Incidental Mutation 'R0025:Mbd4'
ID |
15137 |
Institutional Source |
Beutler Lab
|
Gene Symbol |
Mbd4
|
Ensembl Gene |
ENSMUSG00000030322 |
Gene Name |
methyl-CpG binding domain protein 4 |
Synonyms |
Med1 |
MMRRC Submission |
038320-MU
|
Accession Numbers |
|
Essential gene? |
Probably non essential
(E-score: 0.192)
|
Stock # |
R0025 (G1)
|
Quality Score |
|
Status
|
Validated
|
Chromosome |
6 |
Chromosomal Location |
115817658-115830332 bp(-) (GRCm39) |
Type of Mutation |
critical splice donor site (2 bp from exon) |
DNA Base Change (assembly) |
A to G
at 115821529 bp (GRCm39)
|
Zygosity |
Heterozygous |
Amino Acid Change |
|
Ref Sequence |
ENSEMBL: ENSMUSP00000144930
(fasta)
|
Gene Model |
predicted gene model for transcript(s):
[ENSMUST00000032469]
[ENSMUST00000122816]
[ENSMUST00000147282]
[ENSMUST00000203643]
[ENSMUST00000203643]
|
AlphaFold |
no structure available at present |
Predicted Effect |
probably null
Transcript: ENSMUST00000032469
|
SMART Domains |
Protein: ENSMUSP00000032469 Gene: ENSMUSG00000030322
Domain | Start | End | E-Value | Type |
MBD
|
66 |
142 |
1.25e-29 |
SMART |
low complexity region
|
178 |
196 |
N/A |
INTRINSIC |
PDB:1NGN|A
|
400 |
554 |
1e-111 |
PDB |
SCOP:d1keaa_
|
405 |
545 |
1e-23 |
SMART |
Blast:ENDO3c
|
439 |
514 |
2e-6 |
BLAST |
|
Predicted Effect |
probably benign
Transcript: ENSMUST00000122816
|
SMART Domains |
Protein: ENSMUSP00000145433 Gene: ENSMUSG00000030322
Domain | Start | End | E-Value | Type |
MBD
|
66 |
142 |
7.6e-32 |
SMART |
low complexity region
|
178 |
196 |
N/A |
INTRINSIC |
|
Predicted Effect |
noncoding transcript
Transcript: ENSMUST00000133830
|
Predicted Effect |
probably benign
Transcript: ENSMUST00000147282
|
SMART Domains |
Protein: ENSMUSP00000125619 Gene: ENSMUSG00000030322
Domain | Start | End | E-Value | Type |
MBD
|
45 |
121 |
1.25e-29 |
SMART |
low complexity region
|
157 |
175 |
N/A |
INTRINSIC |
|
Predicted Effect |
noncoding transcript
Transcript: ENSMUST00000203044
|
Predicted Effect |
noncoding transcript
Transcript: ENSMUST00000203620
|
Predicted Effect |
probably null
Transcript: ENSMUST00000203643
|
SMART Domains |
Protein: ENSMUSP00000144930 Gene: ENSMUSG00000030322
Domain | Start | End | E-Value | Type |
Pfam:HhH-GPD
|
56 |
168 |
2.7e-5 |
PFAM |
|
Predicted Effect |
probably null
Transcript: ENSMUST00000203643
|
SMART Domains |
Protein: ENSMUSP00000144930 Gene: ENSMUSG00000030322
Domain | Start | End | E-Value | Type |
Pfam:HhH-GPD
|
56 |
168 |
2.7e-5 |
PFAM |
|
Meta Mutation Damage Score |
0.9594 |
Coding Region Coverage |
- 1x: 75.6%
- 3x: 62.5%
- 10x: 33.3%
- 20x: 15.9%
|
Validation Efficiency |
95% (69/73) |
MGI Phenotype |
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] The protein encoded by this gene is a member of a family of nuclear proteins related by the presence of a methyl-CpG binding domain (MBD). These proteins are capable of binding specifically to methylated DNA, and some members can also repress transcription from methylated gene promoters. This protein contains an MBD domain at the N-terminus that functions both in binding to methylated DNA and in protein interactions and a C-terminal mismatch-specific glycosylase domain that is involved in DNA repair. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jan 2013] PHENOTYPE: Mice homozygous for a null allele have an increased rate of DNA mutation, specifically at CpGs. [provided by MGI curators]
|
Allele List at MGI |
All alleles(8) : Targeted(6) Gene trapped(2)
|
Other mutations in this stock |
Total: 40 list
Gene | Ref | Var | Chr/Loc | Mutation | Predicted Effect | Zygosity |
Acsm1 |
A |
T |
7: 119,257,538 (GRCm39) |
T435S |
probably damaging |
Het |
Agtpbp1 |
G |
A |
13: 59,648,014 (GRCm39) |
T602I |
probably benign |
Het |
Ahnak2 |
T |
A |
12: 112,749,154 (GRCm39) |
D231V |
probably damaging |
Het |
Ampd3 |
G |
A |
7: 110,392,876 (GRCm39) |
D215N |
probably benign |
Het |
Ate1 |
A |
G |
7: 130,105,523 (GRCm39) |
S332P |
probably damaging |
Het |
Ces1f |
T |
C |
8: 93,998,513 (GRCm39) |
E161G |
probably benign |
Het |
Ces2g |
A |
G |
8: 105,692,628 (GRCm39) |
|
probably benign |
Het |
Cntnap4 |
T |
G |
8: 113,529,796 (GRCm39) |
L668R |
probably damaging |
Het |
Col1a2 |
G |
A |
6: 4,518,822 (GRCm39) |
|
probably benign |
Het |
Csf1 |
A |
G |
3: 107,655,960 (GRCm39) |
V245A |
probably benign |
Het |
Ctss |
A |
G |
3: 95,457,448 (GRCm39) |
Y302C |
probably damaging |
Het |
Dbt |
C |
T |
3: 116,328,432 (GRCm39) |
H158Y |
probably benign |
Het |
Dennd6b |
T |
C |
15: 89,070,386 (GRCm39) |
I428V |
probably benign |
Het |
Dnah9 |
G |
A |
11: 65,860,781 (GRCm39) |
|
probably benign |
Het |
Dock3 |
G |
T |
9: 106,790,467 (GRCm39) |
Q1419K |
possibly damaging |
Het |
Enpp6 |
A |
G |
8: 47,519,035 (GRCm39) |
K268E |
probably damaging |
Het |
Eps15l1 |
T |
G |
8: 73,135,341 (GRCm39) |
|
probably benign |
Het |
Gm10800 |
C |
A |
2: 98,496,925 (GRCm39) |
M209I |
probably benign |
Het |
Herc3 |
C |
T |
6: 58,851,293 (GRCm39) |
P514L |
probably damaging |
Het |
Mark2 |
T |
C |
19: 7,263,287 (GRCm39) |
D160G |
probably damaging |
Het |
Mink1 |
T |
C |
11: 70,503,868 (GRCm39) |
W1263R |
probably damaging |
Het |
Nlrp14 |
A |
T |
7: 106,780,465 (GRCm39) |
|
probably benign |
Het |
Osbp |
T |
C |
19: 11,961,322 (GRCm39) |
Y454H |
probably damaging |
Het |
Pak5 |
T |
C |
2: 135,942,704 (GRCm39) |
K479E |
possibly damaging |
Het |
Pard3 |
C |
A |
8: 127,888,058 (GRCm39) |
D73E |
probably damaging |
Het |
Pmp22 |
A |
T |
11: 63,049,076 (GRCm39) |
|
probably null |
Het |
Scn4a |
C |
T |
11: 106,215,386 (GRCm39) |
V1197I |
probably benign |
Het |
Slc36a2 |
A |
G |
11: 55,053,621 (GRCm39) |
L339P |
probably damaging |
Het |
Smg1 |
G |
A |
7: 117,811,666 (GRCm39) |
T104I |
possibly damaging |
Het |
Stx18 |
T |
A |
5: 38,249,908 (GRCm39) |
Y74N |
probably damaging |
Het |
Stxbp5 |
A |
T |
10: 9,638,492 (GRCm39) |
H1102Q |
probably damaging |
Het |
Tom1l2 |
T |
C |
11: 60,120,960 (GRCm39) |
K450E |
probably damaging |
Het |
Tpo |
T |
C |
12: 30,150,389 (GRCm39) |
Q497R |
probably benign |
Het |
Tsc2 |
A |
G |
17: 24,849,978 (GRCm39) |
|
probably benign |
Het |
Tut7 |
A |
T |
13: 59,953,142 (GRCm39) |
D99E |
probably benign |
Het |
Vit |
G |
A |
17: 78,907,264 (GRCm39) |
G229R |
probably benign |
Het |
Vwf |
T |
A |
6: 125,659,775 (GRCm39) |
I2658N |
probably benign |
Het |
Wdr36 |
T |
A |
18: 32,992,360 (GRCm39) |
D632E |
probably damaging |
Het |
Zfp654 |
A |
G |
16: 64,605,181 (GRCm39) |
V466A |
probably benign |
Het |
Zfp941 |
T |
C |
7: 140,393,185 (GRCm39) |
D58G |
probably benign |
Het |
|
Other mutations in Mbd4 |
Allele | Source | Chr | Coord | Type | Predicted Effect | PPH Score |
IGL01516:Mbd4
|
APN |
6 |
115,826,491 (GRCm39) |
missense |
probably damaging |
0.99 |
IGL01545:Mbd4
|
APN |
6 |
115,827,758 (GRCm39) |
missense |
probably damaging |
1.00 |
IGL01657:Mbd4
|
APN |
6 |
115,826,598 (GRCm39) |
missense |
probably damaging |
0.99 |
IGL02406:Mbd4
|
APN |
6 |
115,825,986 (GRCm39) |
missense |
possibly damaging |
0.96 |
E0370:Mbd4
|
UTSW |
6 |
115,826,116 (GRCm39) |
missense |
possibly damaging |
0.91 |
R0025:Mbd4
|
UTSW |
6 |
115,821,529 (GRCm39) |
critical splice donor site |
probably null |
|
R0538:Mbd4
|
UTSW |
6 |
115,826,443 (GRCm39) |
missense |
probably damaging |
0.99 |
R2085:Mbd4
|
UTSW |
6 |
115,825,918 (GRCm39) |
missense |
probably benign |
0.01 |
R4405:Mbd4
|
UTSW |
6 |
115,826,076 (GRCm39) |
missense |
possibly damaging |
0.92 |
R4464:Mbd4
|
UTSW |
6 |
115,826,463 (GRCm39) |
missense |
probably damaging |
0.99 |
R4780:Mbd4
|
UTSW |
6 |
115,826,345 (GRCm39) |
missense |
probably benign |
|
R4782:Mbd4
|
UTSW |
6 |
115,822,283 (GRCm39) |
missense |
possibly damaging |
0.49 |
R4799:Mbd4
|
UTSW |
6 |
115,822,283 (GRCm39) |
missense |
probably benign |
0.26 |
R4814:Mbd4
|
UTSW |
6 |
115,826,260 (GRCm39) |
missense |
possibly damaging |
0.85 |
R4860:Mbd4
|
UTSW |
6 |
115,825,887 (GRCm39) |
missense |
possibly damaging |
0.51 |
R4860:Mbd4
|
UTSW |
6 |
115,825,887 (GRCm39) |
missense |
possibly damaging |
0.51 |
R4976:Mbd4
|
UTSW |
6 |
115,827,685 (GRCm39) |
missense |
possibly damaging |
0.95 |
R5126:Mbd4
|
UTSW |
6 |
115,825,929 (GRCm39) |
splice site |
probably null |
|
R5202:Mbd4
|
UTSW |
6 |
115,826,363 (GRCm39) |
missense |
probably damaging |
0.96 |
R5485:Mbd4
|
UTSW |
6 |
115,827,679 (GRCm39) |
missense |
probably benign |
0.21 |
R6179:Mbd4
|
UTSW |
6 |
115,822,386 (GRCm39) |
missense |
probably benign |
0.00 |
R6661:Mbd4
|
UTSW |
6 |
115,826,116 (GRCm39) |
nonsense |
probably null |
|
R7008:Mbd4
|
UTSW |
6 |
115,827,685 (GRCm39) |
missense |
possibly damaging |
0.95 |
R7244:Mbd4
|
UTSW |
6 |
115,821,564 (GRCm39) |
missense |
probably benign |
0.00 |
R7723:Mbd4
|
UTSW |
6 |
115,822,324 (GRCm39) |
missense |
possibly damaging |
0.47 |
R7755:Mbd4
|
UTSW |
6 |
115,821,546 (GRCm39) |
missense |
probably damaging |
0.99 |
R7837:Mbd4
|
UTSW |
6 |
115,826,500 (GRCm39) |
missense |
probably benign |
0.20 |
R8032:Mbd4
|
UTSW |
6 |
115,821,594 (GRCm39) |
missense |
probably damaging |
1.00 |
R9707:Mbd4
|
UTSW |
6 |
115,826,559 (GRCm39) |
missense |
probably benign |
0.04 |
|
Protein Function and Prediction |
MBD4 (alternatively, methyl-CpG-binding endonuclease; MED1) is a mismatch-specific DNA N-glycosylase active on thymine, uracil, 5-fluorouracil and, weakly, 3,N4-ethenocytosine paired with guanine [(1;2); reviewed in (3)]. The thymine and uracil glycosylase activity of MBD1 prefers G:T and G:U mismatches located in the context of methylated and unmethylated CpG sites (1;2). MBD4 binds to methylated (fully and hemimethylated) DNA to mediate the effects of DNA methylation (4;5). MBD4 also has endonuclease activity on supercoiled plasmid DNA in vitro (5). MBD4 upregulation is proposed to be involved in prenatal remethylation in the male and female germlines (6). MBD4 is a candidate tumor suppressor gene and mutations have been linked to human colorectal, gastric, endometrial, and pancreatic cancer [reviewed in (3)].
|
Expression/Localization |
MBD4 is expressed in somatic tissues (it is proposed to be ubiquitously expressed) and colocalizes with foci of heavily methylated satellite DNA (4).
|
Background |
Mbd4tm1Bird/tm1Bird; MGI:2183491
involves: 129P2/OlaHsd * C57BL/6
In homozygotes the frequency of of C --> T transitions at CpG sites was increased by a factor of three. On a cancer-susceptible Apc(Min/+) background, homozygous mice showed accelerated tumor formation with CpG --> TpG mutations in the Apc gene. Thus MBD4 suppresses CpG mutability and tumorigenesis in vivo (7).
Mbd4tm1Wed/tm1Wed; MGI:2447611
B6.Cg-Mbd4tm1Wed/J
Homozygotes have abnormal DNA methylation (8).
Mbd4tm1Wed/tm1Wed; MGI:2447611
involves: 129/Sv * C57BL/6 * SJL
Heterozygous and homozygous Mbd4 mutant mice develop normally and do not show increased cancer susceptibility or reduced survival (9). Mbd4 inactivation resulted in a 2- to 3-fold increase in C-->T transition mutations at CpG sequences in splenocytes and epithelial cells of the small intestinal mucosa (9).
Mbd4tm2Abc/tm2Abc; MGI:2684310
involves: 129/Sv * 129X1/SvJ * C57BL/6
Homozygous embryonic fibroblasts failed to undergo G2-M cell cycle arrest and apoptosis upon treatment with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), 5-fluorouracil and irinotecan (10).
|
References |
1. Hendrich, B., Hardeland, U., Ng, H. H., Jiricny, J., and Bird, A. (1999) The Thymine Glycosylase MBD4 can Bind to the Product of Deamination at Methylated CpG Sites. Nature. 401, 301-304.
2. Petronzelli, F., Riccio, A., Markham, G. D., Seeholzer, S. H., Stoerker, J., Genuardi, M., Yeung, A. T., Matsumoto, Y., and Bellacosa, A. (2000) Biphasic Kinetics of the Human DNA Repair Protein MED1 (MBD4), a Mismatch-Specific DNA N-Glycosylase. J Biol Chem. 275, 32422-32429.
5. Bellacosa, A., Cicchillitti, L., Schepis, F., Riccio, A., Yeung, A. T., Matsumoto, Y., Golemis, E. A., Genuardi, M., and Neri, G. (1999) MED1, a Novel Human Methyl-CpG-Binding Endonuclease, Interacts with DNA Mismatch Repair Protein MLH1. Proc Natl Acad Sci U S A. 96, 3969-3974.
6. Galetzka, D., Weis, E., Tralau, T., Seidmann, L., and Haaf, T. (2007) Sex-Specific Windows for High mRNA Expression of DNA Methyltransferases 1 and 3A and Methyl-CpG-Binding Domain Proteins 2 and 4 in Human Fetal Gonads. Mol Reprod Dev. 74, 233-241.
7. Millar, C. B., Guy, J., Sansom, O. J., Selfridge, J., MacDougall, E., Hendrich, B., Keightley, P. D., Bishop, S. M., Clarke, A. R., and Bird, A. (2002) Enhanced CpG Mutability and Tumorigenesis in MBD4-Deficient Mice. Science. 297, 403-405.
8. Hitoshi, S., Ishino, Y., Kumar, A., Jasmine, S., Tanaka, K. F., Kondo, T., Kato, S., Hosoya, T., Hotta, Y., and Ikenaka, K. (2011) Mammalian Gcm Genes Induce Hes5 Expression by Active DNA Demethylation and Induce Neural Stem Cells. Nat Neurosci. 14, 957-964.
9. Wong, E., Yang, K., Kuraguchi, M., Werling, U., Avdievich, E., Fan, K., Fazzari, M., Jin, B., Brown, A. M., Lipkin, M., and Edelmann, W. (2002) Mbd4 Inactivation Increases Cright-arrowT Transition Mutations and Promotes Gastrointestinal Tumor Formation. Proc Natl Acad Sci U S A. 99, 14937-14942.
10. Cortellino, S., Turner, D., Masciullo, V., Schepis, F., Albino, D., Daniel, R., Skalka, A. M., Meropol, N. J., Alberti, C., Larue, L., and Bellacosa, A. (2003) The Base Excision Repair Enzyme MED1 Mediates DNA Damage Response to Antitumor Drugs and is Associated with Mismatch Repair System Integrity. Proc Natl Acad Sci U S A. 100, 15071-15076.
|
Posted On |
2012-12-12 |
Science Writer |
Anne Murray |