Phenotypic Mutation 'Eeyore' (pdf version)
Allele | Eeyore |
Mutation Type |
missense
|
Chromosome | 7 |
Coordinate | 141,693,356 bp (GRCm38) |
Base Change | T ⇒ C (forward strand) |
Gene |
Muc2
|
Gene Name | mucin 2 |
Synonym(s) | 2010015E03Rik |
Chromosomal Location |
141,276,583-141,308,428 bp (+) (GRCm39)
|
MGI Phenotype |
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes a member of the mucin protein family. Mucins are high molecular weight glycoproteins produced by many epithelial tissues. The protein encoded by this gene is secreted and forms an insoluble mucous barrier that protects the gut lumen. The protein polymerizes into a gel of which 80% is composed of oligosaccharide side chains by weight. The protein features a central domain containing tandem repeats rich in threonine and proline that varies between 50 and 115 copies in different individuals. Downregulation of this gene has been observed in patients with Crohn disease and ulcerative colitis. [provided by RefSeq, Oct 2016] 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. [provided by MGI curators]
|
Accession Number | NCBI RefSeq: NM_023566.2; MGI: 1339364
|
Mapped | Yes |
Amino Acid Change |
Methionine changed to Isoleucine
|
Institutional Source | Australian Phenomics Network |
Gene Model |
not available |
AlphaFold |
no structure available at present |
SMART Domains |
Protein: ENSMUSP00000136692 Gene: ENSMUSG00000025515
Domain | Start | End | E-Value | Type |
C8
|
11 |
85 |
1.61e-32 |
SMART |
Blast:VWD
|
102 |
128 |
5e-8 |
BLAST |
|
Predicted Effect |
probably benign
|
SMART Domains |
Protein: ENSMUSP00000141040 Gene: ENSMUSG00000025515 AA Change: M194I
Domain | Start | End | E-Value | Type |
low complexity region
|
5 |
18 |
N/A |
INTRINSIC |
VWD
|
20 |
183 |
1.5e-40 |
SMART |
C8
|
216 |
290 |
3.9e-15 |
SMART |
Pfam:TIL
|
293 |
349 |
5.4e-10 |
PFAM |
VWC
|
351 |
411 |
7e-4 |
SMART |
VWD
|
378 |
542 |
8.8e-44 |
SMART |
C8
|
579 |
653 |
1.2e-36 |
SMART |
SCOP:d1coua_
|
654 |
728 |
4e-8 |
SMART |
VWC_def
|
820 |
865 |
1.3e-2 |
SMART |
|
Predicted Effect |
probably benign
PolyPhen 2
Score 0.353 (Sensitivity: 0.90; Specificity: 0.89)
(Using ENSMUST00000185406)
|
Meta Mutation Damage Score |
Not available |
Is this an essential gene? |
Probably nonessential (E-score: 0.099) |
Phenotypic Category |
Autosomal Semidominant |
Candidate Explorer Status |
loading ... |
Single pedigree Linkage Analysis Data
|
|
Penetrance | 100% |
Alleles Listed at MGI | All alleles( 7) : Targeted, knock-out( 1) Targeted, other( 2) Chemically induced( 4)
|
Lab Alleles |
Allele | Source | Chr | Coord | Type | Predicted Effect | PPH Score |
kenny
|
APN |
7 |
|
nonsense |
|
|
Winnie
|
APN |
7 |
141286029 |
missense |
probably damaging |
1.00 |
IGL01303:Muc2
|
APN |
7 |
141306132 |
missense |
probably benign |
|
IGL01482:Muc2
|
APN |
7 |
141307797 |
missense |
probably damaging |
0.96 |
IGL01875:Muc2
|
APN |
7 |
141306477 |
missense |
probably damaging |
0.99 |
IGL02088:Muc2
|
APN |
7 |
141305241 |
missense |
probably damaging |
1.00 |
IGL02415:Muc2
|
APN |
7 |
141305609 |
nonsense |
probably null |
|
IGL02548:Muc2
|
APN |
7 |
141305594 |
missense |
probably damaging |
1.00 |
IGL02836:Muc2
|
APN |
7 |
141300450 |
unclassified |
probably benign |
|
IGL03196:Muc2
|
APN |
7 |
141301367 |
missense |
probably damaging |
0.97 |
Muskatenwein
|
UTSW |
7 |
141307176 |
missense |
unknown |
|
nomoco
|
UTSW |
7 |
141307456 |
missense |
probably damaging |
1.00 |
Schlendrian
|
UTSW |
7 |
141281925 |
missense |
probably damaging |
1.00 |
Seco
|
UTSW |
7 |
141284976 |
missense |
probably damaging |
1.00 |
BB001:Muc2
|
UTSW |
7 |
141281631 |
missense |
probably damaging |
1.00 |
BB011:Muc2
|
UTSW |
7 |
141281631 |
missense |
probably damaging |
1.00 |
E0370:Muc2
|
UTSW |
7 |
141282598 |
missense |
probably damaging |
1.00 |
R0127:Muc2
|
UTSW |
7 |
141302691 |
missense |
probably benign |
0.00 |
R0179:Muc2
|
UTSW |
7 |
141302708 |
missense |
probably damaging |
1.00 |
R0201:Muc2
|
UTSW |
7 |
141699185 |
frame shift |
probably null |
|
R0299:Muc2
|
UTSW |
7 |
141306466 |
missense |
probably damaging |
1.00 |
R0547:Muc2
|
UTSW |
7 |
141699185 |
frame shift |
probably null |
|
R0699:Muc2
|
UTSW |
7 |
141306037 |
missense |
probably damaging |
1.00 |
R0900:Muc2
|
UTSW |
7 |
141699185 |
frame shift |
probably null |
|
R1348:Muc2
|
UTSW |
7 |
141699185 |
frame shift |
probably null |
|
R1466:Muc2
|
UTSW |
7 |
141302711 |
missense |
probably damaging |
1.00 |
R1466:Muc2
|
UTSW |
7 |
141302711 |
missense |
probably damaging |
1.00 |
R1625:Muc2
|
UTSW |
7 |
141283405 |
missense |
probably damaging |
1.00 |
R2010:Muc2
|
UTSW |
7 |
141287444 |
missense |
probably damaging |
0.99 |
R2149:Muc2
|
UTSW |
7 |
141699185 |
frame shift |
probably null |
|
R2163:Muc2
|
UTSW |
7 |
141699185 |
frame shift |
probably null |
|
R3008:Muc2
|
UTSW |
7 |
141281347 |
missense |
possibly damaging |
0.93 |
R3110:Muc2
|
UTSW |
7 |
141299225 |
unclassified |
probably benign |
|
R3112:Muc2
|
UTSW |
7 |
141299225 |
unclassified |
probably benign |
|
R3424:Muc2
|
UTSW |
7 |
141279595 |
missense |
probably damaging |
0.99 |
R3786:Muc2
|
UTSW |
7 |
141283590 |
missense |
probably benign |
0.01 |
R3854:Muc2
|
UTSW |
7 |
141308081 |
missense |
probably damaging |
1.00 |
R3964:Muc2
|
UTSW |
7 |
141286233 |
missense |
probably benign |
0.17 |
R3965:Muc2
|
UTSW |
7 |
141286233 |
missense |
probably benign |
0.17 |
R3966:Muc2
|
UTSW |
7 |
141286233 |
missense |
probably benign |
0.17 |
R3973:Muc2
|
UTSW |
7 |
141300541 |
unclassified |
probably benign |
|
R3974:Muc2
|
UTSW |
7 |
141300541 |
unclassified |
probably benign |
|
R3976:Muc2
|
UTSW |
7 |
141300541 |
unclassified |
probably benign |
|
R4327:Muc2
|
UTSW |
7 |
141281577 |
missense |
probably damaging |
0.96 |
R4694:Muc2
|
UTSW |
7 |
141306082 |
missense |
probably damaging |
1.00 |
R4764:Muc2
|
UTSW |
7 |
141299345 |
missense |
possibly damaging |
0.88 |
R4769:Muc2
|
UTSW |
7 |
141286260 |
critical splice donor site |
probably null |
|
R4798:Muc2
|
UTSW |
7 |
141307877 |
missense |
probably benign |
0.01 |
R4900:Muc2
|
UTSW |
7 |
141303280 |
missense |
probably benign |
0.32 |
R5383:Muc2
|
UTSW |
7 |
141307456 |
missense |
probably damaging |
1.00 |
R5489:Muc2
|
UTSW |
7 |
141305169 |
missense |
probably benign |
0.00 |
R5615:Muc2
|
UTSW |
7 |
141277446 |
missense |
probably damaging |
1.00 |
R5856:Muc2
|
UTSW |
7 |
141299381 |
unclassified |
probably benign |
|
R5919:Muc2
|
UTSW |
7 |
141281171 |
missense |
probably damaging |
0.97 |
R5953:Muc2
|
UTSW |
7 |
141287951 |
missense |
probably damaging |
0.96 |
R5979:Muc2
|
UTSW |
7 |
141305143 |
missense |
probably damaging |
0.99 |
R5979:Muc2
|
UTSW |
7 |
141283493 |
splice site |
probably null |
|
R6175:Muc2
|
UTSW |
7 |
141282875 |
missense |
probably damaging |
1.00 |
R6213:Muc2
|
UTSW |
7 |
141305151 |
missense |
probably damaging |
1.00 |
R6281:Muc2
|
UTSW |
7 |
141306140 |
missense |
probably damaging |
1.00 |
R6321:Muc2
|
UTSW |
7 |
141287397 |
missense |
probably benign |
0.28 |
R6390:Muc2
|
UTSW |
7 |
141305883 |
missense |
probably damaging |
0.97 |
R6485:Muc2
|
UTSW |
7 |
141300473 |
unclassified |
probably benign |
|
R6582:Muc2
|
UTSW |
7 |
141282941 |
missense |
probably benign |
0.00 |
R6683:Muc2
|
UTSW |
7 |
141305214 |
missense |
probably benign |
0.38 |
R6896:Muc2
|
UTSW |
7 |
141306432 |
missense |
possibly damaging |
0.48 |
R6906:Muc2
|
UTSW |
7 |
141284976 |
missense |
probably damaging |
1.00 |
R6924:Muc2
|
UTSW |
7 |
141284077 |
missense |
possibly damaging |
0.87 |
R7040:Muc2
|
UTSW |
7 |
141305194 |
missense |
unknown |
|
R7222:Muc2
|
UTSW |
7 |
141290758 |
missense |
|
|
R7251:Muc2
|
UTSW |
7 |
141278965 |
missense |
possibly damaging |
0.91 |
R7282:Muc2
|
UTSW |
7 |
141306481 |
missense |
|
|
R7315:Muc2
|
UTSW |
7 |
141276645 |
missense |
probably damaging |
0.99 |
R7421:Muc2
|
UTSW |
7 |
141301863 |
missense |
|
|
R7556:Muc2
|
UTSW |
7 |
141307439 |
missense |
|
|
R7651:Muc2
|
UTSW |
7 |
141290750 |
missense |
|
|
R7710:Muc2
|
UTSW |
7 |
141287452 |
missense |
possibly damaging |
0.92 |
R7776:Muc2
|
UTSW |
7 |
141290942 |
missense |
|
|
R7813:Muc2
|
UTSW |
7 |
141282543 |
splice site |
probably null |
|
R7843:Muc2
|
UTSW |
7 |
141281662 |
missense |
probably benign |
0.03 |
R7869:Muc2
|
UTSW |
7 |
141303471 |
missense |
|
|
R7924:Muc2
|
UTSW |
7 |
141281631 |
missense |
probably damaging |
1.00 |
R7993:Muc2
|
UTSW |
7 |
141308173 |
missense |
|
|
R8053:Muc2
|
UTSW |
7 |
141284575 |
missense |
probably benign |
0.01 |
R8068:Muc2
|
UTSW |
7 |
141298422 |
missense |
|
|
R8099:Muc2
|
UTSW |
7 |
141299175 |
splice site |
probably null |
|
R8192:Muc2
|
UTSW |
7 |
141305215 |
missense |
|
|
R8194:Muc2
|
UTSW |
7 |
141290801 |
missense |
|
|
R8545:Muc2
|
UTSW |
7 |
141306130 |
missense |
unknown |
|
R8701:Muc2
|
UTSW |
7 |
141281850 |
missense |
probably damaging |
1.00 |
R8883:Muc2
|
UTSW |
7 |
141287469 |
missense |
probably damaging |
0.98 |
R8894:Muc2
|
UTSW |
7 |
141280758 |
missense |
probably damaging |
1.00 |
R8905:Muc2
|
UTSW |
7 |
141279643 |
missense |
probably benign |
0.00 |
R9024:Muc2
|
UTSW |
7 |
141287936 |
missense |
probably damaging |
0.98 |
R9032:Muc2
|
UTSW |
7 |
141287058 |
missense |
probably damaging |
1.00 |
R9085:Muc2
|
UTSW |
7 |
141287058 |
missense |
probably damaging |
1.00 |
R9091:Muc2
|
UTSW |
7 |
141290816 |
missense |
|
|
R9104:Muc2
|
UTSW |
7 |
141286224 |
missense |
probably damaging |
1.00 |
R9114:Muc2
|
UTSW |
7 |
141287983 |
nonsense |
probably null |
|
R9270:Muc2
|
UTSW |
7 |
141290816 |
missense |
|
|
R9297:Muc2
|
UTSW |
7 |
141302759 |
missense |
|
|
R9325:Muc2
|
UTSW |
7 |
141298559 |
missense |
|
|
R9354:Muc2
|
UTSW |
7 |
141307157 |
missense |
|
|
R9386:Muc2
|
UTSW |
7 |
141279389 |
missense |
probably damaging |
1.00 |
R9529:Muc2
|
UTSW |
7 |
141287453 |
missense |
possibly damaging |
0.55 |
R9550:Muc2
|
UTSW |
7 |
141308242 |
missense |
probably damaging |
1.00 |
R9583:Muc2
|
UTSW |
7 |
141300559 |
missense |
|
|
R9607:Muc2
|
UTSW |
7 |
141305190 |
missense |
|
|
R9646:Muc2
|
UTSW |
7 |
141276643 |
missense |
probably benign |
|
R9651:Muc2
|
UTSW |
7 |
141288014 |
missense |
probably damaging |
0.99 |
R9774:Muc2
|
UTSW |
7 |
141285811 |
missense |
probably benign |
|
R9784:Muc2
|
UTSW |
7 |
141280785 |
nonsense |
probably null |
|
Z1176:Muc2
|
UTSW |
7 |
141300451 |
missense |
|
|
Z1177:Muc2
|
UTSW |
7 |
141298531 |
missense |
|
|
|
Mode of Inheritance |
Autosomal Semidominant |
Local Stock | Sperm, gDNA |
Repository | |
Last Updated |
2017-09-13 3:37 PM
by Diantha La Vine
|
Record Created |
2010-02-03 3:48 PM
by Nora G. Smart
|
Record Posted |
2010-02-04 |
Phenotypic Description |
The Eeyore phenotype was identified amongst the G3 progeny of an ENU-treated C57BL/6 founder by their visible phenotype of spontaneous watery diarrhoea and high incidence of rectal bleeding and prolapse, suggestive of ulcerative colitis. Due to the similarities in phenotype between Winnie and Eeyore animals, these strains were crossed and noncomplementation was demonstrated indicating that both Winnie and Eeyore contained mutations within the same gene. Eeyore homozgyous animals exhibited a slightly more severe phenotype than Winnie homozygotes, with 40% dead by 1 year of age compared to 25% of Winnie animals having died. Compared with wild-type littermates, Eeyore small and large intestines were characterized by fewer goblet cells with smaller thecae, and a reduction in stored and secreted mucin. Eeyore homozygous mice also displayed increased intestinal epithelial proliferation and apoptosis (Figure 1).
In addition to spontaneous inflammation, Eeyore mice exhibited increased susceptibility to environmentally induced colitis. After being administered 2% of the luminal toxin dextran sodium sulfate (DSS), Eeyore showed earlier faecal occult blood than did wild-type mice (after exclusion of mice with spontaneous rectal bleeding or prolapses), and higher histological colitis scores after 3 days, whereas by day 7 colitis scores in wild-type mice were closer to those of mutant mice (Figure 2) (1).
|
Nature of Mutation | The Eeyore mutation corresponds to a T to C transition at position 5251 of the Muc2 transcript in exon 34 of 47 total exons (2).
5234 TCCTACAATGGCCTTTCTTTCTCCATCCGGCTG
1743 -S--Y--N--G--L--S--F--S--I--R--L-
The mutated nucleotide is indicated in red lettering, and causes a serine to proline change at amino acid 1748 of the MUC2 protein.
|
Illustration of Mutations in
Gene & Protein |
|
---|
Protein Prediction |
The Eeyore mutation alters a serine residue located in the fourth VWF-like domain (Figure 3).
For more information about Muc2, please see the record for Schlendrian.
|
Putative Mechanism | The Eeyore mutation alters a serine in the C-terminal VWF-like D4 domain of MUC2. The phenotype of Eeyore mutant mice suggests that this residue may affect MUC2 biosynthesis and assembly. While the D3 and CK domains of MUC2 have been implicated in trimerization and dimerization of MUC2 molecules through the formation of disulfide bonds (3-5), sequences present in the D4 domain may also play a role in intermolecular interactions between MUC2 molecules. The D4 domain contains a GDPH autocatalytic cleavage site with cleavage occurring between the D and P residues (6). 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. Although the serine residue affected by the Eeyore mutation is not located within this sequence, it is possible that the alteration of this residue may affect cleavage at the GDPH site. In Eeyore mice, the development of colitis resulted from the aberrant oligomerization and subsequent accumulation of MUC2 in the endoplasmic reticulum (ER), which leads to ER stress, triggering of the unfolded protein response (UPR), subsequent inflammation and goblet cell apoptosis (Figure 4) (1).
|
Primers |
Primers cannot be located by automatic search.
|
References | 1. Heazlewood, C. K., Cook, M. C., Eri, R., Price, G. R., Tauro, S. B., Taupin, D., Thornton, D. J., Png, C. W., Crockford, T. L., Cornall, R. J., Adams, R., Kato, M., Nelms, K. A., Hong, N. A., Florin, T. H., Goodnow, C. C., and McGuckin, M. A. (2008) Aberrant Mucin Assembly in Mice Causes Endoplasmic Reticulum Stress and Spontaneous Inflammation Resembling Ulcerative Colitis. PLoS Med. 5, e54.
2. Escande, F., Porchet, N., Bernigaud, A., Petitprez, D., Aubert, J. P., and Buisine, M. P. (2004) The Mouse Secreted Gel-Forming Mucin Gene Cluster. Biochim. Biophys. Acta. 1676, 240-250.
3. Godl, K., Johansson, M. E., Lidell, M. E., Morgelin, M., Karlsson, H., Olson, F. J., Gum, J. R.,Jr, Kim, Y. S., and Hansson, G. C. (2002) The N Terminus of the MUC2 Mucin Forms Trimers that are Held Together within a Trypsin-Resistant Core Fragment. J. Biol. Chem. 277, 47248-47256.
5. Lidell, M. E., Johansson, M. E., Morgelin, M., Asker, N., Gum, J. R.,Jr, Kim, Y. S., and Hansson, G. C. (2003) The Recombinant C-Terminus of the Human MUC2 Mucin Forms Dimers in Chinese-Hamster Ovary Cells and Heterodimers with Full-Length MUC2 in LS 174T Cells. Biochem. J. 372, 335-345.
|
Science Writers | Nora G. Smart |
Illustrators | Diantha La Vine |
Authors | Chad K. Heazlewood, Matthew C. Cook, Rajaraman Eri, Gareth R. Price, Sharyn B. Tauro, Douglas Taupin, David J. Thornton, Chin Wen Png, Tanya L. Crockford, Richard J. Cornall, Rachel Adams, Masato Kato, Keats A. Nelms, Nancy A. Hong, Timothy H. J. Florin, Christopher C. Goodnow and Michael A. McGuckin |