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HGNC Approved Gene Symbol: AMBP
Cytogenetic location: 9q32 Genomic coordinates (GRCh38): 9:114,060,127-114,078,300 (from NCBI)
The alpha-1-microglobulin/bikunin precursor gene (AMBP) codes for a precursor that splits into alpha-1-microglobulin (A1M; formerly protein HC), which belongs to the lipocalin superfamily, and bikunin (ITIL; formerly HI-30, urinary trypsin inhibitor, inhibitor subunit of inter-alpha-(trypsin) inhibitor), which is made up of 2 tandemly arranged protease inhibitor domains and belongs to the superfamily of Kunitz-type protease inhibitors. The bikunin chain is a member of the inter-alpha-inhibitor (ITI) superfamily. It is a light chain that forms a complex with ITI heavy chains (see ITIH1, 147270) and is also present as a free molecule in plasma (summary by Salier et al., 1992).
Protein HC and the HI-30 domain of the ITI light chain are encoded as a single polypeptide chain by a unique mRNA, as shown by sequence analysis of cDNA clones independently isolated from 2 cDNA libraries. Traboni and Cortese (1986) isolated and sequenced a full-length AMBP cDNA clone from a human liver library.
Protein HC is a 31-kD, single-chain plasma glycoprotein (alpha-1-microglobulin) that appears to be involved in regulation of the inflammatory process (Mendez et al., 1986). It was originally isolated from the urine of a patient with chronic cadmium poisoning. It is normally present as a free form and as a complex with IgA in the blood, spinal fluid, and urine in relatively low concentration but is present in high concentration in the urine of patients with tubular proteinuria and in blood and urine of patients on renal dialysis (Pervaiz and Brew, 1985). The protein, as well as its IgA complex, inhibits neutrophil chemotaxis to endotoxin-activated serum.
Inter-alpha-trypsin inhibitor (ITI) is a serine protease inhibitor that can be isolated from plasma and urine as a high and as a low molecular weight form (Hochstrasser et al., 1976). Salier et al. (1987) proposed that inter-alpha-trypsin inhibitor is a multifunctional protein composed of polypeptide chains that are synthesized in the liver by 2 distinct mRNAs encoding heavy and light chains. The heavy chain (see ITIH1, 147270) contains potential calcium-binding sites and also regions homologous to the proposed reactive site for thiol-proteinase inhibitors.
Reviews
Pugia et al. (2007) reviewed the expression and structure of bikunin, as well as its roles in biologic processes and pathophysiologic conditions.
Vetr and Gebhard (1990) isolated the human AMBP gene. It contains 10 exons which span 1.3 kb and 9 introns with an aggregate length of about 16.5 kb. The largest intron (6.5 kb) separates exon 6 (coding for the C-terminal sequence of alpha-1-microglobulin) from exon 7 (coding for a linker peptide and the N-terminal peptide of bikunin). Repetitive DNA sequences of the Alu type were found downstream of the polyadenylation site as well as within introns 4 and 6 and upstream of the putative promoter region.
Traboni et al. (1987) mapped the AMBP gene to chromosome 9 by probing DNA from a panel of somatic cell hybrids. By in situ hybridization experiments, Traboni et al. (1989) narrowed the assignment to 9q22.3-q33. Leveillard et al. (1988) defined a RFLP of the ITIL gene. Diarra-Mehrpour et al. (1989) mapped the ITIL gene to 9q32-q33 by in situ hybridization.
By in situ hybridization, Salier et al. (1992) mapped the mouse equivalent of AMBP (Intin-4) to mouse chromosome 4 and the Intin-1 and Intin-3 genes to mouse chromosome 14.
Sato et al. (2001) found that Uti -/- mice appeared healthy, but that Uti -/- females displayed a severe reduction in fertility. Wildtype embryos transplanted into Uti -/- ovaries developed normally, suggesting that Uti -/- mice are able to maintain pregnancy. Uti -/- mice had reduced numbers of naturally ovulated oocytes compared with wildtype mice. Histologic analysis showed that the frequency of oocytes with disorganized corona radiata was increased in Uti -/- ovaries after hormonal stimulation. Transplantation of Uti -/- ovaries into wildtype mice resulted in production of pups, suggesting that Uti -/- ovaries are functional if supplied with Uti from systemic circulation. Sato et al. (2001) concluded that UTI plays an important role in formation of the stable cumulus-oocyte complex essential for oocyte maturation and ovulation.
Diarra-Mehrpour, M., Bourguignon, J., Sesboue, R., Mattei, M.-G., Passage, E., Salier, J.-P., Martin, J.-P. Human plasma inter-alpha-trypsin inhibitor is encoded by four genes on three chromosomes. Europ. J. Biochem. 179: 147-154, 1989. [PubMed: 2465147] [Full Text: https://doi.org/10.1111/j.1432-1033.1989.tb14532.x]
Hochstrasser, K., Bretzel, G., Feuth, H., Hilla, W., Lempart, K. The inter-alpha-trypsin inhibitor as precursor of the acid-stable proteinase inhibitors in human serum and urine. Hoppe Seylers Z. Physiol. Chem. 357: 153-162, 1976. [PubMed: 3463] [Full Text: https://doi.org/10.1515/bchm2.1976.357.1.153]
Leveillard, T., Bourguignon, J., Sesboue, R., Hanauer, A., Salier, J. P., Diarra-Mehrpour, M., Martin, J. P. BstXI RFLP in the human inter-alpha-trypsin inhibitor light chain gene. Nucleic Acids Res. 16: 2744 only, 1988. [PubMed: 2452409] [Full Text: https://doi.org/10.1093/nar/16.6.2744]
Mendez, E., Fernandez-Luna, J. L., Grubb, A., Leyva-Cobian, F. Human protein HC and its IgA complex are inhibitors of neutrophil chemotaxis. Proc. Nat. Acad. Sci. 83: 1472-1475, 1986. [PubMed: 2419908] [Full Text: https://doi.org/10.1073/pnas.83.5.1472]
Pervaiz, S., Brew, K. Homology of beta-lactoglobulin, serum retinol-binding protein, and protein HC. Science 228: 335-337, 1985. [PubMed: 2580349] [Full Text: https://doi.org/10.1126/science.2580349]
Pugia, M. J., Valdes, R., Jr., Jortani, S. A. Bikunin (urinary trypsin inhibitor): structure, biological relevance, and measurement. Adv. Clin. Chem. 44: 223-245, 2007. [PubMed: 17682344] [Full Text: https://doi.org/10.1016/s0065-2423(07)44007-0]
Salier, J. P., Diarra-Mehrpour, M., Sesboue, R., Bourguignon, J., Benarous, R., Ohkubo, I., Kurachi, S., Kurachi, K., Martin, J. P. Isolation and characterization of cDNAs encoding the heavy chain of human inter-alpha-trypsin inhibitor (IATI): unambiguous evidence for multipolypeptide chain structure of IATI. Proc. Nat. Acad. Sci. 84: 8272-8276, 1987. [PubMed: 2446322] [Full Text: https://doi.org/10.1073/pnas.84.23.8272]
Salier, J. P., Simon, D., Rouet, P., Raguenez, G., Muscatelli, F., Gebhard, W., Guenet, J. L., Mattei, M. G. Homologous chromosomal locations of the four genes for inter-alpha-inhibitor and pre-alpha-inhibitor family in human and mouse: assignment of the ancestral gene for the lipocalin superfamily. Genomics 14: 83-88, 1992. [PubMed: 1385302] [Full Text: https://doi.org/10.1016/s0888-7543(05)80287-3]
Sato, H., Kajikawa, S., Kuroda, S., Horisawa, Y., Nakamura, N., Kaga, N., Kakinuma, C., Kato, K., Morishita, H., Niwa, H., Miyazaki, J. Impaired fertility in female mice lacking urinary trypsin inhibitor. Biochem. Biophys. Res. Commun. 281: 1154-1160, 2001. [PubMed: 11243855] [Full Text: https://doi.org/10.1006/bbrc.2001.4475]
Traboni, C., Cortese, R. Sequence of a full length cDNA coding for human protein HC (alpha-1-microglobulin). Nucleic Acids Res. 14: 6340 only, 1986. [PubMed: 2428011] [Full Text: https://doi.org/10.1093/nar/14.15.6340]
Traboni, C., Tosini, F., Covone, A., Romeo, G., Rocchi, M. The gene coding for proteins HC and HI-30 of inter-alpha-trypsin inhibitor maps to 9q22.3-q33. Cytogenet. Cell Genet. 50: 46-48, 1989. [PubMed: 2472935] [Full Text: https://doi.org/10.1159/000132717]
Traboni, C., Tosini, F., Romeo, G., Rocchi, M. The gene coding for protein HC and H1-30 domain of inter-alpha-trypsin inhibitor maps on chromosome 9. (Abstract) Cytogenet. Cell Genet. 46: 705 only, 1987.
Vetr, H., Gebhard, W. Structure of the human alpha-1-microglobulin-bikunin gene. Biol. Chem. Hoppe Seyler 371: 1185-1196, 1990. [PubMed: 1708673] [Full Text: https://doi.org/10.1515/bchm3.1990.371.2.1185]