HGNC Approved Gene Symbol: TBXA2R
Cytogenetic location: 19p13.3 Genomic coordinates (GRCh38): 19:3,594,507-3,606,875 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.3 | {Bleeding disorder, platelet-type, 13, susceptibility to} | 614009 | Autosomal dominant | 3 |
The TBXA2R gene encodes the thromboxane A2 receptor, which is a member of the family of G protein-coupled receptors. It plays an essential role in hemostasis by interacting with thromboxane A2 (TXA2) to induce platelet aggregation (summary by Hirata et al., 1994). Thromboxane A2 is an arachidonate metabolite that is a potent stimulator of platelet aggregation and a constrictor of vascular and respiratory smooth muscles. TXA2 has been implicated as a mediator in diseases such as myocardial infarction, stroke, and bronchial asthma (summary by Ushikubi et al., 1989).
Ushikubi et al. (1989) purified the cell surface receptor for TXA2, using a stable analog of TXA2. Using an oligonucleotide probe corresponding to its partial amino acid sequence, Hirata et al. (1991) obtained a cDNA encoding the receptor from human placenta and a partial cDNA clone from cultured human megakaryocytic leukemia cells. The placenta cDNA encoded a protein of 343 amino acids with 7 putative transmembrane domains. The protein expressed in COS-7 cells bound drugs with affinities identical to those of the platelet receptor, and that expressed in Xenopus oocytes opened calcium-ion-activated chloride channels on agonist stimulation. Northern blot analysis and nucleotide sequences of the 2 clones suggested that an identical form of thromboxane A2 receptor is present in platelets and vascular tissues.
Two isoforms of the human TXA2 receptor have been cloned: one from placenta and the other from endothelium, referred to as TXR-alpha and TXR-beta, respectively. These isoforms differ only in their C-terminal tails. Hirata et al. (1996) found that both isoforms are present in human platelets. The 2 isoforms expressed in cultured cells show similar ligand-binding characteristics and phospholipase C activation but oppositely regulated adenylyl cyclase activity: TXR-alpha activates adenylyl cyclase, while TXR-beta inhibits it.
Nusing et al. (1993) reported that the TBXA2R gene is present in the genome in single copy, spans over 15 kb, and contains 3 exons divided by 2 introns. Intron 1 exists in the 5-prime noncoding region, 83 bp upstream from the ATG start site, and is 6.3 kb long. Intron 2, with a length of 4.3 kb, is located at the end of the sixth transmembrane region, thereby separating it from the downstream coding sequences, including the seventh transmembrane region and the 3-prime untranslated region. By rapid amplification of 5-prime cDNA ends, Nusing et al. (1993) determined transcription initiation sites starting in 2 different putative promoter regions.
Using transcribed 3-prime untranslated DNA sequence polymorphisms, Schwengel et al. (1993) localized the TBXA2R gene to chromosome 19 by PCR amplification in a series of monochromosomal human/rodent somatic cell hybrids. Linkage mapping placed TBXA2R closest to D19S120, with a maximum lod = 19.55 at theta = 0.05 in the CEPH panel of DNAs. Multipoint linkage analysis placed TBXA2R between the markers D19S120 and PMS207 on the telomeric end of 19p13.3.
Using fluorescence in situ hybridization of cloned genomic DNA to metaphase chromosomes, Nusing et al. (1993) demonstrated that the TBXA2R gene is located on 19p13.3. The map position was confirmed by Duncan et al. (1995), who also noted minor in situ hybridization signals at 12q24.3-q24.4 and 15q25-q26.
Taketo et al. (1994) used the mouse homolog of the human TXA2 receptor as a cDNA probe to map the gene in the mouse (Tbxa2r) to chromosome 10, using a panel of DNA samples from an interspecific cross. The best gene order suggested that TBXA2R is located distal to Myb and proximal to Pah.
In affected members of 2 unrelated families with an autosomal dominant platelet-type bleeding disorder (BDPLT13; 614009) characterized by defective platelet response to TBXA2, Hirata et al. (1994) identified a heterozygous mutation in the TBXA2R gene (R60L; 188070.0001).
Mumford et al. (2010) concluded that heterozygosity for mutations in the TBXA2R gene is sufficient to cause abnormal platelet functional responses in vitro, but is insufficient to cause clinically significant dysfunction in vivo.
Unoki et al. (2000) surveyed 29 possible candidate genes for bronchial asthma for single nucleotide polymorphisms (SNPs) in genomic DNA from Japanese patients. They identified 33 SNPs, only 4 of which had previously been reported, among 14 of these genes. They also performed association studies using 585 bronchial asthma patients and 343 normal controls for these SNPs. Only 1 of the 33 SNPs showed a positive association with bronchial asthma: a 924T-C polymorphism in the TBXA2R gene, seen most often in adult patients.
The actions of TXA2 are mediated by G protein-coupled thromboxane-prostanoid (TP) receptors. TP receptors have been implicated in the pathogenesis of cardiovascular diseases. To investigate the physiologic functions of TP receptors, Thomas et al. (1998) generated TP receptor-deficient mice by gene targeting. Tp -/- animals reproduced and survived in expected numbers, and their major organ systems were normal. Thromboxane agonist binding could not be detected in tissues from Tp -/- mice. Bleeding times were prolonged in these mice and their platelets did not aggregate after exposure to TXA2 agonists. Aggregation responses after collagen stimulation were also delayed, although ADP-stimulated aggregation was normal. In summary, Tp -/- mice had a mild bleeding disorder and altered vascular responses to TXA2 and arachidonic acid. Their studies suggested that most of the recognized functions of TXA2 are mediated by the single known Tp gene locus.
Cheng et al. (2002) demonstrated that injury-induced vascular proliferation and platelet activation are enhanced in mice that are genetically deficient in the PGI2 receptor (600022) but are depressed in mice genetically deficient in the TXA2 receptor or treated with a TXA2 receptor antagonist. The augmented response to vascular injury was abolished in mice deficient in both receptors. Thus, PGI2 modulates platelet-vascular interactions in vivo and specifically limits the response to TXA2. This interplay may help explain the adverse cardiovascular effects associated with selective COX2 inhibitors, which, unlike aspirin and nonsteroidal antiinflammatory drugs, inhibit PGI2 but not TXA2.
Kabashima et al. (2003) used mice deficient in Tbxa2r to investigate the role of TBXA2R in the immune system. They showed that Tbxa2r, which is highly expressed in mouse spleen and thymus, is expressed on naive but not memory T cells. Tbxa2r -/- mice were apparently normal, but they developed marked cervical lymphadenopathy with disruption of the zonal structure of lymph nodes with age. Contact hypersensitivity was also enhanced in these mice. Treating cells with a TBXA2R agonist increased random chemokinesis of naive T cells and inhibited adhesion of dendritic cells (DCs) to T cells and DC-dependent T-cell proliferation. Kabashima et al. (2003) concluded that TBXA2-TBXA2R signaling negatively regulates DC-T cell interactions.
In affected members of 2 unrelated families with autosomal dominant platelet-type bleeding disorder-13 (BDPLT13; 614009) characterized by defective platelet response to TBXA2, Hirata et al. (1994) identified a heterozygous 179G-T transversion in the TBXA2R gene, resulting in an arg60-to-leu (R60L) substitution in the first cytoplasmic loop. The proband in 1 family was homozygous for the mutation and had a slightly more severe phenotype. The families had been reported by Ushikubi et al. (1987) and Fuse et al. (1993), respectively, who demonstrated impaired platelet aggregation responses to TBXA2 and its analogs, despite a normal response to thrombin. Expression of the mutant receptor in Chinese hamster ovary cells by Hirata et al. (1994) showed decreased agonist-induced second messenger formation despite normal ligand binding affinities. Dominant inheritance of the disorder suggested that the mutation produces a dominant-negative effect.
Hirata et al. (1996) showed that the R60L mutant of the TXR-alpha isoform of the human TXA2 receptor, which had been shown to impair phospholipase C activation, also impaired adenylyl cyclase stimulation, whereas TXR-beta with the same mutation retained its activity to inhibit adenylyl cyclase.
In a 14-year-old white boy with mild mucocutaneous platelet-type bleeding disorder-13 (BDPLT13; 614009) characterized by defective platelet response to TBXA2, Mumford et al. (2010) identified a heterozygous 910G-A transition in the TBXA2R gene, resulting in an asp304-to-asn (D304N) substitution in transmembrane domain 7. The patient's father, who also carried the mutation, had no bleeding symptoms. In vitro studies of platelets from both the boy and his father showed impaired aggregation and ATP secretion responses to arachidonic acid and a TBXA2R agonist. In vitro functional expression studies in CHO cells showed normal surface membrane expression of the mutant protein, but there was significantly decreased binding and a significant reduction (more than 85%) in intracellular calcium levels in response to a TBXA2R agonist compared to wildtype, consistent with a loss of function. Noting the phenotypic differences between the boy and his father, Mumford et al. (2010) speculated that the clinical bleeding phenotype demonstrated by the boy represented the effect of the heterozygous D304N mutation combined with an additional unidentified hemostatic defect. Mumford et al. (2010) concluded that heterozygosity for mutations in the TBXA2R gene is sufficient to cause abnormal platelet functional responses in vitro, but is insufficient to cause clinically significant dysfunction in vivo.
In an individual whose platelets showed defective response to TBXA2 in vitro, consistent with susceptibility to platelet-type bleeding disorder-13 (BDPLT13; 614009), Flamm et al. (2012) identified a heterozygous T-to-G transversion in exon 2 of the TBXA2R gene, resulting in a val241-to-gly (V241G) substitution at a highly conserved residue in the third intracellular loop of the receptor near the inner membrane. In vitro functional expression studies showed normal expression of the mutant receptor, but impaired calcium mobilization and aggregation in response to a TBXA2 agonist. Because G protein signaling through ADP was normal, Flamm et al. (2012) concluded that the mutation caused abnormal coupling of TBXA2R to Gq, resulting in impaired calcium mobilization. The individual's platelets also showed impaired response to the anticoagulants aspirin and indomethacin, which inhibit the production of thromboxane A2. The individual had no self-reported bleeding tendencies.
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Flamm, M. H., Colace, T. V., Chatterjee, M. S., Jing, H., Zhou, S., Jaeger, D., Brass, L. F., Sinno, T., Diamond, S. L. Multiscale prediction of patient-specific platelet function under flow. Blood 120: 190-198, 2012. [PubMed: 22517902] [Full Text: https://doi.org/10.1182/blood-2011-10-388140]
Fuse, I., Mito, M., Hattori, A., Higuchi, W., Shibata, A., Ushikubi, F., Okuma, M., Yahata, K. Defective signal transduction induced by thromboxane A2 in a patient with a mild bleeding disorder: impaired phospholipase C activation despite normal phospholipase A2 activation. Blood 81: 994-1000, 1993. [PubMed: 8428006]
Hirata, M., Hayashi, Y., Ushikubi, F., Yokota, Y., Kageyama, R., Nakanishi, S., Narumiya, S. Cloning and expression of cDNA for a human thromboxane A2 receptor. Nature 349: 617-620, 1991. [PubMed: 1825698] [Full Text: https://doi.org/10.1038/349617a0]
Hirata, T., Kakizuka, A., Ushikubi, F., Fuse, I., Okuma, M., Narumiya, S. Arg60-to-leu mutation of the human thromboxane A2 receptor in a dominantly inherited bleeding disorder. J. Clin. Invest. 94: 1662-1667, 1994. [PubMed: 7929844] [Full Text: https://doi.org/10.1172/JCI117510]
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Kabashima, K., Murata, T., Tanaka, H., Matsuoka, T., Sakata, D., Yoshida, N., Katagiri, K., Kinashi, T., Tanaka, T., Miyasaka, M., Nagai, H., Ushikubi, F., Narumiya, S. Thromboxane A2 modulates interaction of dendritic cells and T cells and regulates acquired immunity. Nature Immun. 4: 694-701, 2003. [PubMed: 12778172] [Full Text: https://doi.org/10.1038/ni943]
Mumford, A. D., Dawood, B. B., Daly, M. E., Murden, S. L., Williams, M. D., Protty, M. B., Spalton, J. C., Wheatley, M., Mundell, S. J., Watson, S. P. A novel thromboxane A2 receptor D304N variant that abrogates ligand binding in a patient with a bleeding diathesis. Blood 115: 363-369, 2010. Note: Erratum: Blood 119: 4092 only, 2012. [PubMed: 19828703] [Full Text: https://doi.org/10.1182/blood-2009-08-236976]
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Schwengel, D. A., Nouri, N., Meyers, D. A., Levitt, R. C. Linkage mapping of the human thromboxane A2 receptor (TBXA2R) to chromosome 19p13.3 using transcribed 3-prime untranslated DNA sequence polymorphisms. Genomics 18: 212-215, 1993. [PubMed: 8288221] [Full Text: https://doi.org/10.1006/geno.1993.1457]
Taketo, M., Rochelle, J. M., Sugimoto, Y., Namba, T., Honda, A., Negishi, M., Ichikawa, A., Narumiya, S., Seldin, M. F. Mapping of the genes encoding mouse thromboxane A2 receptor and prostaglandin E receptor subtypes EP2 and EP3. Genomics 19: 585-588, 1994. [PubMed: 7910583] [Full Text: https://doi.org/10.1006/geno.1994.1113]
Thomas, D. W., Mannon, R. B., Mannon, P. J., Latour, A., Oliver, J. A., Hoffman, M., Smithies, O., Koller, B. H., Coffman, T. M. Coagulation defects and altered hemodynamic responses in mice lacking receptors for thromboxane A(2). J. Clin. Invest. 102: 1994-2001, 1998. [PubMed: 9835625] [Full Text: https://doi.org/10.1172/JCI5116]
Unoki, M., Furuta, S., Onouchi, Y., Watanabe, O., Doi, S., Fujiwara, H., Miyatake, A., Fujita, K., Tamari, M., Nakamura, Y. Association studies of 33 single nucleotide polymorphisms (SNPs) in 29 candidate genes for bronchial asthma: positive association a T924C polymorphism in the thromboxane A2 receptor gene. Hum. Genet. 106: 440-446, 2000. [PubMed: 10830912] [Full Text: https://doi.org/10.1007/s004390000267]
Ushikubi, F., Nakajima, M., Hirata, M., Okuma, M., Fujiwara, M., Narumiya, S. Purification of the thromboxane A2/prostaglandin H2 receptor from human blood platelets.. J. Biol. Chem. 264: 16496-16501, 1989. [PubMed: 2528545]
Ushikubi, F., Okuma, M., Kanaji, K., Sugiyama, T., Ogorochi, T., Narumiya, S., Uchino, H. Hemorrhagic thrombocytopathy with platelet thromboxane A2 abnormality: defective signal transduction with normal binding activity. Thromb. Haemost. 57: 158-164, 1987. [PubMed: 2955539]