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Schema Name MUC2 Schema for Crohn's disease
Accession MS020700035.2
Gene(s) MUC2, XBP1, IL10
Schema Caption The role of mutation in MUC2 gene for increasing Crohn’s disease risk.
Schema Description MUC2 is a secretory mucin and is expressed from goblet cells. In an Affymetrix DNA microarray analysis, one MUC2 variant (rs11825977) is found to be associated with Crohn’s disease (pmid: 17058067). There is no GWAS marker on MUC2 gene from large meta-analysis. There could be several reasons for that. We can understand from this present mechanism schema, why this can happen for MUC2 gene, which is one of the most important gel-forming secreted mucus protein, forming the mucus layer and giving protection from invading bacteria. From this mechanism schema, we can observe that due to misfolding of MUC2 carrying a genetic variant, there can be an increased rate of apoptosis. If Goblet cell number gets reduced due to apoptosis, less MUC2 is likely to be secreted per goblet cell, and the unfolded protein response (UPR) will initiate a translational block. The mucin that is secreted could be incorrectly oligomerized and affect the rheological properties of mucus. Now ER stress can be generated in the cell due to the presence of other misfolded proteins in ER. The resultant UPR could lead to a translational block decreasing MUC2 synthesis, and the ER stress could cause MUC2 misfolding, even in the absence of mutations in MUC2, duplicating the ER stress / reduced mucus barrier phenotype (pmid: 18318598). This could be one of the reasons why MUC2 is not a GWAS locus in any meta-analysis. The present mechanism schema is addressing how MUC2 variant is causing mucosal barrier defect and ER stress for Crohn's disease risk.
Author(s) Lipika R. Pal, Kunal Kundu, Lindley Darden and John Moult
Curator(s) Lipika R. Pal, John Moult
Last Modified Fri Aug 10 2018 15:17:01 GMT-0400 (Eastern Daylight Time)
Sub-state Perturbation (SSP) Annotations
Component ID: SSP1
Stage: DNA
SSP Class: Other
Other SSP Class: SNV [HET/HOM]
Modifier: NA
Ontology:
SSP Instance: rs11825977 in MUC2
Confidence Score: 3
Comment: In an affymetrix DNA microarray analysis, one MUC2 variant is found to be associated with Crohn’s disease. This variant (rs11825977) is a coding variant at chromosome 11 (hg19: chr11:1075920). There is no GWAS marker on MUC2 gene from large meta-analysis. There could be several reasons for that. We will see why this can happen for MUC2 gene, which is one of the most important gel forming secreted mucus protein, forming mucus layer and giving protection to it from invading bacteria or other pathogens.
For Evidence: PMID:17058067
Against Evidence:
Component ID: SSP2
Stage: Protein
SSP Class: Other
Other SSP Class: Missense variant
Modifier: NA
Ontology:
SSP Instance: V116M in MUC2
Confidence Score: 5
Comment: The transcript of this protein is NP_002448:p.Val116Met, substitution of Val by Met. Computational analysis methods classify it as benign impact on protein function. As structural prediction is not available for this mutation, we are not sure exact effect of this mutation on protein structure. After this SSP, there is branching in the next mechanism components with ‘AND’ labeling in the branches as we have indirect evidences for both of them from mouse model.
For Evidence: PMID:16412461, PMID:16169011, PMID:18318598
Against Evidence:
Component ID: SSP3
Stage: Cell
SSP Class: Other
Other SSP Class: Activated Unfolded Protein Response
Modifier: NA
Ontology:
SSP Instance: Misfolded MUC2 at ER
Confidence Score: 3
Comment: Due to altered protein folding rate in mutant MUC2, misfolded/ aberrant assembly of MUC2 was found at Endoplasmic Reticulum in the mouse study. After this SSP, more than one processes get activated and so there is branching in the next mechanism components with ‘AND’ labeling in the branches. Ambiguity continues from the earlier mechanism component.
For Evidence: PMID:18318598
Against Evidence:
Component ID: SSP7
Stage: Cell
SSP Class: Other
Other SSP Class: Cell Product Abundance
Modifier: Increased
Ontology:
SSP Instance: Pro-inflammatory Chemokines, Cytokines
Confidence Score: 5
Comment: Activation of NF-kB pathway leads to higher expression of pro-inflammatory chemokines and cytokines.
For Evidence: PMID:28052300, PMID:23149663
Against Evidence:
Component ID: SSP4
Stage: Cell
SSP Class: Other
Other SSP Class: ER Stress
Modifier: Increased
Ontology:
SSP Instance: Increased XBP1 spliced form
Confidence Score: 5
Comment: Activated unfolded protein response (UPR) will lead to increased ER stress due to accumulation of misfolded MUC2 at ER. XBP1 spliced form will increase compared to unspliced form due to activated UPR. This process will also activate NF-kB pathway, which is already mentioned at MM3A2.
For Evidence: PMID:18318598, PMID:29118753
Against Evidence:
Component ID: SSP5
Stage: Cell
SSP Class: Other
Other SSP Class: Goblet Cell Abundance
Modifier: Decreased
Ontology:
SSP Instance: Increased apoptosis
Confidence Score: 3
Comment: Activated unfolded protein response (UPR) will lead to increase in Apoptosis , due to which Goblet cell number gets reduced. Now for ulcerative colitis, this reduction in Goblet cell number is observed, whereas for Crohn’s patients, this process is not observed. So we used medium confidence here because of the ambiguity in the observation.
For Evidence: PMID:18318598, PMID:29118753
Against Evidence:
Component ID: SSP9
Stage: Protein
SSP Class: Protein Quartenary Structure
Other SSP Class:
Modifier: Altered
Ontology: AURA
SSP Instance: Defective MUC2 mucus network
Confidence Score: 3
Comment: After oligomerization, the large polymers are stored in mucin granulae in the goblet cells before being secreted. The secreted mucus is organized into the firmly adherent mucus that shows a stratified appearance. This mucus layer contains densely packed MUC2 that is bacteria free region. At a certain distance from the epithelium, it is converted into a non-attached loose mucus layer. This is expanded in volumes four times compared to the firm layer, due to the proteolysis within the cysteine rich part of MUC2. Commensal bacteria are usually allowed in this loose mucus layer and get nutrients from glycans. If there is defect in the oligomerization of MUC2, then there will be defect in the MUC2 mucus network as well. Reason for ambiguity continues from the earlier mechanism component.
For Evidence: PMID:20615996
Against Evidence:
Component ID: SSP10
Stage: Cell
SSP Class: Other
Other SSP Class: Defective Barrier Integrity
Modifier: NA
Ontology:
SSP Instance: Loss of MUC2 mucus barrier
Confidence Score: 5
Comment: With increased permeability at the epithelial cell, there will be defective barrier integrity of MUC2 mucus layer.
For Evidence: PMID:22177113
Against Evidence:
Component ID: SSP11
Stage: Phenotype
SSP Class: Other
Other SSP Class: Disease Risk
Modifier: Increased
Ontology:
SSP Instance: Crohn's disease
Confidence Score: 5
Comment: Two branches will rejoin here – both bacterial penetrance and increased inflammation will lead to increased risk of Crohn’s disease
For Evidence: PMID:28636192, PMID:28560287
Against Evidence:
Biomarker(s) Annotations
Mechanism Module (MM) Annotations
Component ID: MM1
Mechanism Class Name: Protein synthesis
Other Mechanism Class Name:
Modifer: NA
Ontology:
Mechanism Instance: Protein synthesis
Confidence Score: 5
Comment: Transcription and translation are believed to be normal for this SNV, and so those steps are telescoped/merged into this one mechanism module.
For Evidence:
Against Evidence:
Component ID: MM2
Mechanism Class Name: Protein Folding Rate
Other Mechanism Class Name:
Modifer: Altered
Ontology:
Mechanism Instance:
Confidence Score: 3
Comment: This particular missense variant is present at the first N-terminal von Willebrand factor (vWF) domain, out of 3 such vWF domains at the N-terminal. These vWF domains are responsible for oligomerization of the protein. There is no direct data, how this mutation is affecting folding rate of the protein. However, in a mouse model study (PMID: 18318598), similar missense variant (Winnie mutation Cys to Tyr at rMUC2-D3) at the third vWF domain of N-terminus is found to be related with the misfolded/aberrant assembly of MUC2 (PMID: 18318598). So we used medium confidence here.
For Evidence: PMID:20615996, PMID:18318598
Against Evidence:
Component ID: MM5
Mechanism Class Name:
Other Mechanism Class Name: Activation of NF-kB pathway
Modifer: NA
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: Activated unfolded protein response will activate NF-kB pathway.
For Evidence: PMID:16581782, PMID:15542827
Against Evidence:
Component ID: MM7
Mechanism Class Name:
Other Mechanism Class Name: Inflammation
Modifer: Increased
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: More inflammation due to higher expression of pro-inflammatory cytokines and chemokines.
For Evidence: PMID:28052300, PMID:23149663
Against Evidence:
Component ID: MM3
Mechanism Class Name:
Other Mechanism Class Name: Accumulation of misfolded MUC2
Modifer: NA
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: Misfolded MUC2 gets accumulated in the ER. Due to which two processes get started in the ER. So there is branching in the next mechanism components with ‘AND’ labeling in the branches.
For Evidence: PMID:18318598
Against Evidence:
Component ID: MM6
Mechanism Class Name:
Other Mechanism Class Name: Secretion of MUC2
Modifer: Decreased
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: If Goblet cell number gets reduced due to apoptosis, less MUC2 is likely to be secreted per goblet cell due to misfolding and the UPR will initiate a translational block. The mucin that is secreted could be incorrectly oligomerised and affect the rheological properties of mucus. Now ER stress can be generated in the cell due to misfolding of MUC2 as well as mutations in XBP1 or other ER chaperones. The resultant UPR could lead to a translational block decreasing MUC2 synthesis and the ER stress could cause MUC2 misfolding, even in the absence of mutations in MUC2, duplicating the ER stress/ reduced mucus barrier phenotype. This could be one of the reasons why MUC2 is not a GWAS locus in any meta-analysis.
For Evidence: PMID:18318598, PMID:29118753
Against Evidence:
Component ID: MM8
Mechanism Class Name:
Other Mechanism Class Name: Oligomerization
Modifer: Altered
Ontology:
Mechanism Instance:
Confidence Score: 3
Comment: The MUC2 mucin encodes a protein of approximately 5200 amino acids. MUC2 has cysteine rich N- and C-terminal parts with four complete von Willebrand Factor (vWF) domains in total. The central PTS domains are rich in serine, threonine, and proline and these domains become heavily O-glycosylated to generate mucin domains. MUC2 forms dimers in the endoplasmic reticulum by disulfide bonds between the C-termini. The dimer is translocated into the Golgi apparatus, where it is O-glycosylated. The MUC2 network is formed by disulfide-linked trimers connecting the N-termini. This V116M variant is present at the N-terminal D1 vWF domain. There is no direct data, how this mutation is participating into oligomerization. However, two other missense variants in mouse model, one at D3 and another at D4 domain are found to be related with the altered oligomerization (hyper-oligomerization) of MUC2 (PMID: 18318598).
For Evidence: PMID:20615996, PMID:18318598
Against Evidence:
Component ID: MM9
Mechanism Class Name:
Other Mechanism Class Name: Mucus layer permeability
Modifer: Increased
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: If there is defect in the mucus layer of MUC2, then it will have increased permeability.
For Evidence: PMID:20615996, PMID:22177113
Against Evidence:
Component ID: MM10
Mechanism Class Name:
Other Mechanism Class Name: Bacterial translocation
Modifer: Increased
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: Through a defective gut wall, more bacteria can invade in, resulting into the higher concentration of bacteria in the tissue beneath the gut wall. At this point MUC1 (membrane-bound mucin) is present at the epithelial cell boundary and supposed to take care of the entering bacteria.
For Evidence: PMID:22177113
Against Evidence:
Component ID: MM4
Mechanism Class Name:
Other Mechanism Class Name: Apoptosis
Modifer: Increased
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: ER stress will lead to increased apoptosis.
For Evidence: PMID:18318598
Against Evidence:
Unknown Mechanism Module (MM) Annotations
Environmental Factor Annotations
Therapeutic Interventions Annotations
Component ID: TT1
Annotation Text: TherapeuticIntervention
Comment: Some local factors may ameliorate the consequences of ER stress; for example, IL-10 has recently been shown to modulate the UPR in intestinal cells by inhibiting nuclear translocation of the ATF6 transcription factor.
For Evidence: PMID:17241871, PMID:18318598, PMID:23123183
Against Evidence: