Alternative titles; symbols
HGNC Approved Gene Symbol: ANTXR1
SNOMEDCT: 721843003;
Cytogenetic location: 2p13.3 Genomic coordinates (GRCh38) : 2:69,013,144-69,249,327 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p13.3 | {?Hemangioma, capillary infantile, susceptibility to} | 602089 | Autosomal dominant | 3 |
| GAPO syndrome | 230740 | Autosomal recessive | 3 |
TEM8 is a tumor-specific endothelial marker highly expressed in tumor endothelial cells but not in normal endothelial cells (St. Croix et al., 2000). Its N terminus encodes the anthrax toxin receptor, or ATR (Bradley et al., 2001).
St. Croix et al. (2000) compared gene expression patterns of endothelial cells derived from blood vessels of normal and malignant colorectal tissues to identify genes involved in tumor angiogenesis. Among the genes they identified was TEM8, which encodes a 564-amino acid protein.
Bradley et al. (2001) isolated a cDNA encoding ATR and determined that the first 364 amino acids of the 368-amino acid ATR protein are identical to those of TEM8. The C-terminal ends of the ATR and TEM8 proteins then diverge, presumably due to alternative splicing, such that ATR has a cytoplasmic tail of only 25 amino acids, whereas TEM8 has a cytoplasmic tail of 221 amino acids. (Bradley et al. (2001) noted in proof that another apparently full-length ATR/TEM8-related cDNA clone (GenBank BC01207) encodes a protein with yet another C-terminal end.) The ATR protein contains a 27-amino acid signal peptide; a 293-amino acid extracellular domain with 3 putative end-length glycosylation sites; and a 23-amino acid putative transmembrane region followed by the short cytoplasmic tail. An extracellular von Willebrand factor type A (VWA) domain is located between residues 44 and 216 of the ATR protein. The cytoplasmic tail of ATR contains an acidic cluster (EESEE) similar to a motif in the cytoplasmic tail of furin (136950) that specifies basolateral sorting of this protease in polarized epithelial cells. The mouse homolog of ATR/TEM8 is highly related to the human clones, showing more than 98% sequence identity in the extracellular domain. ATR and/or TEM8 is expressed in a number of different tissues, including central nervous system, heart, lung, and lymphocytes.
Using in situ hybridization analysis of human colorectal cancer, Carson-Walter et al. (2001) demonstrated that TEM8 was expressed clearly in the endothelial cells of the tumor stroma but not in the endothelial cells of normal colonic tissue. They also detected mouse Tem8 in the vasculature of developing embryonic liver and brain, as well as in the vessels of transplanted syngeneic and human tumors. Using in situ hybridization to assay expression in various normal mouse adult tissues, Carson-Walter et al. (2001) detected only weak Tem8 staining of endothelial cells in brain, heart, intestine, lung, skeletal muscle, and pancreas.
Oberthuer et al. (2005) noted that the ANTXR1 gene maps to chromosome 2p13.1.
Bradley et al. (2001) confirmed that the VWA domain of ATR binds directly to the protective antigen (PA) of anthrax, suggesting that ATR may also function as a PA receptor. They suggested that the finding that the soluble VWA domain of ATR inhibits toxin action, coupled with the use of the cloned receptor as a tool for identifying inhibitors of the PA-receptor interaction, holds promise for the development of novel approaches for the treatment of anthrax.
Rainey et al. (2005) found that the pH threshold for conversion of the anthrax PA toxin prepore to pore and translocation of toxin from the endosome to the cytosol differed by a pH unit depending on which receptor was used. PA associated with the relatively low-affinity ANTXR1 receptor could proceed through these events at near neutral pH and showed low sensitivity to ammonium chloride. In contrast, PA associated with the high-affinity ANTXR2 (608041) receptor required more acidic conditions to proceed through these events and could be inhibited by ammonium chloride. Rainey et al. (2005) also found that PA dissociated from ANTXR1 or ANTXR2 upon pore formation. They proposed that toxin can form pores at different points in the endocytic pathway depending on which receptor is used for entry.
Capillary Infantile Hemangioma
Jinnin et al. (2008) identified a mutation in the TEM8 gene (606410.0001) in a patient with infantile hemangioma (602089).
GAPO Syndrome
In 4 unrelated patients with GAPO syndrome (GAPOS; 230740) (growth retardation, alopecia, pseudoanodontia, and optic atrophy), Stranecky et al. (2013) identified homozygosity for 2 nonsense mutations and 1 splice site mutation in the ANTXR1 gene (606410.0002-606410.0004, respectively). Phalloidin staining demonstrated a striking reorganization of actin cytoskeletal microfilaments in GAPO fibroblasts, suggesting that ANTXR1 is crucial for actin assembly and that disruption of the actin network might be the major pathogenetic event leading to altered cell adhesion properties and progressive extracellular matrix build-up observed in individuals with GAPO syndrome.
In 5 affected individuals from 3 Turkish families with GAPO syndrome, Bayram et al. (2014) identified 3 novel homozygous mutations in the ANTXR1 gene (606410.0005-606410.0007). All 3 mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were predicted to produce an abnormal gene product. None of the mutations were reported in the 1000 Genomes Project, NHLBI Exome Sequencing Project, or dbSNP databases, or in an internal database of over 2,600 exomes. A search of the internal exome database found heterozygous ANTXR1 missense variants in 4/465 (0.86%) members of the Turkish population; a search of an international multiethnic comparison database found heterozygous missense variants in ANTXR1 in 42/5,748 (0.73%) Europeans and in 84/2,854 (2.9%) African Americans.
Besschetnova et al. (2015) found that mice lacking Antxr1 had embryonic and postnatal vascular and connective tissue defects with growth retardation, bone loss, shortened skulls with frontal bossing, and midfacial hypoplasia. Blood vessel defects and cell signaling changes in Antxr1 -/- skin resembled human infantile hemangioma, with reduced expression of Vegfr (KDR; 191306) and Itgb1 (135630) and increased expression of downstream targets, including Vegf (192240) and Cxcl12 (600835). Some collagens showed increased expression, including Col1a1 (120150) and Col6a1 (120220), whereas others showed reduced expression, including Col4a1 (120130) and Col8a1 (120251). Mmp2 (120360) activity was dramatically reduced in Atxr1 -/- mice. Besschetnova et al. (2015) proposed that loss-of-function mutations in ANTXR1 may explain the vascular and connective tissue abnormalities observed in GAPO and potentially, through loss of MMP2 activity, mechanisms underlying NAO (MONA; 259600) and Winchester (WNCHRS; 277950) syndromes.
In a patient with infantile hemangioma (602089), Jinnin et al. (2008) identified a heterozygous G-to-A transition in the TEM8 gene, resulting in an ala326-to-thr (A326T) substitution in the transmembrane domain. The mutation was not identified in 110 individuals with hemangioma or in 295 controls. Expression of VEGFR1 in hemangioma endothelial cells was markedly reduced compared to controls. In normal endothelial cells, FLT1 transcription is dependent on NFAT (see, e.g., NFATC2; 600490) activation. Further studies indicated that low VEGFR1 expression in hemangioma cells was caused by reduced activity of a pathway involving ITGB1 (135630), TEM8, VEGFR2 (KDR; 191306) and NFAT. The TEM8 mutation disrupted interaction of the molecules in a dominant-negative manner, resulting in an increased risk for development of hemangioma.
In a Czech man with GAPO syndrome (230740) originally reported by Baxova et al. (1997) and who died at age 19 years from myocardial infarction, Stranecky et al. (2013) identified homozygosity for a c.505C-T transition in the ANTXR1 gene, resulting in an arg169-to-ter (R169X) substitution in the von Willebrand type A domain. The mutation was present in heterozygosity in his unaffected parents but was not found in 200 control samples, in dbSNP, 1000 Genomes Project, or Exome Variant Server databases, or in more than 120 exomes from an internal exome database. Quantitative PCR analysis of patient skin fibroblasts showed a significantly reduced amount of ANTXR1 cDNA compared to controls, and phalloidin staining demonstrated a striking reorganization of actin cytoskeletal microfilaments in GAPO fibroblasts.
In 2 unrelated Egyptian boys with GAPO syndrome (230740), 1 of whom had been reported by Meguid et al. (1997) and died at 12 years of age from renal failure, Stranecky et al. (2013) identified homozygosity for a c.262C-T transition in the ANTXR1 gene, resulting in an arg88-to-ter (R88X) substitution in the von Willebrand type A domain. The mutation was present in heterozygosity in the 3 unaffected parents for whom DNA was available but was not found in 200 control samples, in dbSNP, 1000 Genomes Project, or Exome Variant Server databases, or in more than 120 exomes from an internal exome database. Haplotype analysis in the 2 probands revealed that the c.262C-T mutations were on 2 distinct haplotypes, indicating that the mutations arose independently or that the 2 families shared a very old ancestral allele. Quantitative PCR analysis of patient skin fibroblasts showed a significantly reduced amount of ANTXR1 cDNA compared to controls, and phalloidin staining demonstrated a striking reorganization of actin cytoskeletal microfilaments in GAPO fibroblasts.
In a 4-year-old Sri Lankan boy with GAPO syndrome (230740), Stranecky et al. (2013) identified homozygosity for a c.1435-12A-G transition in intron 19 of the ANTXR1 gene, predicted to generate an alternative strong splice acceptor site 11 nucleotides upstream of the last exon that would cause a frameshift of the complete reading frame of exon 20, resulting in a truncated ANTXR1 containing an neopeptide composed of 118 unique amino acids in the C terminus (Gly479PhefsX119).
In a child with GAPO syndrome (GAPOS; 230740) from a consanguineous Turkish family (HOU2001), Bayram et al. (2014) identified homozygosity for a 1-bp insertion (c.1220_1221insT) in exon 5 of the ANTXR1 gene, resulting in a frameshift predicting protein truncation 2 amino acids downstream of the frameshift (Ala408CysfsTer2) in the anthrax receptor C-terminal region. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. The unaffected parents and a sib were heterozygous for the mutation.
In 3 sibs with GAPO syndrome (GAPOS; 230740) from a consanguineous Turkish family (HOU2034), Bayram et al. (2014) identified homozygosity for a c.411A-G transition in exon 5 of the ANTXR1 gene, resulting in a synonymous gly137-to-gly (G137G) substitution in the VWA domain, predicted to affect a nearby canonical splice donor site and thus the protein structure. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Both parents were heterozygous for the mutation.
In 2 cousins with GAPO syndrome (GAPOS; 230740) from a consanguineous Turkish family (HOU285), Bayram et al. (2014) identified homozygosity for a c.1150G-A transition in exon 15 of the ANTXR1 gene, resulting in gly384-to-ser (G384S) substitution. DNA from the parents was not available for testing, but an unaffected brother was heterozygous for the mutation.
Baxova, A., Kozlowski, K., Obersztyn, E., Zeman, J. GAPO syndrome (radiographic clues to early diagnosis). Radiol. Med. 93: 289-291, 1997. [PubMed: 9180938]
Bayram, Y., Pehlivan, D., Karaca, E., Gambin, T., Jhangiani, S. N., Erdin, S., Gonzaga-Jauregui, C., Wiszniewski, W., Muzny, D., Baylor-Hopkins Center for Mendelian Genomics, Elcioglu, N. H., Yildirim, M. S., Bozkurt, B., Zamani, A. G., Boerwinkle, E., Gibbs, R. A., Lupski, J. R.. Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome. Am. J. Med. Genet. 164A: 2328-2334, 2014. [PubMed: 25045128] [Full Text: https://doi.org/10.1002/ajmg.a.36678]
Besschetnova, T. Y., Ichimura, T., Katebi, N., St. Croix, B., Bonventre, J. V., Olsen, B. R. Regulatory mechanisms of anthrax toxin receptor 1-dependent vascular and connective tissue homeostasis. Matrix Biol. 42: 56-73, 2015. [PubMed: 25572963] [Full Text: https://doi.org/10.1016/j.matbio.2014.12.002]
Bradley, K. A., Mogridge, J., Mourez, M., Collier, R. J., Young, J. A. T. Identification of the cellular receptor for anthrax toxin. Nature 414: 225-229, 2001. [PubMed: 11700562] [Full Text: https://doi.org/10.1038/n35101999]
Carson-Walter, E. B., Watkins, D. N., Nanda, A., Vogelstein, B., Kinzler, K. W., St. Croix, B. Cell surface tumor endothelial markers are conserved in mice and humans. Cancer Res. 61: 6649-6655, 2001. [PubMed: 11559528]
Jinnin, M., Medici, D., Park, L., Limaye, N., Liu, Y., Boscolo, E., Bischoff, J., Vikkula, M., Boye, E., Olsen, B. R. Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma. Nature Med. 14: 1236-1246, 2008. [PubMed: 18931684] [Full Text: https://doi.org/10.1038/nm.1877]
Meguid, N. A., Afifi, H. H., Ramzy, M. I., Hindawy, A., Temtamy, S. A. GAPO syndrome: first Egyptian case with ultrastructural changes in the gingiva. Clin. Genet. 52: 110-115, 1997. [PubMed: 9298746] [Full Text: https://doi.org/10.1111/j.1399-0004.1997.tb02527.x]
Oberthuer, A., Skowron, M., Spitz, R., Kahlert, Y., Westermann, F., Mehler, F., Berthold, F., Fischer, M. Characterization of a complex genomic alteration on chromosome 2p that leads to four alternatively spliced fusion transcripts in the neuroblastoma cell lines IMR-5, IMR-5/75 and IMR-32. Gene 363: 41-50, 2005. [PubMed: 16216448] [Full Text: https://doi.org/10.1016/j.gene.2005.07.038]
Rainey, G. J. A., Wigelsworth, D. J., Ryan, P. L., Scobie, H. M., Collier, R. J., Young, J. A. T. Receptor-specific requirements for anthrax toxin delivery into cells. Proc. Nat. Acad. Sci. 102: 13278-13283, 2005. [PubMed: 16141341] [Full Text: https://doi.org/10.1073/pnas.0505865102]
St. Croix, B., Rago, C., Velculescu, V., Traverso, G., Romans, K. E., Montgomery, E., Lal, A., Riggins, G. J., Lengauer, C., Vogelstein, B., Kinzler, K. W. Genes expressed in human tumor endothelium. Science 289: 1197-1202, 2000. [PubMed: 10947988] [Full Text: https://doi.org/10.1126/science.289.5482.1197]
Stranecky, V., Hoischen, A., Hartmannova, H., Zaki, M. S., Chaudhary, A., Zudaire, E., Noskova, L., Baresova, V., Pristoupilova, A., Hodanova, K., Sovova, J., Hulkova, H., and 13 others. Mutations in ANTXR1 cause GAPO syndrome. Am. J. Hum. Genet. 92: 792-799, 2013. [PubMed: 23602711] [Full Text: https://doi.org/10.1016/j.ajhg.2013.03.023]