Alternative titles; symbols
HGNC Approved Gene Symbol: EGF
Cytogenetic location: 4q25 Genomic coordinates (GRCh38): 4:109,912,883-110,013,766 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q25 | ?Hypomagnesemia 4, renal | 611718 | Autosomal recessive | 3 |
What is now known as epidermal growth factor was first described by Cohen (1962). Epidermal growth factor has a profound effect on the differentiation of specific cells in vivo and is a potent mitogenic factor for a variety of cultured cells of both ectodermal and mesodermal origin (Carpenter and Cohen, 1979).
Gray et al. (1983) presented the sequence of a mouse EGF cDNA clone, which suggested that EGF is synthesized as a large protein precursor of 1,168 amino acids. Mature EGF is a single-chain polypeptide consisting of 53 amino acids and has a molecular mass of about 6.0 kD. Urdea et al. (1983) synthesized the gene for human EGF.
Smith et al. (1982) synthesized and cloned the gene for human beta-urogastrone. Urogastrone is a polypeptide hormone found predominantly in the duodenum and in the salivary glands. It is a potent inhibitor of gastric acid secretion and also promotes epithelial cell proliferation. Beta-urogastrone contains a single polypeptide chain of 53 amino acids, while gamma-urogastrone has the same sequence of amino acids 1-52 but lacks the carboxy-terminal arginine of the beta form. Sequence comparison indicates that urogastrone is identical to EGF (Scott, 1999).
By RT-PCR analysis of human tissues, Groenestege et al. (2007) detected strong EGF expression in kidney, salivary gland, cerebrum, and prostate, moderate expression in trachea and thyroid, and low expression in bone marrow, heart, spleen, thymus, uterus, and colon. No expression was detected in adrenal gland, liver, lung, cerebellum, placenta, and small intestine. EGF localized to the distal convoluted tubule in rat kidney.
EGF is produced in abundance by the mouse submandibular gland. Tsutsumi et al. (1986) found that sialoadenectomy decreased circulating EGF to levels below detection but did not affect testosterone or FSH levels. At the same time a decrease in spermatids in the testis and mature sperm in the epididymis decreased. The changes were corrected by administration of EGF. A role of EGF in some cases of human male infertility, particularly those with unexplained oligospermia, was proposed.
During the immediate-early response of mammalian cells to mitogens, histone H3 (see 602810) is rapidly and transiently phosphorylated by one or more kinases. Sassone-Corsi et al. (1999) demonstrated that EGF-stimulated phosphorylation of H3 requires RSK2 (300075), a member of the pp90(RSK) family of kinases implicated in growth control.
Using the beta-actin promoter to induce widespread expression, Wong et al. (2000) generated transgenic mice overexpressing an active form of human EGF. Transgenic mice showed stunted growth, and adult males were sterile with hypospermatogenesis. Chan and Wong (2000) determined that these effects were associated with a reduction of serum insulin-like growth factor-binding protein-3 (IGFBP3; 146732). Growth retardation was associated with altered chondrocyte development in the growth plate, and osteoblasts accumulated in the endosteum and periosteum. There were no signs of tumor formation in the transgenic animals.
Futamura et al. (2002) measured EGF protein levels in postmortem brains and in fresh serum of patients with schizophrenia (181500) and control subjects. In the patients, EGF protein levels were decreased in the prefrontal cortex and striatum, and EGF receptor (EGFR; 131550) expression was elevated in the prefrontal cortex. Serum EGF levels were reduced, even in young, drug-free patients. Futamura et al. (2002) found that chronic treatment of rats with haloperidol had no influence on EGF levels in the brain or serum. Futamura et al. (2002) suggested that there is abnormal EGF production in central and peripheral tissues in patients with schizophrenia.
Groenestege et al. (2007) showed that EGF-treatment of TRPM6 (607009)-transfected HEK293 cells resulted in a dose-dependent increase in channel activity. Western blot analysis showed endogenous expression of EGFR in these HEK293 cells. Preincubation with an anti-EGFR monoclonal antibody abolished the stimulatory effect of EGF on TRPM6 activity as shown by patch-clamp analysis of TRPM6-expressing HEK293 cells. They also demonstrated that colorectal cancer patients treated with an anti-EGFR monoclonal antibody develop hypomagnesemia. Groenestege et al. (2007) concluded that EGF is a magnesiotropic hormone crucial for total body Mg(2+) balance.
By the study of human-rodent somatic cell hybrids with a genomic DNA probe, Brissenden et al. (1984) mapped the EGF locus to 4q21-4qter, possibly near TCGF, the locus coding for T-cell growth factor (147680). Both nerve growth factor (see NGFB, 162030) and epidermal growth factor are on mouse chromosome 3 but they are on different chromosomes in man: 1p and 4, respectively (Zabel et al., 1985). Zabel et al. (1985) pointed out that mouse chromosome 3 has one segment with rather extensive homology to distal 1p of man and a second with homology to proximal 1p of man. By in situ hybridization, Morton et al. (1986) assigned EGF to 4q25-q27. The EGFR gene is on chromosome 7.
Looking for the genetic factors that mediate susceptibility to, and outcome of, sporadic malignant melanoma, Shahbazi et al. (2002) focused on epidermal growth factor because of its role in mitogenesis. They tested for genetic polymorphisms in EGF in 135 white European patients with malignant melanoma and in 99 healthy white European controls. They identified a single-nucleotide substitution, 61A-G (rs4444903) in the 5-prime untranslated region of the EGF gene. Frequencies of the A and G alleles of EGF were 56% and 44%, respectively, in controls. Cells from individuals homozygous for the 61A allele produced significantly less EGF than cells from 61G homozygotes or A/G heterozygotes. Compared with the A/A genotype, G/G was significantly associated with risk of malignant melanoma (odds ratio 4.9, p less than 0.0001).
Tanabe et al. (2008) found that EGF secretion was 2.3-fold higher in 61G/G hepatocellular carcinoma cell lines compared to A/A cell lines, and that mRNA transcripts with the G allele showed a longer half-life and increased stability. Among 207 patients with cirrhosis, liver EGF levels were 2.4-fold higher in G/G patients compared to A/A patients. Fifty-nine of the 207 patients with cirrhosis also had hepatocellular carcinoma, and there was a 4-fold increased odds of hepatocellular carcinoma in G/G patients compared with A/A patients. The association was validated in a second cohort of 121 patients with alcoholic cirrhosis and hepatocellular carcinoma. Tanabe et al. (2008) concluded that the EGF polymorphism rs4444903 is associated with risk for development of hepatocellular carcinoma in liver cirrhosis through modulation of EGF levels.
In a consanguineous Dutch family with normocalciuric renal hypomagnesemia (611718), Groenestege et al. (2007) analyzed the candidate EGF gene and identified homozygosity for a mutation (P1070L; 131530.0001) in the 2 affected sisters.
In 2 sisters from a consanguineous Dutch family with normocalciuric renal hypomagnesemia (HOMG4; 611718), Groenestege et al. (2007) identified homozygosity for a 3209C-T transition in exon 22 of the EGF gene, resulting in a pro1070-to-leu (P1070L) substitution at a highly conserved residue within the cytoplasmic tail. The unaffected parents, 2 unaffected sibs, and an unaffected paternal aunt were heterozygous for the mutation, which was not found in 126 ethnically matched controls. Studies in HEK293 cells revealed that the mutation leads to impaired basolateral sorting of pro-EGF, causing inadequate stimulation of renal EGFR (131550), resulting in insufficient activation of TRPM6 and thereby loss of Mg(2+).
Brissenden, J. E., Ullrich, A., Francke, U. Chromosomal mapping of loci for insulin-like growth factors I and II and for epidermal growth factor in man. (Abstract) Am. J. Hum. Genet. 36: 133S only, 1984.
Brissenden, J. E., Ullrich, A., Francke, U. Human chromosomal mapping of genes for insulin-like growth factors I and II and epidermal growth factor. Nature 310: 781-784, 1984. [PubMed: 6382023] [Full Text: https://doi.org/10.1038/310781a0]
Carpenter, G., Cohen, S. Epidermal growth factor. Ann. Rev. Biochem. 48: 193-216, 1979. [PubMed: 382984] [Full Text: https://doi.org/10.1146/annurev.bi.48.070179.001205]
Chan, S.-Y., Wong, R. W.-C. Expression of epidermal growth factor in transgenic mice causes growth retardation. J. Biol. Chem. 275: 38693-38698, 2000. [PubMed: 11001946] [Full Text: https://doi.org/10.1074/jbc.M004189200]
Cohen, S. Isolation of a mouse submaxillary gland protein accelerating incisor eruption and eyelid opening in the new-born animal. J. Biol. Chem. 237: 1555-1562, 1962. [PubMed: 13880319]
Futamura, T., Toyooka, K., Iritani, S., Niizato, K., Nakamura, R., Tsuchiya, K., Someya, T., Kakita, A., Takahashi, H., Nawa, H. Abnormal expression of epidermal growth factor and its receptor in the forebrain and serum of schizophrenic patients. Molec. Psychiat. 7: 673-682, 2002. [PubMed: 12192610] [Full Text: https://doi.org/10.1038/sj.mp.4001081]
Gray, A., Dull, T. J., Ullrich, A. Nucleotide sequence of epidermal growth factor cDNA predicts a 128,000-molecular weight protein precursor. Nature 303: 722-725, 1983. [PubMed: 6304537] [Full Text: https://doi.org/10.1038/303722a0]
Groenestege, W. M. T., Thebault, S., van der Wijst, J., van den Berg, D., Janssen, R., Tejpar, S., van den Heuvel, L. P., van Cutsem, E., Hoenderop, J. G., Knoers, N. V., Bindels, R. J. Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia. J. Clin. Invest. 117: 2260-2267, 2007. [PubMed: 17671655] [Full Text: https://doi.org/10.1172/JCI31680]
Morton, C. C., Byers, M. G., Nakai, H., Bell, G. I., Shows, T. B. Human genes for insulin-like growth factors I and II and epidermal growth factor are located on 12q22-q24.1, 11p15, and 4q25-q27, respectively. Cytogenet. Cell Genet. 41: 245-249, 1986. [PubMed: 3486749] [Full Text: https://doi.org/10.1159/000132237]
Sassone-Corsi, P., Mizzen, C. A., Cheung, P., Crosjo, C., Monaco, L., Jacquot, S., Hanauer, A., Allis, C. D. Requirement of Rsk-2 for epidermal growth factor-activated phosphorylation of histone H3. Science 285: 886-891, 1999. [PubMed: 10436156] [Full Text: https://doi.org/10.1126/science.285.5429.886]
Scott, A. F. Personal Communication. Baltimore, Md. 10/11/1999.
Shahbazi, M., Pravica, V., Nasreen, N., Fakhoury, H., Fryer, A. A., Strange, R. C., Hutchinson, P. E., Osborne, J. E., Lear, J. T., Smith, A. G., Hutchinson, I. V. Association between functional polymorphism in EGF gene and malignant melanoma. Lancet 359: 397-401, 2002. [PubMed: 11844511] [Full Text: https://doi.org/10.1016/S0140-6736(02)07600-6]
Smith, J., Cook, E., Fotheringham, I., Pheby, S., Derbyshire, R., Eaton, M. A. W., Doel, M., Lilley, D. M. J., Pardon, J. F., Patel, T., Lewis, H., Bell, L. D. Chemical synthesis and cloning of a gene for human beta-urogastrone. Nucleic Acids Res. 10: 4467-4482, 1982. [PubMed: 6290982] [Full Text: https://doi.org/10.1093/nar/10.15.4467]
Sudhof, T. C., Russell, D. W., Goldstein, J. L., Brown, M. S., Sanchez-Pescador, R., Bell, G. I. Cassette of eight exons shared by genes for LDL receptor and EGF precursor. Science 228: 893-895, 1985. [PubMed: 3873704] [Full Text: https://doi.org/10.1126/science.3873704]
Tanabe, K. K., Lemoine, A., Finkelstein, D. M., Kawasaki, H., Fujii, T., Chung, R. T., Lauwers, G. Y., Kulu, Y., Muzikansky, A., Kuruppu, D., Lanuti, M., Goodwin, J. M., Azoulay, D., Fuchs, B. C. Epidermal growth factor gene functional polymorphism and the risk of hepatocellular carcinoma in patients with cirrhosis. JAMA 299: 53-60, 2008. [PubMed: 18167406] [Full Text: https://doi.org/10.1001/jama.2007.65]
Tsutsumi, O., Kurachi, H., Oka, T. A physiological role of epidermal growth factor in male reproductive function. Science 233: 975-977, 1986. [PubMed: 3090686] [Full Text: https://doi.org/10.1126/science.3090686]
Urdea, M. S., Merryweather, J. P., Mullenbach, G. T., Coit, D., Heberlein, U., Valenzuela, P., Barr, P. J. Chemical synthesis of a gene for human epidermal growth factor urogastrone and its expression in yeast. Proc. Nat. Acad. Sci. 80: 7461-7465, 1983. [PubMed: 6369317] [Full Text: https://doi.org/10.1073/pnas.80.24.7461]
Wong, R. W.-C., Kwan, R. W.-P., Mak, P. H.-S., Mak, K. K.-L., Sham, M.-H., Chan, S.-Y. Overexpression of epidermal growth factor induced hypospermatogenesis in transgenic mice. J. Biol. Chem. 275: 18297-18301, 2000. [PubMed: 10748057] [Full Text: https://doi.org/10.1074/jbc.M001965200]
Zabel, B. U., Eddy, R. L., Lalley, P. A., Scott, J., Bell, G. I., Shows, T. B. Chromosomal locations of the human and mouse genes for precursors of epidermal growth factor and the beta subunit of nerve growth factor. Proc. Nat. Acad. Sci. 82: 469-473, 1985. [PubMed: 3871525] [Full Text: https://doi.org/10.1073/pnas.82.2.469]