HGNC Approved Gene Symbol: MUC2
Cytogenetic location: 11p15.5 Genomic coordinates (GRCh38): 11:1,074,874-1,110,508 (from NCBI)
Many epithelial tissues including those of trachea, submaxillary gland, mammary gland, pancreas, stomach, cervix, and intestine produce high molecular weight, complex glycoconjugates known as mucins. These consist of a polypeptide core (apomucin) covered almost entirely by O-linked carbohydrate chains which may constitute up to 80% of the total molecular weight. Because of their heavy glycosylation, the apomucins were difficult to analyze by conventional peptide sequencing methods. It has been easier to isolate cDNAs and deduce the structure of the proteins therefrom. Gum et al. (1989) cloned a cDNA for human intestinal mucin and by in vitro translation of a polyadenylated RNA from human small intestine, colon, and colon cancer cells, produced a 162-kD peptide that was immunoprecipitated with antibodies to deglycosylated mucin. Griffiths et al., 1990 stated that MUC2 resembles the gene for the urinary mucin PUM (MUC1; 158340) in showing high level of polymorphism, some of which appears to be due to variation in allele length, as observed for PUM. Jany et al. (1991) concluded that the same mucin gene is expressed in both intestine and bronchus and is homologous to a gene or genes expressed in the gallbladder, cervix, and mammary gland.
Allen et al. (1998) indicated that a total of 9 human MUC genes had been identified to date. Like the others, MUC2 is characterized by tandem and irregular repeat sequences rich in threonine and serine, the potential sites of attachment of the oligosaccharide chains. The MUC2 gene product has more than 5,100 amino acids in its commonest allelic form. The MUC2 product is polymerized end to end through disulfide bridges to form large secreted polymeric gel-forming mucins.
Rousseau et al. (2004) described the domain structure of human MUC2. MUC2 contains an N-terminal signal peptide, followed by several Von Willebrand factor (VWF; 193400)-like domains, a cysteine-rich domain, a small invariant tandem repeat domain, a second cysteine-rich domain, the main tandem repeat domain, a second group of VWF-like domains, and a C-terminal cystine knot domain.
Using real-time RT-PCR, Moehle et al. (2006) found that MUC2 was highly expressed in adult small intestine and colon. Expression was lower in fetal lung and adult trachea and stomach, with weak expression in skeletal muscle, testis, and prostate. No expression was detected in other tissues examined.
As the first intestinal mucin gene to be described, MUC2 has become important as a prototype for secreted mucins in several organ systems. Toribara et al. (1991) showed that MUC2 contains 2 distinct regions which have with a high degree of internal homology but no significant homology to each other. Region 1 consists mostly of 48-bp repeats which are interrupted in places by 21 to 24 bp segments. Region 2 is composed of 69-bp tandem repeats arranged in an uninterrupted array of up to 115 individual units. Southern analysis of genomic DNA samples using TaqI and HinfI revealed both length and sequence polymorphisms occurring in region 2. The sequence polymorphisms had different ethnic distributions while the length polymorphisms were attributable to variable numbers of tandem repeats (VNTRs).
Rousseau et al. (2004) determined that the MUC2 gene contains twenty-nine 5-prime exons, 1 large central exon containing the tandem repeat sequences, and nineteen 3-prime exons.
Using the clone isolated by Gum et al. (1989) in the study of somatic cell hybrids, Griffiths et al. (1989) showed that the MUC2 gene is located on chromosome 11. By in situ hybridization, Griffiths et al. (1990) assigned the gene to 11p15. Analysis of the CEPH (Centre d'Etude du Polymorphisme Humain) families showed that MUC2 is part of the tight linkage group on 11p15 that contains HRAS (190020), INS (176730), TH (191290), and HBB (141900).
Rousseau et al. (2004) determined that the MUC2 and MUC6 (158374) genes are located 38.5 kb apart in a head-to-head orientation within a gene complex on chromosome 11p15.5.
Tracheobronchial mucin (MUC5AC; 158373), which was also mapped to 11p15, was thought to be distinct from MUC2. However, Shankar et al. (1995) presented evidence that they may be identical. MUC2 is a protein of greater than 500 amino acids that can be divided into 3 major structural domains. MUC transcripts in the intestine and trachea showed sequence identity in 3 areas: the region of imperfect repeats; the sequence immediately upstream of the 69-bp tandem repeats; and the extreme C terminus. Shankar et al. (1995) granted that differences may exist in the extreme N terminus of the MUC2 gene transcripts in the intestine and trachea, possibly due to alternative splicing.
Three of the 4 distinct mucin genes that map to 11p15.5 show a high level of genetically determined polymorphism: MUC2, MUC5AC, and MUC6. Pigny et al. (1996) performed linkage analysis of these 3 genes in the CEPH families and demonstrated that all 3 genes are clustered on 11p15.5 between HRAS and IGF2 (147470). Pulsed-field gel electrophoresis was used to make a detailed physical map of the MUC cluster and to integrate the physical and genetic maps. The gene order was determined to be tel-HRAS--MUC6--MUC2--MUC5AC--MUC5B--IGF2--cen. The MUC genes span a region of some 400 kb. Pigny et al. (1996) noted that the order of the MUC genes on the map corresponds to the relative order of their expression along the anterior-posterior axis of the body, suggesting a possible functional significance to the gene order.
Allen et al. (1998) stated that the primary function of the MUC2 gene product is to provide a protective barrier between the epithelial surfaces and the gut lumen. There is decreased expression of MUC2 in colonic cancer and defective polymerization of secreted mucin in ulcerative colitis (see 266600).
Mucus is especially thick in the colon and helps protect the colonic epithelium from enteric pathogens, such as Entamoeba histolytica (Eh), which adheres to mucin oligosaccharides via a 170-kD lectin. In a small percentage of cases, Eh overcomes the mucus barrier and invades the epithelium by means of cysteine proteases. Lidell et al. (2006) found that Eh cysteine proteases digested recombinant C-terminal, but not N-terminal, cysteine-rich regions of MUC2, as well as mucins from an MUC2-producing cell line. The major cleavage site was predicted to disrupt MUC2 polymers, thereby disrupting the mucus gel. Lidell et al. (2006) proposed that Eh cysteine proteases use this mechanism in the pathogenesis of invasive amoebiasis.
By microarray analysis, Moehle et al. (2006) found coordinated downregulation of mucins, including MUC2, in ileum and colon of Crohn disease and ulcerative colitis (see 266600) patients compared with controls. They identified an NF-kappa-B (see 164011)-binding site in the MUC2 promoter and showed that activation of the NF-kappa-B signaling pathway by inflammatory cytokines TNF-alpha (TNF; 191160) and TGF-beta (TGFB1; 190180) upregulated MUC2 mRNA expression nearly 6-fold and 3-fold, respectively.
Shan et al. (2013) showed that the small intestine has a porous mucus layer, which permitted the uptake of MUC2 by antigen-sampling dendritic cells. Glycans associated with MUC2 imprinted dendritic cells with antiinflammatory properties by assembling a galectin-3 (153619)-dectin-1 (606264)-Fc-gamma-RIIB (604590) receptor complex that activated beta-catenin (116806). This transcription factor interfered with dendritic cell expression of inflammatory but not tolerogenic cytokines by inhibiting gene transcription through NF-kappa-B. MUC2 induced additional conditioning signals in intestinal epithelial cells. Shan et al. (2013) concluded that mucus does not merely form a nonspecific physical barrier, but also constrains the immunogenicity of gut antigens by delivering tolerogenic signals.
To test the hypothesis that short MUC2 alleles predispose to ulcerative colitis (see 266600), Swallow et al. (1999) analyzed DNA from 125 unrelated individuals with inflammatory bowel disease. They found no evidence of an association between MUC2 allele length and ulcerative colitis.
Velcich et al. (2002) generated mice deficient in MUC2, the most abundant secreted gastrointestinal mucin. Heterozygous mice were indistinguishable from wildtype mice, and homozygous mutant mice were born at the expected mendelian frequency. Muc2 -/- mice showed absence of recognizable goblet cells along the entire length of the intestine upon alcian blue staining. However, expression of intestinal trefoil factor (600633), another product of fully differentiated goblet cells, was detectable, suggesting that at least some aspects of the differentiation program of the goblet cell lineage persist in Muc2 -/- mice. Muc2 -/- mice had increased proliferation, decreased apoptosis, and increased migration of intestinal epithelial cells. Muc2 -/- mice frequently developed adenomas in the small intestine that progressed to invasive adenocarcinoma, as well as rectal tumors, with up to 68% of mice manifesting with gastrointestinal tumors at 1 year of age.
Allen, A., Hutton, D. A., Pearson, J. P. The MUC2 gene product: a human intestinal mucin. Int. J. Biochem. Cell Biol. 30: 797-801, 1998. [PubMed: 9722984] [Full Text: https://doi.org/10.1016/s1357-2725(98)00028-4]
Griffiths, B., Gum, J., West, L. F., Povey, S., Swallow, D. M., Kim, Y. S. Mapping of the gene coding for intestinal mucin to chromosome 11p15. (Abstract) Cytogenet. Cell Genet. 51: 1008 only, 1989.
Griffiths, B., Matthews, D. J., West, L., Attwood, J., Povey, S., Swallow, D. M., Gum, J. R., Kim, Y. S. Assignment of the polymorphic intestinal mucin gene (MUC2) to chromosome 11p15. Ann. Hum. Genet. 54: 277-285, 1990. [PubMed: 1980995] [Full Text: https://doi.org/10.1111/j.1469-1809.1990.tb00383.x]
Gum, J. R., Byrd, J. C., Hicks, J. W., Toribara, N. W., Lamport, D. T. A., Kim, Y. S. Molecular cloning of human intestinal mucin cDNAs: sequence analysis and evidence for genetic polymorphism. J. Biol. Chem. 264: 6480-6487, 1989. [PubMed: 2703501]
Jany, B. H., Gallup, M. W., Yan, P.-S., Gum, J. R., Kim, Y. S., Basbaum, C. B. Human bronchus and intestine express the same mucin gene. J. Clin. Invest. 87: 77-82, 1991. [PubMed: 1985113] [Full Text: https://doi.org/10.1172/JCI115004]
Lidell, M. E., Moncada, D. M., Chadee, K., Hansson, G. C. Entamoeba histolytica cysteine proteases cleave the MUC2 mucin in its C-terminal domain and dissolve the protective colonic mucus gel. Proc. Nat. Acad. Sci. 103: 9298-9303, 2006. [PubMed: 16754877] [Full Text: https://doi.org/10.1073/pnas.0600623103]
Moehle, C., Ackermann, N., Langmann, T., Aslanidis, C., Kel, A., Kel-Margoulis, O., Schmitz-Madry, A., Zahn, A., Stremmel, W., Schmitz, G. Aberrant intestinal expression and allelic variants of mucin genes associated with inflammatory bowel disease. J. Molec. Med. 84: 1055-1066, 2006. [PubMed: 17058067] [Full Text: https://doi.org/10.1007/s00109-006-0100-2]
Nguyen, V. C., Aubert, J. P., Gross, M. S., Porchet, N., Degand, P., Frezal, J. Assignment of human tracheobronchial mucin gene(s) to 11p15 and a tracheobronchial mucin-related sequence to chromosome 13. Hum. Genet. 86: 167-172, 1990. [PubMed: 2265829] [Full Text: https://doi.org/10.1007/BF00197699]
Pigny, P., Guyonnet-Duperat, V., Hill, A. S., Pratt, W. S., Galiegue-Zouitina, S., Collyn d'Hooge, M., Laine, A., Van-Seuningen, I., Degand, P., Gum, J. R., Kim, Y. S., Swallow, D. M., Aubert, J.-P., Porchet, N. Human mucin genes assigned to 11p15.5: identification and organization of a cluster of genes. Genomics 38: 340-352, 1996. [PubMed: 8975711] [Full Text: https://doi.org/10.1006/geno.1996.0637]
Rousseau, K., Byrne, C., Kim, Y. S., Gum, J. R., Swallow, D. M., Toribara, N. W. The complete genomic organization of the human MUC6 and MUC2 mucin genes. Genomics 83: 936-939, 2004. [PubMed: 15081123] [Full Text: https://doi.org/10.1016/j.ygeno.2003.11.003]
Shan, M., Gentile, M., Yeiser, J. R., Walland, A. C., Bornstein, V. U., Chen, K., He, B., Cassis, L., Bigas, A., Cols, M., Comerma, L., Huang, B., Blander, J. M., Xiong, H., Mayer, L., Berin, C., Augenlicht, L. H., Velcich, A., Cerutti, A. :Mucus enhances gut homeostasis and oral tolerance by delivering immunoregulatory signals. Science 342: 447-453, 2013. [PubMed: 24072822] [Full Text: https://doi.org/10.1126/science.1237910]
Shankar, V., Gilmore, M. S., Sachdev, G. P. Further evidence that the human MUC2 gene transcripts in the intestine and trachea are identical. (Letter) Biochem. J. 306: 311-312, 1995. [PubMed: 7864825] [Full Text: https://doi.org/10.1042/bj3060311]
Swallow, D. M., Vinall, L. E., Gum, J. R., Kim, Y. S., Yang, H., Rotter, J. I., Mirza, M., Lee, J. C. W., Lennard-Jones, J. E. Ulcerative colitis is not associated with differences in MUC2 mucin allele length. (Letter) J. Med. Genet. 36: 859-860, 1999. [PubMed: 10636731]
Toribara, N. W., Gum, J. R., Jr., Culhane, P. J., Lagace, R. E., Hicks, J. W., Petersen, G. M., Kim, Y. S. MUC-2 human small intestinal mucin gene structure: repeated arrays and polymorphism. J. Clin. Invest. 88: 1005-1013, 1991. [PubMed: 1885763] [Full Text: https://doi.org/10.1172/JCI115360]
Velcich, A., Yang, W., Heyer, J., Fragale, A., Nicholas, C., Viani, S., Kucherlapati, R., Lipkin, M., Yang, K., Augenlicht, L. Colorectal cancer in mice genetically deficient in the mucin Muc2. Science 295: 1726-1729, 2002. [PubMed: 11872843] [Full Text: https://doi.org/10.1126/science.1069094]