Alternative titles; symbols
HGNC Approved Gene Symbol: HBEGF
Cytogenetic location: 5q31.3 Genomic coordinates (GRCh38): 5:140,332,843-140,346,603 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q31.3 | {Diphtheria, susceptibility to} | 1 |
Diphtheria toxin inhibits protein synthesis in eukaryotic cells by catalyzing inactivation of elongation factor-2 (EF2; 130610). Entry of toxin into cells is dependent on binding to the cell surface. Mice and rats are resistant to diphtheria toxin, and the resistance extends to cultured cells. Mouse-human hybrid cells are sensitive to diphtheria toxin. Creagan et al. (1975) showed that sensitivity is determined by human chromosome 5, which presumably carries a gene for a receptor for toxin. Diphtheria toxin consists of a single polypeptide chain coded by a viral gene and produced by strains of Corynebacterium diphtheriae lysogenic for phage carrying the 'tox' gene. The polypeptide chain has 2 fragments. One fragment, called the effectomer, has the EF2-inactivating activity. The other fragment, called the haptomer, is responsible for surface binding (Pappenheimer and Gill, 1973). Chang and Neville (1978) concluded that the rat and mouse (diphtheria-toxin-resistant species), like guinea pig, rabbit, and man (toxin-sensitive species), have surface membrane receptors for the toxin and that toxin resistance results from a defect in or lack of the transport process.
Naglich et al. (1992) isolated a monkey cDNA encoding the diphtheria toxin sensitivity determinant by expression cloning in mouse L-M cells. Unlike wildtype L-M cells, transfected mouse cells were extremely toxin sensitive and specifically bound radioiodinated diphtheria toxin. Intoxication of the transfected cells required receptor-mediated endocytosis of the bound toxin. The cDNA was predicted to encode an integral membrane protein identical to the precursor of a heparin-binding EGF-like growth factor (Higashiyama et al. (1991, 1992)). Thus, the DT sensitivity protein is a growth factor precursor that the toxin exploits as a receptor.
Fen et al. (1993) demonstrated that treatment of endothelial cells with tumor necrosis factor-alpha (TNFA; 191160) produced a 10-fold increase in HBEGF mRNA.
Using healthy human skin fragments obtained as surgical residua, Sorensen et al. (2006) demonstrated that sterile wounding of human skin induced epidermal expression of the antimicrobial polypeptides beta-defensin-103 (DEFB103; 606611), lipocalin-2 (LCN2; 600181), and secretory leukocyte protease inhibitor (SLPI; 107285) through activation of EGFR (131550) by HBEGF.
Using immunohistochemical analysis, Bollee et al. (2011) found that expression of HBEGF was induced in crescentic rapidly progressive glomerulonephritis (RPGN). In normal human kidneys, HBEGF expression was weak and restricted to tubules and vascular smooth muscle cells. In kidneys of RPGN patients, elevated HBEGF expression was detected in glomeruli, particularly in podocytes, parietal epithelial cells, and tubules. HBEGF staining was more intense and diffuse in glomeruli with crescents than in less-affected glomeruli within the same tissue sample. Weaker but consistent HBEGF expression was detected in inflammatory infiltrates. Similar upregulation of Hbegf was detected in a mouse model of RPGN. Upregulation of Hbegf in RPGN mice increased the phosphorylation of Egfr and induced a migratory phenotype in podocytes in vitro. Deficiency for Hbegf in mice or conditional deletion of Egfr from podocytes significantly improved the course of RPGN and survival. Pharmacologic blockade of Egfr likewise alleviated the severity of experimental RPGN. Bollee et al. (2011) concluded that activation of the HBEGF-EGFR pathway in podocytes results in RPGN.
Fen et al. (1993) determined that the HBEGF gene contains 6 exons and and spans 14 kb.
Hayes et al. (1987) used microcell hybrids to localize the DTS gene to chromosome 5q23. By analysis of DNA isolated from human-mouse somatic hybrid cell lines, Fen et al. (1993) assigned the HBEGF gene to chromosome 5, thus confirming the assignment of the gene on the basis of its role in relation to diphtheria toxin susceptibility.
Pathak et al. (1995) showed that in the mouse, Hegfl maps to chromosome 18.
Xie et al. (2007) found that crosses of Hbegf -/- female mice with fertile Hbegf -/- males resulted in delayed implantation and compromised term pregnancy with significantly reduced litter size compared with wildtype littermates. Amphiregulin (AREG; 104640) partially compensated for loss of Hbegf during implantation, and the authors found that reduced preimplantation estrogen secretion due to ovarian Hbegf deficiency caused sustained expression of uterine amphiregulin before initiation of implantation. Conditional deletion of Hbegf in uterus still deferred implantation without altering preimplantation ovarian estrogen secretion. Normal induction of uterine amphiregulin surrounding the blastocyst at the time of attachment in conditional mutant mice suggested a compensatory role of amphiregulin for uterine loss of Hbegf, preventing complete failure of pregnancy. Xie et al. (2007) concluded that HBEGF is critical for normal implantation.
Bollee, G., Flamant, M., Schordan, S., Fligny, C., Rumpel, E., Milon, M., Schordan, E., Sabaa, N., Vandermeersch, S., Galaup, A., Rodenas, A., Casal, I., and 14 others. Epidermal growth factor receptor promotes glomerular injury and renal failure in rapidly progressive crescentic glomerulonephritis. Nature Med. 17: 1242-1250, 2011. Note: Erratum: Nature Med. 17: 2 p following 1250, 2011. Nature Med. 17: 1521 only, 2011. [PubMed: 21946538] [Full Text: https://doi.org/10.1038/nm.2491]
Chang, T.-M., Neville, D. M., Jr. Demonstration of diphtheria toxin receptors on surface membranes from both toxin-sensitive and toxin-resistant species. J. Biol. Chem. 253: 6866-6871, 1978. [PubMed: 690129]
Creagan, R. P., Chen, S.-H., Ruddle, F. H. Genetic analysis of the cell surface: association of human chromosome 5 with sensitivity to diphtheria toxin in mouse-human somatic cell hybrids. Proc. Nat. Acad. Sci. 72: 2237-2241, 1975. [PubMed: 1056028] [Full Text: https://doi.org/10.1073/pnas.72.6.2237]
Fen, Z., Dhadly, M. S., Yoshizumi, M., Hilkert, R. J., Quertermous, T., Eddy, R. L., Shows, T. B., Lee, M.-E. Structural organization and chromosomal assignment of the gene encoding the human heparin-binding epidermal growth factor-like growth factor/diphtheria toxin receptor. Biochemistry 32: 7932-7938, 1993. [PubMed: 8347598] [Full Text: https://doi.org/10.1021/bi00082a014]
George, D. L., Francke, U. Regional mapping of human genes for hexosaminidase B and diphtheria toxin sensitivity on chromosome 5 using mouse X human hybrid cells. Somat. Cell Genet. 3: 629-638, 1977. [PubMed: 601683] [Full Text: https://doi.org/10.1007/BF01539070]
Gupta, R. S., Siminovitch, L. Isolation and characterization of mutants of human diploid fibroblasts resistant to diphtheria toxin. Proc. Nat. Acad. Sci. 75: 3337-3340, 1978. [PubMed: 277932] [Full Text: https://doi.org/10.1073/pnas.75.7.3337]
Hayes, H., Kaneda, Y., Uchida, T., Okada, Y. Regional assignment of the gene for diphtheria toxin sensitivity using subchromosomal fragments in microcell hybrids. Chromosoma 96: 26-32, 1987. [PubMed: 3436221] [Full Text: https://doi.org/10.1007/BF00285879]
Higashiyama, S., Abraham, J. A., Miller, J., Fiddes, J. C., Klagsbrun, M. A heparin-binding growth factor secreted by macrophage-like cells that is related to EGF. Science 251: 936-939, 1991. [PubMed: 1840698] [Full Text: https://doi.org/10.1126/science.1840698]
Higashiyama, S., Lau, K., Besner, G. E., Abraham, J. A., Klagsbrun, M. Structure of heparin-binding EGF-like growth factor: multiple forms, primary structure, and glycosylation of the mature protein. J. Biol. Chem. 267: 6205-6212, 1992. [PubMed: 1556128]
Naglich, J. G., Metherall, J. E., Russell, D. W., Eidels, L. Expression cloning of a diphtheria toxin receptor: identity with a heparin-binding EGF-like growth factor precursor. Cell 69: 1051-1061, 1992. [PubMed: 1606612] [Full Text: https://doi.org/10.1016/0092-8674(92)90623-k]
Pappenheimer, A. M., Jr., Gill, D. M. Diphtheria. Science 182: 353-358, 1973. [PubMed: 4202002] [Full Text: https://doi.org/10.1126/science.182.4110.353]
Pappenheimer, A. M., Jr. Diphtheria toxin. Ann. Rev. Biochem. 46: 69-94, 1977. [PubMed: 20040] [Full Text: https://doi.org/10.1146/annurev.bi.46.070177.000441]
Pathak, B. G., Gilbert, D. J., Harrison, C. A., Luetteke, N. C., Chen, X., Klagsbrun, M., Plowman, G. D., Copeland, N. G., Jenkins, N. A., Lee, D. C. Mouse chromosomal location of three EGF receptor ligands: amphiregulin (Areg), betacellulin (Btc), and heparin-binding EGF (Hegfl). Genomics 28: 116-118, 1995. [PubMed: 7590736] [Full Text: https://doi.org/10.1006/geno.1995.1116]
Roberts, M., Ruddle, F. H. The Chinese hamster gene map: assignment of four genes (DTS, PGM2, 6PGD, Eno1) to chromosome 2. Exp. Cell Res. 127: 47-54, 1980. [PubMed: 6445830] [Full Text: https://doi.org/10.1016/0014-4827(80)90413-9]
Sorensen, O. E., Thapa, D. R., Roupe, K. M., Valore, E. V., Sjobring, U., Roberts, A. A., Schmidtchen, A., Ganz, T. Injury-induced innate immune response in human skin mediated by transactivation of the epidermal growth factor receptor. J. Clin. Invest. 116: 1878-1885, 2006. [PubMed: 16778986] [Full Text: https://doi.org/10.1172/JCI28422]
Xie, H., Wang, H., Tranguch, S., Iwamoto, R., Mekada, E., DeMayo, F. J., Lydon, J. P., Das, S. K., Dey, S. K. Maternal heparin-binding-EGF deficiency limits pregnancy success in mice. Proc. Nat. Acad. Sci. 104: 18315-18320, 2007. [PubMed: 17986609] [Full Text: https://doi.org/10.1073/pnas.0707909104]