domain and a short cytoplasmic segment. Although the overall sequence homology in comparison with other integrin alpha subunits (e.g., ITGA1, 192968) is 18 to 25%, GP Ia comprises a similar distribution of cysteine residues and cation-binding domains. A major characteristic of GP Ia is the presence of a 191-amino acid insert ('I domain') that contains potential sites for interaction with collagen.
Jacquelin et al. (2001) noted that the proximal 5-prime regulatory region of the ITGA2 gene contains a core promoter within nucleotides -92 to -30 relative to the transcription start site, plus upstream enhancer and silencer elements. Within and immediately upstream of the promoter are 2 confirmed Sp1 (189906)/Sp3 (601804)-binding sites. Jacquelin et al. (2001) confirmed that a third consensus Sp1-binding sequence at nucleotides -107 to -99 is also functional.
Jaspers et al. (1991, 1991) mapped the alpha-2 subunit of the VLA2 receptor (CD49B) to chromosome 5 by several independent approaches: expression of the subunit at the protein level in human-mouse hybrid cell lines, as detected by immunofluorescence with a monoclonal antibody; PCR probing of human-mouse hybrids using primers derived from the known alpha-2 cDNA sequence; and in situ hybridization with a cDNA probe. The last method localized CD49B to 5q23-q31.
Inoue et al. (2003) identified a collagen (see COL1A1; 120150) peptide that bound exclusively to alpha-2-beta-1 integrin and generated tyrosine kinase-based intracellular signaling during spreading of human platelets on collagen-coated surfaces. Murine platelets deficient in Gp6 (605546)-Fc receptor gamma chain (FCERIG; 147139) showed a similar response to the collagen peptide. Both responses were inhibited by alpha-2-beta-1 blockade. The intracellular signaling cascade used by alpha-2-beta-1 shared many features of GP6 signaling, including participation of Src kinases (see 190090) and phospholipase C gamma-2 (PLCG2; 600220). Inoue et al. (2003) concluded that alpha-2-beta-1 has a role in platelet activation by collagen and in control of thrombus formation.
Using RNA sequencing analysis, Fan et al. (2018) found that mouse Cd49b was expressed in activated regulatory T (Treg) cells that were enriched in vasculature and skin and exhibited enhanced migration and circulation properties. Analysis with T cell-deficient mice showed that Cd49b-positive Treg cells were more suppressive than other Treg cells, but that Cd49b itself was nonessential for Treg function. Comparison of the shared repertoires of Cd49b-positive and -negative Treg cells demonstrated that Cd49b-positive Treg cells arose from skin- and peripheral lymph node-homing Cd49b-negative Treg cells that had undergone extensive rounds of proliferation, leading to transcriptional changes that mediated their ability to recirculate to inflammation sites to suppress inflammation.
For a discussion of biochemical evidence for a platelet-type bleeding disorder due to decreased platelet expression of the GPIa/GPIIa complex, see BDPLT9 (614200).
Alloantibodies
In sera obtained from 4 mothers of children with neonatal alloimmune thrombocytopenia (NAIT), Kiefel et al. (1988) found a platelet-specific alloantibody, anti-Br(a), which defined an antigen apparently different from all previously known platelet alloantigens. All 4 fathers were Br(a) positive, whereas all mothers were Br(a) negative. Frequency of the antigen in the German population was about 20%. In demonstrating the new alloantigen, Kiefel et al. (1988) used their glycoprotein-specific enzyme immunoassay.
NAIT due to antibodies against the platelet-specific antigen Br(a), also known as HPA-5b, is the second most frequent type of NAIT in European populations (Mueller-Eckhardt et al., 1989). Anti-Br(a) ranks first among Japanese. Fetomaternal Br(a), or HPA-5a, incompatibility is expected to be very rare because of the high phenotype frequency of Br(b), about 99%, and the resulting very low number of Br(a) homozygous mothers, about 1%. Bettaieb et al. (1991) and Kiefel et al. (1991) reported 4 cases of NAIT in 3 families caused by anti-Br(b). The mother in the case reported by Bettaieb et al. (1991) had the May-Hegglin anomaly (155100); the serum of 7 unrelated May-Hegglin subjects contained no platelet-specific antibody. Kaplan et al. (1991) reported an experience with 39 cases of NAIT involving the Br(a) antigen.
Woods et al. (1989) found that sera from 2 unrelated patients with systemic lupus erythematosus (SLE; 152700) contained antibodies that immunoprecipitated platelet GP Ia and platelet GP IIa. One of the patients had multiple pregnancies and the other had multiple blood transfusions. These SLE antibodies were alloreactive as they precipitated VLA molecules from 5 of 22 normal donors' platelets and did not react with the lupus patients' own platelets. The alloantigen was termed Hc(a). Since only about 5% of SLE patients had VLA-reactive alloantibodies, Woods et al. (1989) concluded that the 2 patients who did have antibodies were probably homozygous for the alloantibody-unreactive allele at the VLAA2 locus. The authors noted that the Hc(a) antigen is identical to the alloantigen Zav(a) and the alloantigen Br(a).
Santoso et al. (1993) demonstrated a single amino acid polymorphism of glycoprotein Ia to be the basis of the platelet alloantigens Br(a) and Br(b).
Santoso et al. (1999) identified a new platelet-specific alloantigen, termed Sit(a), in a severe case of neonatal alloimmune thrombocytopenia. The Sit(a) alloantigen was of low frequency (1/400) in the German population. Immunochemical studies demonstrated that the Sit(a) epitopes reside on platelet glycoprotein Ia. Nucleotide sequence analysis of ITGA2 cDNA derived from Sit(a)-positive platelets showed a 2531C-T transition, resulting in a thr799-to-met dimorphism. Analysis of genomic DNA from 22 Sit(a)-negative normal individuals showed that thr799 to met was encoded by the synonymous codons ACG and ACA in 90.9% and 9.1%, respectively. PCR-RFLP analysis on DNA derived from 100 donors using the restriction enzyme MaeIII showed that the met799 form of GP Ia is restricted to the Sit(a)-positive phenotype. Platelet aggregation responses of Sit(a)-positive individuals were diminished in response to collagen, indicating that the thr799-to-met mutation affects the function of the GP Ia/IIa complex.
Kunicki et al. (1997) identified 2 silent, linked polymorphisms, 807C-T and 873G-A, within the coding region of the ITGA2 gene that were associated with GP Ia/IIa surface expression. High surface expression was found in platelets derived from 807T homozygotes, whereas low surface expression was found in platelets from 807C homozygotes.
Kritzik et al. (1998) demonstrated that nucleotide polymorphisms in the ITGA2 gene are associated with differences in platelet alpha-2/beta-1 density and that this density correlates with the rate of platelet attachment in whole blood to type I collagen. A possible clinical impact of these findings was demonstrated by the association of the GP Ia 807C-T gene polymorphism with nonfatal myocardial infarction and stroke in younger individuals (Santoso et al., 1999; Carlsson et al., 1999).
Von Beckerath et al. (2000) studied the relationship of these polymorphisms to major adverse cardiac events within the first 30 days after coronary artery stenting. Stent placement in coronary arteries had become the most common intervention for symptomatic coronary artery disease. Compared to plain angioplasty, stenting allowed for a higher primary success rate and a reduced restenosis rate. However, early thrombotic events remained a serious problem of coronary stenting. The placement of coronary stents induces marked platelet activation. Von Beckerath et al. (2000) could find no significant influence of the 807C-T genotype on the major adverse events occurring after coronary artery stenting.
Jacquelin et al. (2001) stated that the 5-prime regulatory region of ITGA2 contains 2 dimorphic sites: -92C-G, which lies downstream from an Sp1-binding site, and -52C-T, which lies between 2 Sp1/Sp3-binding sites. They had previously shown that the -52C-T change results in decreased binding of Sp1/Sp3 to the adjacent sites, decreased ITGA2 transcription, and reduced densities of platelet alpha-2/beta-1. Using human megakaryocytic cell lines, Jacquelin et al. (2001) showed that the -92C-G change also decreased ITGA2 transcription significantly. Moreover, the -92C-G and -52C-T changes acted synergistically to decrease ITGA2 transcription rates.
Bettaieb, A., Fromont, P., Rodet, M., Godeau, B., Duedari, N., Bierling, P. Br(b), a platelet alloantigen involved in neonatal alloimmune thrombocytopenia. Vox Sang. 60: 230-234, 1991. [PubMed: 1926830] [Full Text: https://doi.org/10.1111/j.1423-0410.1991.tb00911.x]
Carlsson, L. E., Santoso, S., Spitzer, C., Kessler, C., Greinacher, A. The alpha-2 gene coding sequence T807/A873 of the platelet collagen receptor integrin alpha-2/beta-1 might be a genetic risk factor for the development of stroke in younger patients. Blood 93: 3583-3586, 1999. [PubMed: 10339462]
Fan, X., Moltedo, B., Mendoza, A., Davydov, A. N., Faire, M. B., Mazutis, L., Sharma, R., Pe'er, D., Chudakov, D. M., Rudensky, A. Y. CD49b defines functionally mature Treg cells that survey skin and vascular tissues. J. Exp. Med. 215: 2796-2814, 2018. [PubMed: 30355617] [Full Text: https://doi.org/10.1084/jem.20181442]
Inoue, O., Suzuki-Inoue, K., Dean, W. L., Frampton, J., Watson, S. P. Integrin alpha-2-beta-1 mediates outside-in regulation of platelet spreading on collagen through activation of Src kinases and PLC-gamma-2. J. Cell Biol. 160: 769-780, 2003. [PubMed: 12615912] [Full Text: https://doi.org/10.1083/jcb.200208043]
Jacquelin, B., Rozenshteyn, D., Kanaji, S., Koziol, J. A., Nurden, A. T., Kunicki, T. J. Characterization of inherited differences in transcription of the human integrin alpha-2 gene. J. Biol. Chem. 276: 23518-23524, 2001. [PubMed: 11313353] [Full Text: https://doi.org/10.1074/jbc.M102019200]
Jaspers, M., Marynen, P., Aly, M. S., Cuppens, H., Hilliker, C., Cassiman, J.-J. Localization of the gene encoding the alpha-2 subunit of the human VLA-2 receptor to chromosome 5q23-31. Somat. Cell Molec. Genet. 17: 505-511, 1991. [PubMed: 1763388] [Full Text: https://doi.org/10.1007/BF01233174]
Jaspers, M., Zhang, Z., Marynen, P., Vekemans, S., Aly, M. S., Cuppens, H., Hillicker, C., Cassiman, J.-J. Localization of the genes encoding the alpha-2 and alpha-4 subunits of the human VLA-receptors to chromosome 5q23-31 and 2q31-32 respectively. (Abstract) Cytogenet. Cell Genet. 58: 1870 only, 1991.
Kaplan, C., Morel-Kopp, M. C., Kroll, H., Kiefel, V., Schlegel, N., Chesnel, N., Mueller-Eckhardt, C. HPA-5b (Br-a) neonatal alloimmune thrombocytopenia: clinical and immunological analysis of 39 cases. Brit. J. Haemat. 78: 425-429, 1991. [PubMed: 1873226] [Full Text: https://doi.org/10.1111/j.1365-2141.1991.tb04459.x]
Kiefel, V., Santoso, S., Katzmann, B., Mueller-Eckhardt, C. A new platelet-specific alloantigen Br(a): report of 4 cases with neonatal alloimmune thrombocytopenia. Vox Sang. 54: 101-106, 1988. [PubMed: 3376460] [Full Text: https://doi.org/10.1111/j.1423-0410.1988.tb01625.x]
Kiefel, V., Shechter, Y., Atias, D., Kroll, H., Santoso, S., Mueller-Eckhardt, C. Neonatal alloimmune thrombocytopenia due to anti-Br(b) (HPA-5a): report of three cases in two families. Vox Sang. 60: 244-245, 1991. [PubMed: 1926833] [Full Text: https://doi.org/10.1111/j.1423-0410.1991.tb00915.x]
Kritzik, M., Savage, B., Nugent, D. J., Santoso, S., Ruggeri, Z. M., Kunicki, T. J. Nucleotide polymorphisms in the alpha-2 gene define multiple alleles that are associated with differences in platelet alpha-2/beta-1 density. Blood 92: 2382-2388, 1998. [PubMed: 9746778]
Kunicki, T. J., Kritzik, M., Annis, D. S., Nugent, D. J. Hereditary variation in platelet integrin alpha-2-beta-1 density is associated with two silent polymorphisms in the alpha-2 gene coding sequence. Blood 89: 1939-1943, 1997. [PubMed: 9058714]
Mueller-Eckhardt, C., Kiefel, V., Grubert, A., Kroll, H., Weisheit, M., Schmidt, S., Mueller-Eckhardt, G., Santoso, S. 348 cases of suspected neonatal alloimmune thrombocytopenia. Lancet 333: 363-366, 1989. Note: Originally Volume I. [PubMed: 2563515] [Full Text: https://doi.org/10.1016/s0140-6736(89)91733-9]
Nieuwenhuis, H. K., Akkerman, J. W. N., Houdijk, W. P., Sixma, J. J. Human blood platelets showing no response to collagen fail to express surface glycoprotein Ia. Nature 318: 470-472, 1985. [PubMed: 2933589] [Full Text: https://doi.org/10.1038/318470a0]
Noris, P., Guidetti, G. F., Conti, V., Ceresa, I. F., Di Pumpo, M., Pecci, A., Torti, M., Savoia, A., Balduini, C. L. Autosomal dominant thrombocytopenias with reduced expression of glycoprotein Ia. Thromb. Haemost. 95: 483-489, 2006. [PubMed: 16525577] [Full Text: https://doi.org/10.1160/TH05-06-0421]
Santoso, S., Amrhein, J., Hofmann, H. A., Sachs, U. J. H., Walka, M. M., Kroll, H., Kiefel, V. A point mutation thr799met on the alpha-2 integrin leads to the formation of new human platelet alloantigen Sit(a) and affects collagen-induced aggregation. Blood 94: 4103-4111, 1999. [PubMed: 10590055]
Santoso, S., Kalb, R., Walka, M., Kiefel, V., Mueller-Eckhardt, C., Newman, P. J. The human platelet alloantigens Br(a) and Br(b) are associated with a single amino acid polymorphism on glycoprotein Ia (integrin subunit alpha-2). J. Clin. Invest. 92: 2427-2432, 1993. [PubMed: 7901236] [Full Text: https://doi.org/10.1172/JCI116849]
Santoso, S., Kunicki, T. J., Kroll, H., Haberbosch, W., Gardemann, A. Association of the platelet glycoprotein Ia C807T gene polymorphism with nonfatal myocardial infarction in younger patients. Blood 93: 2449-2453, 1999. [PubMed: 10194421]
Takada, Y., Hemler, M. E. The primary structure of the VLA-2/collagen receptor alpha-2 subunit (platelet GPIa): homology to other integrins and the presence of a possible collagen-binding domain. J. Cell Biol. 109: 397-407, 1989. [PubMed: 2545729] [Full Text: https://doi.org/10.1083/jcb.109.1.397]
von Beckerath, N., Koch, W., Mehilli, J., Bottiger, C., Schomig, A., Kastrati, A. Glycoprotein Ia gene C807T polymorphism and risk for major adverse cardiac events within the first 30 days after coronary artery stenting. Blood 95: 3297-3301, 2000. [PubMed: 10828008]
Woods, V. L., Jr., Pischel, K. D., Avery, E. D., Bluestein, H. G. Antigenic polymorphism of human very late activation protein-2 (platelet glycoprotein Ia-IIa): platelet alloantigen Hc(a). J. Clin. Invest. 83: 978-985, 1989. [PubMed: 2646323] [Full Text: https://doi.org/10.1172/JCI113984]