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) question?
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

DomainStartEndE-ValueType
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

DomainStartEndE-ValueType
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

DomainStartEndE-ValueType
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

DomainStartEndE-ValueType
Pfam:HhH-GPD 56 168 2.7e-5 PFAM
Predicted Effect probably null
Transcript: ENSMUST00000203643
SMART Domains Protein: ENSMUSP00000144930
Gene: ENSMUSG00000030322

DomainStartEndE-ValueType
Pfam:HhH-GPD 56 168 2.7e-5 PFAM
Meta Mutation Damage Score 0.9594 question?
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
GeneRefVarChr/LocMutationPredicted EffectZygosity
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
AlleleSourceChrCoordTypePredicted EffectPPH 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
Posted On 2012-12-12
Science Writer Anne Murray