Phenotypic Mutation 'Winnie' (pdf version)
Allele | Winnie |
Mutation Type |
missense
|
Chromosome | 7 |
Coordinate | 141,286,029 bp (GRCm39) |
Base Change | G ⇒ A (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; MGI: 1339364
|
Mapped | Yes |
Amino Acid Change |
Cysteine changed to Tyrosine
|
Institutional Source | Australian Phenomics Network |
Gene Model |
not available |
AlphaFold |
no structure available at present |
SMART Domains |
Protein: ENSMUSP00000128250 Gene: ENSMUSG00000025515 AA Change: C52Y
Domain | Start | End | E-Value | Type |
Pfam:VWD
|
3 |
72 |
2.3e-14 |
PFAM |
C8
|
107 |
181 |
1.82e-31 |
SMART |
|
Predicted Effect |
probably damaging
PolyPhen 2
Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)
(Using ENSMUST00000167366)
|
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
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
|
SMART Domains |
Protein: ENSMUSP00000140855 Gene: ENSMUSG00000025515 AA Change: C53Y
Domain | Start | End | E-Value | Type |
Pfam:VWD
|
3 |
73 |
5.6e-14 |
PFAM |
C8
|
108 |
182 |
1.4e-35 |
SMART |
|
Predicted Effect |
probably damaging
PolyPhen 2
Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)
(Using ENSMUST00000185823)
|
Predicted Effect |
probably benign
|
Predicted Effect |
probably benign
|
Meta Mutation Damage Score |
Not available |
Is this an essential gene? |
Probably nonessential (E-score: 0.100) |
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 |
Eeyore
|
APN |
7 |
141693356 |
missense |
probably benign |
0.35 |
kenny
|
APN |
7 |
|
nonsense |
|
|
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 | None |
Repository | Australian PhenomeBank: 91
|
Last Updated |
2017-09-13 3:35 PM
by Diantha La Vine
|
Record Created |
2010-02-03 3:47 PM
by Nora G. Smart
|
Record Posted |
2010-02-04 |
Phenotypic Description |
The Winnie 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. Compared with wild-type littermates, Winnie small and large intestines were characterized by fewer goblet cells with smaller thecae, and a reduction in stored and secreted mucin. The cellular distribution and processing of MUC2 was altered with increased cytoplasmic and non-glycosylated MUC2 present in mutant tissue. Animals also displayed increased intestinal epithelial proliferation and apoptosis (Figure 1). Winnie homozygous animals exhibited classical signs of murine colitis, including crypt elongation, neutrophilic infiltrates, goblet cell loss, crypt abscesses, and focal epithelial erosions particularly in the distal large intestine (Figure 2).
In addition to spontaneous inflammation, Winnie mice exhibited increased susceptibility to environmentally induced colitis. Low doses dextran sodium sulfate (0.5% DSS), resulted in rapid weight loss and lethal ulcerating colitis in Winnie by day 30, whereas wild-type mice gained weight and survived for at least 9 weeks. After being administered 2% DSS, Winnie animals 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. After oral 3% DSS for 7 days, Winnie mice exhibited more severe colitis than did wild-type controls, based on rate and extent of weight loss, colon length, changes in stool scores, haematocrit, blood haemoglobin, and leukocyte counts (Figure 3).
Winnie heterozygotes exhibited increased rectal bleeding in response to DSS, indicating that these mutations are not simple recessive mutations under environmental stress. On day 4, only one in five wild-type mice showed rectal bleeding compared to five of five Winnie and five of five heterozygous mice (Figure 3) (1).
|
Nature of Mutation | The Winnie mutation corresponds to a G to A transition at position 2967 of the Muc2 transcript in exon 24 of 47 total exons (2).
2951 CTGCAGGGCACTGTATGTGGTCTGTGTGGGAAC
982 -Y--K--G--T--V--C--G--L--C--G--N-
The mutated nucleotide is indicated in red lettering, and causes a cysteine to tyrosine change at amino acid 987 of the MUC2 protein.
|
Illustration of Mutations in
Gene & Protein |
|
---|
Protein Prediction |
The Winnie mutation alters a conserved cysteine residue located in the third VWF-like domain (Figure 4).
For more information about Muc2, please see the record for Schlendrian.
|
Putative Mechanism |
The Winnie mutation alters a cysteine in the N-terminal D3 domain of MUC2, which has been shown to mediate MUC2 trimerization through the formation of disulfide bonds (3). It is likely that the amino acid change affects MUC2 biosynthesis and assembly, perhaps by disrupting the formation of an important disulfide bond. In Winnie mice, the development of colitis resulted from the aberrant oligomerization (Figure 5) and subsequent accumulation of MUC2 in the ER, which leads to ER stress, triggering of the unfolded protein response (UPR), subsequent inflammation and goblet cell apoptosis (Figure 6). MUC2 in Winnie mice displayed altered N-terminal oligomerization resulting in hyperoligomerization of the protein (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.
|
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 |