Alternative titles; symbols
HGNC Approved Gene Symbol: MUC1
SNOMEDCT: 726017001;
Cytogenetic location: 1q22 Genomic coordinates (GRCh38): 1:155,185,824-155,192,915 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q22 | Tubulointerstitial kidney disease, autosomal dominant, 2 | 174000 | Autosomal dominant | 3 |
Mucins are heavily glycosylated proteins thought to function in the protection of epithelial surfaces. Secreted and transmembrane mucins form a protective mucous barrier, and transmembrane mucins may also function in signaling the presence of adverse conditions in the extracellular environment. MUC1 is a transmembrane mucin normally expressed on the apical borders of secretory epithelial cells (Yin et al., 2003).
Gendler et al. (1990) and Lan et al. (1990) independently cloned full-length human MUC1. The deduced protein contains an N-terminal domain that harbors a signal peptide and degenerate repeats, followed by a long variable number of tandem repeats (VNTR) domain, and a C-terminal domain that has a degenerate repeat region, a transmembrane domain, and a short cytoplasmic domain. The VNTR region consists of a variable number of a 20-amino acid repeat and contains numerous serine and threonine residues that represent potential O-glycosylation sites. The C-terminal domain contains 5 possible N-glycosylation sites and several additional potential O-glycosylation sites. The deduced MUC1 protein reported by Lan et al. (1990) had approximately 42 tandem repeats, resulting in a 1,255-amino acid protein with a calculated molecular mass of 122 kD. Using Northern blot analysis, Lan et al. (1990) detected a major 4.4-kb MUC1 transcript in several pancreatic and breast tumor cell lines.
Levitin et al. (2005) stated that alternative splicing of MUC1 produces isoforms that differ in their N and C termini, lack the tandem repeat array of full-length MUC1, or may be secreted rather than tethered to the cell membrane. They identified a splice variant encoding a MUC1 isoform, called MUC1/ZD, that lacks both the tandem repeat array and has a unique C terminus due to a frame shift. The 73-amino acid protein is identical to full-length MUC1 only in the N-terminal signal peptide and subsequent 30 amino acids. Immunohistochemical analysis of skin showed MUC1/ZD expression in epithelial cells of sebaceous glands, hair follicles, and epidermis. Full-length MUC1 was also expressed in epithelial cells of sebaceous glands. MUC1/ZD localized to the cell surface and interstitial space. It had an apparent molecular mass of 7 to 8 kD by SDS-PAGE. Under nonreducing conditions, its mass was about 64 kD, suggesting that MUC1/ZD forms oligomers linked by disulfide bonds between cysteine residues.
Wei et al. (2006) stated that MUC1 is translated as a single polypeptide that is cleaved into 2 subunits in the endoplasmic reticulum. The extracellular N-terminal subunit (MUC1N) contains variable numbers of 20-amino acid tandem repeats that are extensively modified by O-linked glycans. The C-terminal subunit (MUC1C) consists of a 58-amino acid extracellular domain, a 28-amino acid transmembrane domain, and a 72-amino acid cytoplasmic tail. MUC1N extends well beyond the glycocalyx and is tethered to the cell membrane by MUC1C. MUC1C also accumulates in the cytosol of transformed cells and is targeted to the nucleus and mitochondria.
Using real-time RT-PCR, Moehle et al. (2006) found that MUC1 was highly expressed in adult prostate, mammary gland, trachea, lung, small intestine, and colon, and in fetal lung. Lower expression was detected in placenta, kidney, and pancreas, followed by testis, uterus, salivary gland and stomach. Weak expression was detected in spinal cord, thyroid, bone marrow, and thymus.
Siddiqui et al. (1988) isolated and sequenced a cDNA coding for human DF3. Marchesi et al. (2010) noted that the mucin encoded by the MUC1 gene is recognized by the monoclonal antibody DF3.
Levitin et al. (2005) reported that the MUC1 gene contains 7 coding exons.
Gendler et al. (1990) identified a TATAA box and multiple GC boxes in the upstream region of the MUC1 gene.
Swallow et al. (1987, 1987) mapped the PUM locus to 1q21-q24 by somatic cell hybrid studies and in situ hybridization.
Swallow et al. (1988) found close linkage of Duffy blood group (110700) and PUM (maximum lod score = 4 at theta = 0). Middleton-Price et al. (1988) found linkage of alpha-spectrin (182860) and PUM (maximum lod score = 5.98 at theta = 0.05); both loci may lie within 1q21. Anderson et al. (1989) presented results of linkage studies of PUM and chromosome 1 markers in the CEPH families.
By analysis of interspecific backcross mice, Kingsmore et al. (1995) mapped the homologous gene to mouse chromosome 3.
Using the murine monoclonal antibody DF3 prepared against human breast carcinoma, Kufe et al. (1984) showed that DF3 antigen levels are elevated in the plasma of patients with breast cancer and that the monoclonal antibody reacts with circulating glycoproteins of different molecular weights ranging from approximately 300 to 450 kD.
Hayes et al. (1988) showed electrophoretic polymorphism of plasma DF3 antigen. DF3 antigen was demonstrated in the urine, where the electrophoretic mobility of the protein moieties was similar but not identical to that in plasma. Family studies suggested that the electrophoretic heterogeneity of plasma DF3 antigen is determined by codominant expression of multiple alleles at a single locus, which presumably codes for the core protein of DF3 antigen. DF3 antigen is present also in human milk. It is expressed on the surface of epithelial cells but is absent from erythrocytes and granulocytes. See Becker et al. (1982) for description of an antigen associated with transforming genes in human and mouse breast cancer.
Gendler et al. (1990) studied the polymorphic epithelial mucin present on the surface of human mammary cells. It is developmentally regulated and aberrantly expressed in breast cancer.
Li et al. (2003) stated that beta-catenin (CTNNB1; 116806) binds directly to a serine-rich motif in the MUC1 cytoplasmic domain (CD), and that the interaction is regulated by MUC1-CD phosphorylation. They showed that MUC1 localized to the surface of transfected rat fibroblasts, and that the MUC1 C-terminal subunit and beta-catenin colocalized in the nucleus. The amount of nuclear beta-catenin increased following MUC1 expression. MUC1-expressing fibroblasts were tumorigenic in nude mice.
Yin et al. (2003) found that oxidative stress increased expression of MUC1 in several human cell lines. In turn, MUC1 induced expression of the antioxidant enzymes superoxide dismutase (SOD1; 147450), catalase (CAT; 115500), and glutathione peroxidase (GPX1; 138320). MUC1 also attenuated the apoptotic response to oxidative stress.
Rahn et al. (2004) stated that ICAM1 (147840) binds the MUC1 extracellular domain and that binding promotes adhesion of MUC1-expressing tumor cells to a simulated vessel wall containing ICAM1 with sufficient strength to withstand shear stress equivalent to physiologic blood flow. They reported that the interaction of MUC1 with ICAM1 triggered intracellular calcium oscillations in MUC1-expressing cells. Oscillations were reduced by inhibition of SRC family kinases (190090), phosphoinositol-3 kinase (see PIK3CA; 171834) and phospholipase C (see PLCG1; 172420), and by disruption of lipid rafts, but not by inhibition of mitogen-activated protein kinases (see MAPK1; 176948).
Wei et al. (2006) found that MUC1C associated with estrogen receptor-alpha (ESR1; 133430) and that the interaction was stimulated by 17-beta-estradiol in human breast carcinoma cell lines. MUC1 bound directly to the ESR1 DNA-binding domain and stabilized ESR1 by blocking its ubiquitination and degradation. Chromatin immunoprecipitation assays demonstrated that MUC1 associated with ESR1 complexes on estrogen-responsive promoters, enhanced ESR1 promoter occupancy, and increased recruitment of p160 (PELP1; 609455) coactivators SRC1 (NCOA1; 602691) and GRIP1 (604597). MUC1 stimulated ESR1-mediated transcription and contributed to estradiol-mediated growth and survival of breast cancer cells.
The amnion membrane of placenta performs a unique physiologic role as a physical barrier between the fetal and external environment, and appears to have antibacterial and antiadhesive properties. Using DNA microarrays to examine gene expression patterns in normal human placenta, Sood et al. (2006) found that MUC1 is highly expressed in the amnion. Muc1 knockout mice have chronic uterine infection caused by overgrowth of normal bacteria of the reproductive tract (DeSouza et al., 1999). The structure and expression patterns of mucin proteins suggest that they may protect the mucous membranes by sterically inhibiting bacterial access to the cell membrane. An association between high expression of MUC1 and aggressiveness of some cancers has prompted speculation that this glycoprotein favors metastasis by inhibiting cell adhesion (Levi et al., 2004). Together, these observations suggested to Sood et al. (2006) that expression of MUC1 may confer antibacterial and antiadhesive properties to amnion.
Lu et al. (2006) noted that MUC1 interacts with Pseudomonas aeruginosa (PA) through flagellin. They found that, compared with wildtype mice, mice deficient in Muc1 cleared PA more efficiently, recruited more neutrophils, and expressed higher levels of Tnf (191160) and Kc (CXCL1; 155730) in bronchoalveolar lavage fluid. ELISA showed that Muc1-deficient alveolar macrophages stimulated with PA flagellin in vitro secreted more Tnf, while Muc1-deficient tracheal epithelial cells produced more Kc. Small interfering RNA-mediated knockdown of MUC1 in human bronchial epithelial cells induced IL8 (146930) expression. Expression of MUC1 in human embryonic kidney cells attenuated TLR5 (603031)-dependent IL8 release in response to flagellin. Expression of MUC1 lacking the cytoplasmic tail in these cells abolished flagellin-induced production of IL8. Lu et al. (2006) concluded that MUC1 suppresses pulmonary innate immunity and proposed that its antiinflammatory activity may play an important modulatory role during microbial infection.
Both MUC1 and galectin-3 (LGALS3; 153619) are widely expressed in human carcinomas. Ramasamy et al. (2007) showed that, following glycosylation on asn36, MUC1C induced galectin-3 expression by suppressing expression of miRNA322 (MIRN322; 300682), a microRNA that destabilizes galectin-3 transcripts. In turn, galectin-3 bound MUC1C at the glycosylated asn36 site and formed a bridge between MUC1 and epidermal growth factor receptor (EGFR; 131550), integrating MUC1 with EGF (131530) signaling.
By microarray analysis, Moehle et al. (2006) found coordinated downregulation of mucins, including MUC1, 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 MUC1 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 MUC1 mRNA expression nearly 8-fold and 2-fold, respectively.
Autosomal Dominant Tubulointerstitial Kidney Disease 2
In affected members of 6 unrelated families with autosomal dominant tubulointerstitial kidney disease-2 (ADTKD2; 174000), Kirby et al. (2013) identified a heterozygous 1-bp insertion of a cytosine in 1 copy of an extremely long (1.5-5.0 kb) GC-rich coding variable number tandem repeat (VNTR) sequence in the MUC1 gene (158340.0001). The insertion was predicted to cause a frameshift, resulting in a mutant protein with many copies of a novel repeat sequence, but lacking a downstream self-cleavage module and both the transmembrane and intracellular domains characteristic of the wildtype MUC1 precursor protein (MUC1fs). A similar cytosine insertion was found in 13 of 21 additional families with the disorder who were studied, consistent with its being a fully penetrant cause of disease. The disorder was characterized by adult onset of slowly progressive renal failure, minimal proteinuria, decreased glomerular filtration rate (GFR), and occasional findings of renal cysts on ultrasound. Renal biopsy showed tubulointerstitial fibrosis and tubular atrophy. End-stage renal disease occurred in the third to seventh decades of life. Antibodies against a peptide synthesized to correspond to the predicted mutant VNTR sequence showed specific intracellular staining in epithelial cells from the loop of Henle, distal tubule, and collecting duct of patients that was not seen in controls. The mutant MUC1 showed partial colocalization with wildtype MUC1 in the collecting duct of a patient. Kirby et al. (2013) emphasized that the mutation was missed by massively parallel sequencing and was found only by diligent analysis of the linked region using cloning, Southern blot analysis, long-range PCR, and reconstruction of the VNTR allele in patients and controls.
Olinger et al. (2020) reported 93 families from Europe or the United States with ADTKD2. Four different MUC1 mutations in the VNTR domain of MUC1 were detected (27dupC, 28dupA, 26_27insG, and 23delinsAT). All were predicted to lead to the same frameshift and premature stop codon (MUC1fs). This truncated protein accumulates in intracellular vesicles and causes tubulointerstitial damage.
Polymorphisms
Karlsson et al. (1983) demonstrated a genetically determined polymorphism of a human urinary mucin by the separation technique of SDS polyacrylamide gel electrophoresis followed by detection with radioiodinated lectins. Peanut agglutinin was the most effective lectin; hence, the proposed designation peanut-reactive urinary mucin (PUM). Karlsson et al. (1983) identified 4 common alleles with codominant inheritance. The same polymorphic protein is expressed in other normal and malignant tissues of epithelial origin including the mammary gland. Variation in white cell DNA detected with a cDNA probe for mammary mucin exactly matches the variation of the protein as demonstrated after electrophoresis using a series of monoclonal antibodies; studies in 2 large families demonstrated the precise correspondence. It appears that a series of tandem repeats constitutes much of the coding region of the PUM gene and that the allelic variation is due to variation in the number of repeats, as occurs in the hypervariable minisatellite regions of DNA.
Swallow et al. (1987) presented evidence obtained using a cDNA that the PUM locus is a hypervariable 'minisatellite' region similar to those described by several groups, but novel in that it is transcribed and translated, and that the same polymorphism is demonstrable in the expressed gene product.
Gendler et al. (1990) found that the number of repeats in the VNTR domain of the MUC1 gene in 69 northern Europeans varied from 21 to 125, with the dominant numbers being 41 and 85. The most common genotype observed (5 of 69 individuals) was the heterozygote consisting of the 2 most common alleles.
A polymorphism due to a G/A substitution in exon 2, responsible for a genetically determined variation in splicing of the MUC1 transcript, was reported by Ligtenberg et al. (1990, 1991). Pratt et al. (1996) reported a CA repeat polymorphism within intron 6 of the gene. The various results supported the notion that the VNTR polymorphism in the coding sequence of MUC1 was not caused by unequal reciprocal recombination at meiosis.
Silva et al. (2001) evaluated the MUC1 VNTR polymorphism in a series of 174 patients with chronic gastritis in a population from northern Portugal with a high incidence of gastric carcinoma (137215). The data were compared with those from blood donors and patients with gastric cancer from the same population. Significant differences were observed between patients with chronic gastritis and blood donors and also between patients with chronic gastritis and patients with gastric cancer. Homozygotes for small MUC1 VNTR alleles were significantly associated with gastric carcinoma as well as with chronic atrophic gastritis and incomplete intestinal metaplasia, the 2 well established precursor lesions of gastric carcinoma, suggesting that MUC1 genotypes may define different susceptibility backgrounds in the gastric carcinogenesis pathway.
Fowler et al. (2003) investigated hypervariability in MUC1 and concluded that it may have functional consequences.
McAuley et al. (2007) observed a rapid progressive increase in gastrointestinal expression of Muc1 after oral infection of mice with Campylobacter jejuni. Systemic spread occurred in Muc1 -/- mice, but not in wildtype mice, and Muc1 -/- mice showed more small intestinal damage, as manifested by increased apoptosis with enucleated and shed villous epithelium, after C. jejuni infection. Muc1 -/- mice were not more susceptible to S. typhimurium than wildtype mice. Testing of chimeric mice showed that prevention of systemic infection was due exclusively to Muc1 expression on mucosal rather than hematopoietic cells. Muc1 enhanced resistance to the C. jejuni cytolethal distending toxin (Cdt), and bacteria lacking Cdt were deficient in colonizing the gastrointestinal tracts of Muc1 -/- mice. McAuley et al. (2007) concluded that MUC1 is critical in limiting mucosal infection and that MUC1 expression enhances resistance to C. jejuni Cdt.
In affected members of 6 unrelated families with autosomal dominant tubulointerstitial kidney disease-2 (ADTKD2; 174000), Kirby et al. (2013) identified a heterozygous 1-bp insertion of a cytosine in 1 copy of an extremely long (1.5-5.0 kb) GC-rich coding variable number tandem repeat (VNTR) sequence in the MUC1 gene. The insertion was within a stretch of 7 cytosines occurring at positions 53-59 in a single copy of the canonical 60-mer repeat. The insertion of cytosine occurred in a different VNTR size in each family, indicating independent occurrence of the mutations. Some of the families had previously been reported (e.g., by Kiser et al., 2004). The insertion was predicted to cause a frameshift, resulting in a mutant protein with many copies of a novel repeat sequence, but lacking a downstream self-cleavage module as well as the transmembrane and intracellular domains characteristic of the wildtype MUC1 precursor protein (MUC1fs). Full genotyping of this region showed that the mutation segregated with the risk-associated haplotype in each family, but was not found in over 500 controls from various populations. A similar cytosine insertion was found in 13 of 21 additional families with the disorder who were studied, consistent with its being a fully penetrant cause of disease. Antibodies against a peptide synthesized to correspond to the predicted mutant VNTR sequence showed specific intracellular staining in epithelial cells from the loop of Henle, distal tubule, and collecting duct of patients that was not seen in controls. The mutant MUC1 showed partial colocalization with wildtype MUC1 in the collecting duct of a patient. Kirby et al. (2013) emphasized that the mutation was missed by massively parallel sequencing and was found only by diligent analysis of the linked region using cloning, Southern blot analysis, long-range PCR, and reconstruction of the VNTR allele in patients and controls.
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Lu, W., Hisatsune, A., Koga, T., Kato, K., Kuwahara, I., Lillehoj, E. P., Chen, W., Cross, A. S., Gendler, S. J., Gewirtz, A. T., Kim, K. C. Cutting edge: enhanced pulmonary clearance of Pseudomonas aeruginosa by Muc1 knockout mice. J. Immun. 176: 3890-3894, 2006. [PubMed: 16547220] [Full Text: https://doi.org/10.4049/jimmunol.176.7.3890]
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