Alternative titles; symbols
HGNC Approved Gene Symbol: SCGB1A1
Cytogenetic location: 11q12.3 Genomic coordinates (GRCh38) : 11:62,419,033-62,423,195 (from NCBI)
SCGB1A1, or uteroglobin, is an evolutionarily conserved, steroid-inducible, secreted protein. It has antiinflammatory and immunomodulatory properties and also manifests antichemotactic, antiallergic, antitumorigenic, and embryonic growth-stimulatory activities. Mucosal epithelia of virtually all organs that communicate with the external environment express uteroglobin, and it is present in blood, urine, and other body fluids (review by Mukherjee et al., 2007).
Uteroglobin is a secretory protein of the rabbit endometrium which is induced by progesterone. Atger et al. (1981) cloned the uteroglobin gene from a library of the rabbit genome and showed that it is present in single copy. Menne et al. (1982) showed that human uteroglobin, also called blastokinin, is encoded by a single-copy gene. The protein is a homodimer.
As reviewed by Mihal and Riedel (1991), the human club cell-specific proteins, CCSP and polychlorinated biphenyl-binding protein (PCB-BP), are homologous to rabbit uteroglobin and are presumably derived from the same ancestral gene. Singh et al. (1988) raised antibodies to a 10-kD protein from lung lavage proteins and showed that they specifically and exclusively stained club cells in human, dog, and rat. Staining of granules of club cells was prominent in the distal bronchioles. Singh et al. (1990) compared the cellular localization, functional activities, and structures of rat and human club cell 10-kD proteins (CC10) with those of rabbit uteroglobin. CC10 is present exclusively in the nonciliated cells of the surface epithelium of the pulmonary airways, whereas uteroglobin is reported to be present in both the lung and the reproductive organs. Hagen et al. (1990) concluded that while the sequence identities in the coding and 5-prime flanking regions of the uteroglobin and CC10 genes point toward a common ancestor, later events such as deletions/insertions may have caused species-specific differences in their regulation.
Wolf et al. (1992) found that the rabbit and human CC10 cDNAs share 75% identity in their coding regions, and both encode 91-amino acid proteins. Northern blot analysis detected strong CC10 expression in human lung, with much weaker expression in an endometrial adenocarcinoma. CC10 expression was not detected in normal human endometrial tissue.
Using Northern blot analysis, Peri et al. (1993) detected a 0.6-kb CC10 transcript that was highly expressed in human lung, trachea, and prostate, but not in any other tissue examined. PCR analysis detected high CC10 expression in lung, trachea, prostate, thyroid, mammary gland, and pituitary, with weaker expression in stomach, ovary, testis, spleen, adrenal gland, aorta, pancreas, liver, and thymus. Little to no expression was detected in uterus, placenta, small intestine, heart, kidney, endothelium, brain, and leukocytes. Immunohistochemical analysis showed CC10 expression in epithelial cells of the prostatic acini, bronchoalveolar epithelium of lung, and in discrete cells of the thymus and pituitary.
Hay et al. (1995) found very high CC10 mRNA levels in freshly isolated human proximal airway epithelial cells, approximately 5-fold greater than gamma-actin mRNA. In situ hybridization localized CC10 mRNA to nonciliated airway epithelial cells. The high level of expression of CC10 in the epithelium of conducting airways and the chromosomal localization of the gene, together with the reported anti-inflammatory and immune-modulating properties of the CC10 protein suggested to Hay et al. (1995) that CC10 may be important in modulating inflammation within the airways.
Sequence data available in 1996 indicated that human CC10 and human uteroglobin are identical. See Stripp et al. (1994) for a discussion of the relationship between club cell secretory protein and uteroglobin, as well as a discussion of the murine gene.
Menne et al. (1982) showed that the UGB gene spans 3 kb and comprises 3 exons and 2 introns. By sequence analysis, Hay et al. (1995) demonstrated that the CC10 gene comprises 3 short exons separated by a long first and a short second intron with a 5-prime flanking region typical of a regulated gene.
Wolf et al. (1992) determined that the 5-prime region of the SCGB1A1 gene contains a typical TATA motif and 2 putative progesterone receptor (PGR; 607311)-binding sites that are conserved between the rabbit and human genes.
Stohr and Weber (1994) described a polymorphic (ATTT)n tetranucleotide repeat in the 5-prime flanking region of the UGB gene.
Wolf et al. (1992) localized the UGB gene to 11q11-qter by Southern hybridization of a 1.7-kb EcoRI-HindIII fragment spanning the transcription start point of the UGB gene to a somatic cell hybrid mapping panel.
By genetic linkage studies in CEPH families, Hay et al. (1995) localized the CC10 gene to 11p12-q13 between markers D11S16 and D11S97, a region linked to atopy (147050) and to the locus for the beta-subunit of the high-affinity immunoglobulin E receptor (FCER1B; 147138).
Zhang et al. (1997) mapped the UGB gene to 11q12.3-q13.1 by fluorescence in situ hybridization.
Jackson et al. (2011) noted that humans have 11 SCGB genes and 5 pseudogenes, whereas mice have 68 Scgb genes. Only 4 human genes have direct mouse orthologs: SCGB1A1, SCGB1C1 (610176), SCGB3A1 (606500), and SCGB3A2 (606531).
See 192020.0001 for a possible association of asthma with variation in the SCGB1A1 gene.
Winkelmann and Noack (2010) reviewed the history of the eponym 'Clara cell,' which had been used to represent a specific type of exocrine bronchiolar cell since the 1950s. They proposed adopting the descriptive term 'club cell,' as used in German and English publications in the 1950s and 1960s, instead of Clara cell.
Zhang et al. (1997) found that mice in which the uteroglobin gene had been disrupted developed severe renal disease that was associated with massive glomerular deposition of predominantly multimeric fibronectin (FN1; 135600). The molecular mechanism that normally prevents fibronectin deposition appears to involve high-affinity binding of UGB with fibronectin to form fibronectin-uteroglobin heteromers that counteract the fibronectin self-aggregation, which is required for abnormal tissue deposition. Thus, uteroglobin is essential for maintaining normal renal function in mice. An analogous pathogenic mechanism may underlie genetic fibronectin-deposit human glomerular disease (Mazzucco et al., 1992; Strom et al., 1995; Assmann et al., 1995; Gemperle et al., 1996). See glomerular nephritis, familial, with fibronectin deposits (GFND; 601894).
Zheng et al. (1999) generated transgenic mice expressing UGB antisense RNA and UGB knockout mice. These mice had abnormal glomerular deposition of FN1 and collagen. Deposition was greater in the mice lacking Ugb. Immunohistochemical analysis demonstrated IgA and C3 (120700) accumulation in the glomeruli of both mouse models, but not accumulation of IgM or IgG. Deposition was moderate in heterozygous mice and heavy in homozygous null mice. The histologic findings were accompanied by high levels of circulating IgA-FN complexes. The Ugb-deficient mice also developed microhematuria, as seen in human IgA nephropathy (IGAN; 161950). In vitro, ELISA analysis showed that Ugb inhibits the formation of IgA-FN complexes. Fluorescence microscopy demonstrated that Ugb -/- mice coinjected with IgA and UGB failed to deposit IgA in the glomerulus. RT-PCR analysis of isolated glomeruli showed increased expression of Fn and collagen (type IV; see 120130) as well as platelet-derived growth factor (Pdgf; see 190040) in Ugb -/- mice compared with Ugb +/+ mice. Immunohistochemical analysis indicated increased expression of Pdgf mRNA but not transforming growth factor-beta (190180) mRNA in the knockout mice. Zheng et al. (1999) proposed that the lung-derived circulating factor that prevents IGAN may be UGB and that the Ugb knockout mouse represents a valid model of human IGAN that has almost all of its clinical features.
Yang et al. (2004) found that Cc10 knockout mice showed a higher incidence of airway epithelial hyperplasia and lung adenomas than wildtype animals following exposure to a tobacco smoke carcinogen. Mutant mice also showed a higher incidence of oncogenic changes and predisposing events at the molecular level associated with carcinogen-induced lung tumorigenesis.
Ray et al. (2005) found that challenge of Ugb-knockout mice with the allergen chicken ovalbumin (OVA) resulted in elevated lung expression of Scca2, the ortholog of human SCCA1 (600517) and SCCA2 (600518), as well as elevated levels of the cytokines Il4 (147780) and Il13 (147683) in lung and exacerbated airway inflammation. These effects were countered by reintroduction of recombinant Ugb. Treatment of cultured human bronchial epithelial cells with IL4 or IL13 stimulated SCCA1 and SCCA2 expression via phosphorylation of the transcription factors STAT1 (600555) and STAT6 (601512). SCCA1 and SCCA2 expression was not upregulated by IL4 or IL13 in the presence of an inhibitor of tyrosine phosphorylation. Ray et al. (2005) proposed that UGB controls allergic asthma by downregulating signaling through IL4 and IL13 and inhibiting SCCA1 and SCCA2 expression.
This variant, formerly titled ASTHMA, SUSCEPTIBILITY TO, has been reclassified based on the findings of Mao et al. (1998) and Mansur et al. (2002).
Laing et al. (1998) demonstrated a CC16 polymorphism, an adenine-to-guanine substitution at position 38 within the noncoding region of exon 1. In an unselected population, 43.6% were homozygous (38GG), and 46.2% heterozygous, for the polymorphic sequence. Compared to those homozygous for the polymorphism, those homozygous for the published sequence (38AA) had a 6.9-fold increased risk of developing asthma (p = 0.049), and heterozygotes (38AG) had a 4.2-fold increased risk (p = 0.028) of developing asthma (see 600807).
In a genetic association study with an intragenic microsatellite repeat in CC16 in 100 Japanese individuals with asthma, Mao et al. (1998) found no significant association between CC16 genotypes and allergic or intrinsic asthma.
In a case-control association study of 217 unrelated northern European Caucasians, Mansur et al. (2002) found the CC16*G allele in homozygosity in 43.4% and in heterozygosity in 45.5% of the unselected population. They found no significant difference in the distribution of positive bronchial reactivity to methacholine across the 3 genotypes. Homozygous individuals for the CC16*A allele did not demonstrate an increased risk of asthma compared to heterozygotes or GG homozygotes. No significant difference was observed in the distribution of the CC16*A or *G alleles in the asthmatics versus nonasthmatics.
Andersson, O., Nordlund-Moller, L., Bronnegard, M., Sirzea, F., Ripe, E., Lund, J. Purification and level of expression in bronchoalveolar lavage of a human polychlorinated biphenyl (PCB)-binding protein: evidence for a structural and functional kinship to the multihormonally regulated protein uteroglobin. Am. J. Resp. Cell Molec. Biol. 5: 6-12, 1991. [PubMed: 1908688] [Full Text: https://doi.org/10.1165/ajrcmb/5.1.6]
Assmann, K. J. M., Koene, R. A. P., Wetzels, J. F. M. Familial glomerulonephritis characterized by massive deposits of fibronectin. Am. J. Kidney Dis. 25: 781-791, 1995. [PubMed: 7747733] [Full Text: https://doi.org/10.1016/0272-6386(95)90555-3]
Atger, M., Atger, P., Tiollais, P., Milgrom, E. Cloning of rabbit genomic fragments containing the uteroglobin gene. J. Biol. Chem. 256: 5970-5972, 1981. [PubMed: 6263898]
Gemperle, O., Neuweiler, J., Reutter, F. W., Hildebrandt, F., Krapf, R. Familial glomerulopathy with giant fibrillar (fibronectin-positive) deposits: 15-year follow-up in a large kindred. Am. J. Kidney Dis. 28: 668-675, 1996. [PubMed: 9158203] [Full Text: https://doi.org/10.1016/s0272-6386(96)90247-4]
Hagen, G., Wolf, M., Katyal, G., Singh, G., Beato, M., Suske, G. Tissue-specific expression, hormonal regulation and 5-prime-flanking gene region of the rat Clara cell 10 kDa protein: comparison to rabbit uteroglobin. Nucleic Acids Res. 18: 2939-2945, 1990. [PubMed: 2349092] [Full Text: https://doi.org/10.1093/nar/18.10.2939]
Hay, J. G., Danel, C., Chu, C.-S., Crystal, R. G. Human CC10 gene expression in airway epithelium and subchromosomal locus suggest linkage to airway disease. Am. J. Physiol. 268: L565-L575, 1995. [PubMed: 7733299] [Full Text: https://doi.org/10.1152/ajplung.1995.268.4.L565]
Jackson, B. C., Thompson, D. C., Wright, M. W., McAndrews, M., Bernard, A., Nebert, D. W. Update of the human secretoglobin (SCGB) gene superfamily and an example of 'evolutionary bloom' of androgen-binding protein genes within the mouse Scgb gene superfamily. Hum. Genomics 5: 691-702, 2011. [PubMed: 22155607] [Full Text: https://doi.org/10.1186/1479-7364-5-6-691]
Laing, I. A., Goldblatt, J., Eber, E., Hayden, C. M., Rye, P. J., Gibson, N. A., Palmer, L. J., Burton, P. R., Le Souef, P. N. A polymorphism of the CC16 gene is associated with an increased risk of asthma. J. Med. Genet. 35: 463-467, 1998. [PubMed: 9643286] [Full Text: https://doi.org/10.1136/jmg.35.6.463]
Mansur, A. H., Fryer, A. A., Hepple, M., Strange, R. C., Spiteri, M. A. An association study between the Clara cell secretory protein CC16 A38G polymorphism and asthma phenotypes. Clin. Exp. Allergy 32: 994-999, 2002. [PubMed: 12100044] [Full Text: https://doi.org/10.1046/j.1365-2222.2002.01426.x]
Mao, X.-Q., Shirakawa, T., Kawai, M., Enomoto, T., Sasaki, S., Dake, Y., Kitano, H., Hagihara, A., Hopkin, J. M., Morimoto, K. Association between asthma and an intragenic variant of CC16 on chromosome 11q13. Clin. Genet. 53: 54-56, 1998. [PubMed: 9550363] [Full Text: https://doi.org/10.1034/j.1399-0004.1998.531530111.x]
Mazzucco, G., Maran, E., Rollino, C., Monga, G. Glomerulonephritis with organized deposits: a mesangiopathic, not immune complex-mediated disease: a pathologic study of two cases in the same family. Hum. Path. 23: 63-68, 1992. [PubMed: 1544672] [Full Text: https://doi.org/10.1016/0046-8177(92)90013-s]
Menne, C., Suske, G., Arnemann, J., Wenz, M., Kato, C. B., Beato, M. Isolation and structure of the gene for the progesterone-inducible protein uteroglobin. Proc. Nat. Acad. Sci. 79: 4853-4857, 1982. [PubMed: 6956897] [Full Text: https://doi.org/10.1073/pnas.79.16.4853]
Mihal, K., Riedel, N. One gene encoding three proteins with different functions. Am. J. Resp. Cell Molec. Biol. 5: 1-3, 1991. [PubMed: 1878249] [Full Text: https://doi.org/10.1165/ajrcmb/5.1.1]
Mukherjee, A. B., Zhang, Z., Chilton, B. S. Uteroglobin: a steroid-inducible immunomodulatory protein that founded the Secretoglobin superfamily. Endocr. Rev. 28: 707-725, 2007. Note: Erratum: Endocr. Rev. 29: 131 only, 2008. [PubMed: 17916741] [Full Text: https://doi.org/10.1210/er.2007-0018]
Peri, A., Cordella-Miele, E., Miele, L., Mukherjee, A. B. Tissue-specific expression of the gene coding for human Clara cell 10-kD protein, a phospholipase A2-inhibitory protein. J. Clin. Invest. 92: 2099-2109, 1993. [PubMed: 8227325] [Full Text: https://doi.org/10.1172/JCI116810]
Ray, R., Choi, M., Zhang, Z., Silverman, G. A., Askew, D., Mukherjee, A. B. Uteroglobin suppresses SCCA gene expression associated with allergic asthma. J. Biol. Chem. 280: 9761-9764, 2005. [PubMed: 15677460] [Full Text: https://doi.org/10.1074/jbc.C400581200]
Singh, G., Katyal, S. L., Brown, W. E., Kennedy, A. L., Singh, U., Wong-Chong, M.-L. Clara cell 10 kDa protein (CC10): comparison of structure and function to uteroglobin. Biochim. Biophys. Acta 1039: 348-355, 1990. [PubMed: 2378892] [Full Text: https://doi.org/10.1016/0167-4838(90)90270-p]
Singh, G., Singh, J., Katyal, S. L., Brown, W. E., Kramps, J. A., Paradis, I. L., Dauber, J. H., Macpherson, T. A., Squeglia, N. Identification, cellular localization, isolation, and characterization of human Clara cell-specific 10 kD protein. J. Histochem. Cytochem. 36: 73-80, 1988. [PubMed: 3275712] [Full Text: https://doi.org/10.1177/36.1.3275712]
Stohr, H., Weber, B. H. F. (ATTT)n-tetranucleotide repeat polymorphism in the 5-prime-flanking region of the UGB gene. Hum. Molec. Genet. 3: 2086 only, 1994. [PubMed: 7874146]
Stripp, B. R., Huffman, J. A., Bohinski, R. J. Structure and regulation of the murine Clara cell secretory protein gene. Genomics 20: 27-35, 1994. [PubMed: 8020953] [Full Text: https://doi.org/10.1006/geno.1994.1123]
Strom, E. H., Banfi, G., Krapf, R., Abt, A. B., Mazzucco, G., Monga, G., Gloor, F., Neuweiler, J., Riess, R., Stosiek, P., Hebert, L. A., Sedmak, D. D., Gudat, F., Mihatsch, M. J. Glomerulopathy associated with predominant fibronectin deposits: a newly recognized hereditary disease. Kidney Int. 48: 163-170, 1995. [PubMed: 7564073] [Full Text: https://doi.org/10.1038/ki.1995.280]
Winkelmann, A., Noack, T. The Clara cell: a 'Third Reich eponym'? Europ. Resp. J. 36: 722-727, 2010. [PubMed: 20223917] [Full Text: https://doi.org/10.1183/09031936.00146609]
Wolf, M., Klug, J., Hackenberg, R., Gessler, M., Grzeschik, K.-H., Beato, M., Suske, G. Human CC10, the homologue of rabbit uteroglobin: genomic cloning, chromosomal localization and expression in endometrial cell lines. Hum. Molec. Genet. 1: 371-378, 1992. [PubMed: 1284526] [Full Text: https://doi.org/10.1093/hmg/1.6.371]
Yang, Y., Zhang, Z., Mukherjee, A. B., Linnoila, R. I. Increased susceptibility of mice lacking Clara cell 10-kDa protein to lung tumorigenesis by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, a potent carcinogen in cigarette smoke. J. Biol. Chem. 279: 29336-29340, 2004. [PubMed: 15148323] [Full Text: https://doi.org/10.1074/jbc.C400162200]
Zhang, Z, Kundu, G. C., Yuan, C.-J., Ward, J. M., Lee, E. J., DeMayo, F., Westphal, H., Mukherjee, A. B. Severe fibronectin-deposit renal glomerular disease in mice lacking uteroglobin. Science 276: 1408-1411, 1997. [PubMed: 9162006] [Full Text: https://doi.org/10.1126/science.276.5317.1408]
Zhang, Z., Zimonjic, D. B., Popescu, N. C., Wang, N., Gerhard, D. S., Stone, E. M., Arbour, N. C., De Vries, H. G., Scheffer, H., Gerritsen, J., Colle'e, J. M., Ten Kate, L. P., Mukherjee, A. B. Human uteroglobin gene: structure, subchromosomal localization, and polymorphism. DNA Cell Biol. 16: 73-83, 1997. [PubMed: 9022046] [Full Text: https://doi.org/10.1089/dna.1997.16.73]
Zheng, F., Kundu, G. C., Zhang, Z., Ward, J., DeMayo, F., Mukherjee, A. B. Uteroglobin is essential in preventing immunoglobulin A nephropathy in mice. Nature Med. 5: 1018-1025, 1999. [PubMed: 10470078] [Full Text: https://doi.org/10.1038/12458]