|Coordinate||141,695,682 bp (GRCm38)|
|Base Change||G ⇒ T (forward strand)|
|Gene Name||mucin 2|
|Chromosomal Location||141,690,340-141,754,693 bp (+)|
|MGI Phenotype||Homozygotes for a point mutation have soft feces at weaning and develop diarrhea associated with malapsorption syndrome. Homozygous null mutants pass blood in their feces at 6 months, and 65% of null mutants have intestinal tumors at 1 year.|
|Amino Acid Change||Cysteine changed to Phenylalanine|
|Institutional Source||Beutler Lab|
|Gene Model||not available|
|Predicted Effect||probably damaging
PolyPhen 2 Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)
|Phenotypic Category||Autosomal Semidominant|
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Semidominant|
|Local Stock||Live Mice, Sperm, gDNA|
|Last Updated||2017-09-13 3:34 PM by Diantha La Vine|
|Nature of Mutation|
The Schlendrian mutation was mapped to Chromosome 7 by outcrossing to C3H/HeN mice, and crossing the F1 hybrids to the C3H/HeN strain (as a dominant phenotype), and corresponds to a G to T transversion at position 1689 of the Muc2 transcript in exon 13 of 47 total exons (1).
The mutated nucleotide is indicated in red lettering, and causes a cysteine to phenylalanine change at amino acid 561 of the MUC2 protein.
The structural feature that is common to all mucins is the tandem-repeat domain, which contains tandem repeats of identical or highly similar sequences that are rich in serine, threonine and proline residues. The specific sequence and number of tandem repeats is highly variable among different mucins and among orthologous mucins from different species (2;3). These domains are O-glycosylated on the serine and threonine residues by the addition of N-acetylgalactosamine (GalNAc). Each O-glycan is then elongated by adding various hexoses such as galactose, N-acetylglucosamine (GlcNAc), fucose, sialic acid, and N-acetylneuraminic acid (3). The composition of mucin oligosaccharides is highly variable, tissue-dependent, and can confer negative charges or hydrophobicity depending on the moiety used or on post-translational modification such as sulfation (2-4).
MUC2 contains two tandem repeat domains that are located in the middle of the protein (Figure 2), and shows extensive polymorphism due to the variable number of tandem repeats that can be present (5-9). For human MUC2, the first tandem repeat domain is invariant and consists of 21 repeats of a 23 amino acid sequence, while the second domain contains between 51-115 repeats of a 16 amino acid sequence (5;10). Thus, the size of the MUC2 protein varies widely between individuals and ethnicities with the most common allelic form containing over 5100 amino acids (6). In mouse, the central repetitive region of MUC2 contains two distinct repetitive regions consisting of 8 and 10 amino acid tandem repeats, respectively (1). The characteristics of the tandem-repeat domains of mucins determine the extent of mucin glycosylation, size, and biochemical characteristics. MUC2, for instance, has a rigid structure and is considered to be insoluble (11).
Unlike the tandem repeat domains, the other domains typically present in mucins tend to be highly conserved (1;7;12). The majority of these motifs in MUC2 are cysteine-rich (Figure 2), and many have high homology with von Willebrand platelet aggregating factor (VWF) (13). These include the five D domains known as D1, D2, D’, D3 and D4, as well as the B, C and cysteine-knot (CK) domains. The D1-D3 domains are located in the N-terminus of the protein, and the D4, B, C and CK domains are located in the C-terminus. The D’ domain is not always considered to be a separate domain, and the B domain is sometimes labeled as C1 (2;3;9). The CK domain is also conserved with a motif found in TGF-β and mediates the dimerization of mucin molecules through disulfide bond formation (14;15). Similarly, the N-terminal D-domains mediate mucin trimerization through disulfide bond formation between cysteines present in the D3 domains (16). The B and C domains of mucins have been shown to associate with trefoil factors (TFF), which play important roles in mucus formation and integrity (17-19). MUC2 also contains two cysteine-rich regions located before and after the first tandem repeat.
In addition to disulfide bonds, MUC2 polymers are held together by other intermolecular bonds, although the nature of these remains unclear (11). Located near the N-terminus of the D4 domain is a GDPH autocatalytic cleavage site with cleavage occurring between the D and P residues. The reaction is not enzyme-mediated and occurs at the low pH of the late secretory pathway (20). It has been suggested that this cleavage leads to the formation of a unique covalent bond between the carboxy-terminal D residue of one MUC2 subunit and an oligosaccharide side chain present on another subunit.
Collagen and heparin binding sites are also present in the MUC2 sequence. The heparin site is near the C-terminal end and consists of clusters of basic residues. In addition, MUC2 contains multiple potential N-glycosylation sites (6). At the very N-terminus is a signal sequence motif.
The Schlendrian mutation alters a conserved cysteine residue located in the second VWFD domain (Figure 2). Expression and localization of the altered protein is being examined.
Using real-time RT-PCR, human MUC2 was found to be 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 (21). These results were similar to studies localizing MUC2 mRNA expression primarily to the intestine, with some expression in the airways and the gallbladder (22;23). MUC2 gene expression in the intestine is initiated early during embryonic development (24). MUC2 protein is highly expressed in the intestinal mucus layers, and localizes to the secretory vesicles of intestinal goblet cells (25;26). Very low levels of MUC2 are present in bronchial mucus (27;28). The expression of Muc2 mRNA and protein in rodents and other mammals is similar to humans (7;12;26).
Mucins are expressed by many epithelial tissues that exist in relatively harsh environments including the stomach, intestinal tract, respiratory tract, cervix and specialized organs such as the liver, pancreas, gall bladder, kidney, mammary gland, salivary gland, lacrimal gland and eye. The layer of mucus produced by these epithelial tissues provides a protective barrier against fluctuations in molecular composition, pH, ionic concentration, pathogens, and toxins. Mucins, with their high molecular weight and complex glycosylation, are major components of epithelial mucus and have a central role in maintaining homeostasis and promoting cell survival under variable conditions. Furthermore, the specific molecular composition and higher-order structures of various mucins contribute to the specialized functions of the different epithelial tissues (2;3). For instance, colonic mucins are reported to be strongly negatively charged due to sialic acid moieties and sulfation and their carbohydrate chains display a characteristic structure, while mucins from colon cancer cell lines display short carbohydrate side chains (31). Mucus gels have been shown to contribute to the immune defense by sequestering multiple cytokines including TNF-α that mediate critical inflammatory responses (2). The immunoglobin (Ig)A antibody is secreted into mucus layers of many epithelial tissues where it provides important antimicrobial activity against pathogens (32). The IgG Fc-binding protein, FcgammaBP, is also localized to the mucus layers of many epithelial tissues, and likely plays a role in immune defense (33). Other bioactive molecules found in mucus layers include trefoil factors (18), epithelial growth factor (EGF), and TGF-α (2).
Because the intestinal mucosal layer plays a critical role in immune defense and protection against commensal bacteria, the disruption of the intestinal mucus layer and epithelium can result in intestinal bowel disease (IBD; OMIM #266600). IBD is a chronically recurring inflammatory disorder of the intestine, and results from excessive and sustained inflammatory host immune responses against antigens of commensal intestinal microbes. The clinical appearance of IBD is heterogeneous, and can include diarrhea, abdominal pain, rectal bleeding, fever, weight loss, and signs of malnutrition. Crohn’s disease (CD) and ulcerative colitis (UC) are the two major forms of IBD. Crohn’s disease can affect any part of the gastrointestinal tract, most frequently the terminal ileum and colon. In contrast, UC exclusively affects the mucosal lining of the colon and rectum (36). MUC2 polymorphisms are associated with the development of CD (21). Moreover, IBD patients often show alterations in mucin composition, including decreases in MUC2 expression, abnormal expression of other mucins, as well as differences in the glycosylation and sulfation of MUC2 (18;21;39;40). The excessive inflammation that occurs in IBD may lead to upregulation of MUC2 as MUC2 is regulated in vitro by a variety of inflammatory mediators including NF-κB, an important effector of the immune system (3;21).
Although not a major component of bronchial mucus (27;28), MUC2 may also play a role in the development of chest diseases such as cystic fibrosis (CF; OMIM #219700), and asthma (OMIM #600807) as upregulation of MUC2 gene transcription occurs in these diseases (41;42). However, the presence of MUC2 protein remains very low in the bronchial secretions of patients with disease (27;28), although this could be due to the insolubility of the MUC2 glycosylated protein.
Targeted inactivation of the murine Muc2 gene resulted in the spontaneous development of intestinal tumors (43), and on certain genetic backgrounds, the development of chronic inflammation and colitis (44). In humans, inflammation due to chronic ulcerative colitis is correlated with a significantly increased incidence of colon tumors (2). Muc2-/- mice lacked morphologically distinguishable goblet cells, although the goblet cell lineage remained intact. Muc2 knockout mice also exhibited increased proliferation, decreased apoptosis and increased migration of epithelial cells along the intestinal crypts. Two missense mutations in murine Muc2 also resulted in the development of ulcerative colitis in mice, although the mechanism behind the development of disease in these animals appears to be somewhat different than complete lack of the protective mucus layer (26) (see Putative Mechanism). In addition, mice lacking the enzyme responsible for appropriately glycosylating MUC2, and mice lacking an enzyme catalyzing the formation of MUC2 disulfide bonds lacked MUC2 protein and were susceptible to DSS-induced colitis (45;46).
The role of MUC2 as a potential tumor suppressor contrasts with the high expression of MUC2 in many epithelial cancers (29). Subsequent studies suggest that the expression of MUC2 in certain cancers is associated with a lack of invasiveness (30). Furthermore, MUC2 expression is decreased in some types of colon cancer (31).
The Schlendrian mutation alters a cysteine in the N-terminal D2 domain of MUC2. The susceptibility of Schlendrian mutant mice to low doses of DSS-induced colitis suggests that this residue may affect MUC2 biosynthesis and assembly, perhaps by disrupting the formation of an important disulfide bond. MUC2 trimerization does occur through disulfide bond formation in the D3 domain of MUC2 (16), but a similar role for D2 has not been demonstrated.
In mice with missense mutations in Muc2, the development of colitis resulted from the aberrant oligomerization and subsequent accumulation of MUC2 in the ER, which lead to ER stress, triggering of the unfolded protein response (UPR), subsequent inflammation and goblet cell apoptosis (26). These mutations resulted in amino acid changes in either the MUC2 D3 domain or the C-terminal D4 domain, further demonstrating the importance of the D domains in MUC2 function and assembly. Several recent reports provide evidence for a causal role for ER stress in IBD. Mice lacking IRE1β, an ER stress sensor expressed in intestinal epithelial cells, are more susceptible to DSS-induced colitis relative to wild type mice (47). These mice exhibit increased levels of the ER chaperone GRP78 in the colonic mucosa, indicative of ER stress. Mice lacking XBP1, a UPR response protein activated by IRE1, in intestinal epithelial cells display a loss of secretory Paneth cells and goblet cells in the intestinal epithelia, as well as spontaneous inflammation in the ileum (48). Elevated levels of GRP78 and CHOP, and IRE1 hyperactivation in the small intestine were also detected in these mice. In addition, single nucleotide polymorphisms (SNPs) in the XBP1 locus have been correlated with IBD in humans (48). Finally, mice with a missense mutation in Mbtps1 encoding the Site I protease (S1P), also demonstrate increased susceptibility to DSS-induced colitis (49) (see the record for woodrat). In response to ER stress, S1P cleaves the ATF6 transcription factor, which then activates transcription of UPR target genes such as XBP1 and GRP78 (50).
We have not demonstrated that the Schlendrian mutation results in MUC2 accumulation in the ER. It is also possible that the Schlendrian mutation results in complete lack of MUC2 protein, which can also result in the development of colitis (44). However, unlike Muc2-/- mice, the Schlendrian mutation is semidominant, suggesting the presence of aberrant protein. It is also possible that secretion of MUC2 in Schlendrian animals will result in alterations of the intestinal mucus layer. Changes in mucus formation may result in inability to bind to molecules such as trefoil factors or sequester important bioactive molecules. Mice with defects in TFF3, TGF-α and the EGF receptor (see the record for Velvet) all develop severe colitis after exposure to DSS (17;51;52).
|Primers||Primers cannot be located by automatic search.|
Schlendrian genotyping is performed by amplifying the region containing the mutation using PCR, followed by sequencing of the amplified region to detect the single nucleotide change.
Primers for PCR amplification
Schlen(F): 5’- TCCTGAACTGCTGCCAGTCAAC -3’
Schlen(R): 5’- TGGACCAGGCTCCCTTTCACAAAC -3’
1) 94°C 2:00
2) 94°C 0:30
3) 56°C 0:30
4) 72°C 1:00
5) repeat steps (2-4) 29X
6) 72°C 7:00
7) 4°C ∞
Primers for sequencing
Schlen_seq(F): 5’- CTCTGTGGAAACTTCAATGGC -3’
Schlen_seq(R): 5’- TGTCCTTGACAAGCCAGTG -3’
The following sequence of 1107 nucleotides (from Genbank genomic region NC_000073 for linear DNA sequence of Muc2) is amplified:
4800 t 4801 cctgaactgc tgccagtcaa cagagccagc tgagattcgg acagcctaag agtctgggca 4861 aggagaggcc ttgtgtcctc aggcagactc tattcttggg tccctgctag tggaaggggg 4921 tggtgggcat gtcaccccat agtatggtgg aaccaaggag ccctgcagcc tttcaccatg 4981 tccttccttg tcttatagcc agcttctcca tcttccaacc ctcctcctac cacattgttg 5041 tgaacacgaa gttcgggctg cggctgcaga tccagttgct tccagtcatg cagctttttg 5101 tgactctgga ccaggctgcc cagggacagg tgcagggtga gtggctctct cctgtcttgt 5161 ctctgaaaaa tccccatgag ggtcctattt ttttccccca cccccaggtt cttcctaatc 5221 ctgtcctggc cctttaggtc tctgtggaaa cttcaatggc ctagagagtg atgacttcat 5281 gacgtctggt ggaatggtgg aggccaccgg tgctggcttc gccaatacct ggaaggccca 5341 atcaagctgc cacgacaagc tggactggct agatgacccc tgctccctca acattgagag 5401 tggtaaggct caggagaagc tggttgctgt ccactggctt gtcaaggaca cacaatcctg 5461 acagtccagc ctcagagcag atggggctcc tgatgaagac ataggatgtg ggtgaggagt 5521 gggtgtaggt cacatggcct atggtgctgg gatcagcaca tttacctgct gtttcagttg 5581 acagtggccc catggtggca gcattccagg tgacaaagta aatggactgg gcaggctaac 5641 tgctgggtgg tggctctcat ctcggcctgg cttaatgcta ggatgacatg cccttctatc 5701 catttctcca tcatatctgt ggatttctag ccccttgggg tcgaaaaagg gagaggtggg 5761 tgttatgcag aaaggtctca tcttgttcat agctgcctgg agttatgaag aaaggggtct 5821 ggctttggtc acccaggaga ccatgtcacc tccatcctgg gtgatcagac tttaggctca 5881 gggtttgtga aagggagcct ggtcca
PCR primer binding sites are underlined; sequencing primer binding sites are highlighted in gray; the mutated G is shown in red text.
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|Science Writers||Nora G. Smart|
|Illustrators||Diantha La Vine|
|Authors||Katharina Brandl, Bruce Beutler|