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MBD4 methyl-CpG binding domain 4, DNA glycosylase [ Homo sapiens (human) ]

Gene ID: 8930, updated on 16-Apr-2024

Summary

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Official Symbol
MBD4provided by HGNC
Official Full Name
methyl-CpG binding domain 4, DNA glycosylaseprovided by HGNC
Primary source
HGNC:HGNC:6919
See related
Ensembl:ENSG00000129071 MIM:603574; AllianceGenome:HGNC:6919
Gene type
protein coding
RefSeq status
REVIEWED
Organism
Homo sapiens
Lineage
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as
MED1; UVM1; TPDS2
Summary
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]
Expression
Ubiquitous expression in lymph node (RPKM 27.7), spleen (RPKM 17.6) and 25 other tissues See more
Orthologs
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Genomic context

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Location:
3q21.3
Exon count:
8
Annotation release Status Assembly Chr Location
RS_2023_10 current GRCh38.p14 (GCF_000001405.40) 3 NC_000003.12 (129430947..129439948, complement)
RS_2023_10 current T2T-CHM13v2.0 (GCF_009914755.1) 3 NC_060927.1 (132175773..132184774, complement)
105.20220307 previous assembly GRCh37.p13 (GCF_000001405.25) 3 NC_000003.11 (129149790..129158791, complement)

Chromosome 3 - NC_000003.12Genomic Context describing neighboring genes Neighboring gene ribosomal protein L32 pseudogene 3 Neighboring gene small nucleolar RNA, H/ACA box 7B Neighboring gene H3K4me1 hESC enhancer GRCh37_chr3:129129626-129130126 Neighboring gene EF-hand calcium binding domain 12 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr3:129137243-129137742 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 20511 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 14724 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 20512 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 20513 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 20514 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 20516 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 20515 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 20517 Neighboring gene Sharpr-MPRA regulatory region 8693 Neighboring gene H3K27ac hESC enhancer GRCh37_chr3:129168229-129168945 Neighboring gene intraflagellar transport 122 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr3:129200162-129201039 Neighboring gene ReSE screen-validated silencer GRCh37_chr3:129208521-129208729 Neighboring gene Sharpr-MPRA regulatory region 10640 Neighboring gene CDK7 strongly-dependent group 2 enhancer GRCh37_chr3:129213542-129214741 Neighboring gene MPRA-validated peak4826 silencer Neighboring gene H3K4me1 hESC enhancer GRCh37_chr3:129247433-129248158 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr3:129248159-129248884 Neighboring gene H3K27ac hESC enhancer GRCh37_chr3:129253999-129254668 Neighboring gene rhodopsin enhancer region Neighboring gene rhodopsin

Genomic regions, transcripts, and products

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Go to nucleotide: Graphics FASTA GenBank

Expression

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  • Project title: HPA RNA-seq normal tissues
  • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
  • BioProject: PRJEB4337
  • Publication: PMID 24309898
  • Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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Related articles in PubMed

  1. MBD4 deficiency is predictive of response to immune checkpoint inhibitors in metastatic uveal melanoma patients. Saint-Ghislain M, et al. Eur J Cancer, 2022 Sep. PMID 35863105
  2. Structural Insights into the Mechanism of Base Excision by MBD4. Pidugu LS, et al. J Mol Biol, 2021 Jul 23. PMID 34107280, Free PMC Article
  3. Germline loss-of-function variants in MBD4 are rare in Finnish patients with uveal melanoma. Repo P, et al. Pigment Cell Melanoma Res, 2020 Sep. PMID 32421892
  4. Germline MBD4 Mutations and Predisposition to Uveal Melanoma. Derrien AC, et al. J Natl Cancer Inst, 2021 Jan 4. PMID 32239153, Free PMC Article
  5. MBD4 guards against methylation damage and germ line deficiency predisposes to clonal hematopoiesis and early-onset AML. Sanders MA, et al. Blood, 2018 Oct 4. PMID 30049810, Free PMC Article

See all (95) citations in PubMed

GeneRIFs: Gene References Into Functions

What's a GeneRIF?
  1. Familial uveal melanoma and other tumors in 25 families with monoallelic germline MBD4 variants.
    Title: Familial uveal melanoma and other tumors in 25 families with monoallelic germline MBD4 variants.
  2. MBD4 loss results in global reactivation of promoters and retroelements with low methylated CpG density.
    Title: MBD4 loss results in global reactivation of promoters and retroelements with low methylated CpG density.
  3. MBD4 deficiency is predictive of response to immune checkpoint inhibitors in metastatic uveal melanoma patients.
    Title: MBD4 deficiency is predictive of response to immune checkpoint inhibitors in metastatic uveal melanoma patients.
  4. Structural Insights into the Mechanism of Base Excision by MBD4.
    Title: Structural Insights into the Mechanism of Base Excision by MBD4.
  5. Germline MBD4 Mutations and Predisposition to Uveal Melanoma.
    Title: Germline MBD4 Mutations and Predisposition to Uveal Melanoma.
  6. Germline loss-of-function variants in MBD4 are rare in Finnish patients with uveal melanoma.
    Title: Germline loss-of-function variants in MBD4 are rare in Finnish patients with uveal melanoma.
  7. [Comparative Analysis of the Activity of the Polymorphic Variants of Human Uracil-DNA-Glycosylases SMUG1 and MBD4].
    Title: [Comparative Analysis of the Activity of the Polymorphic Variants of Human Uracil-DNA-Glycosylases SMUG1 and MBD4].
  8. MBD4 is sumoylated in vivo in a DNA damage-specific manner
    Title: Modification of the base excision repair enzyme MBD4 by the small ubiquitin-like molecule SUMO1.
  9. These findings suggest that RNF144A is epigenetically silenced in breast cancer cells by promoter hypermethylation and MBD4.
    Title: Epigenetic silencing of RNF144A expression in breast cancer cells through promoter hypermethylation and MBD4.
  10. Germ line MBD4 deficiency stimulates clonal hematopoiesis and guides the development of leukemia via recurrent mutations in DNMT3A.
    Title: MBD4 guards against methylation damage and germ line deficiency predisposes to clonal hematopoiesis and early-onset AML.
Submit: New GeneRIF Correction See all GeneRIFs (45)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Associated conditions

Description Tests
Melanoma, uveal, susceptibility to, 1
MedGen: C1847724 OMIM: 606660 GeneReviews: Not available
Compare labs
Tumor predisposition syndrome 2
MedGen: C5774186 OMIM: 619975 GeneReviews: Not available
Compare labs

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Genotypes

Pathways from PubChem

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Interactions

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Products Interactant Other Gene Complex Source Pubs Description

General gene information

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Markers

Homology

Gene Ontology Provided by GOA

Function Evidence Code Pubs
enables DNA N-glycosylase activity TAS
Traceable Author Statement
more info
  
enables DNA binding IBA
Inferred from Biological aspect of Ancestor
more info
  
enables DNA endonuclease activity TAS
Traceable Author Statement
more info
 PubMed 
enables protein binding IPI
Inferred from Physical Interaction
more info
 PubMed 
enables pyrimidine-specific mismatch base pair DNA N-glycosylase activity IDA
Inferred from Direct Assay
more info
 PubMed 
enables satellite DNA binding TAS
Traceable Author Statement
more info
 PubMed 
Process Evidence Code Pubs
involved_in DNA repair TAS
Traceable Author Statement
more info
 PubMed 
involved_in depyrimidination TAS
Traceable Author Statement
more info
  
involved_in response to estradiol IEA
Inferred from Electronic Annotation
more info
  
Component Evidence Code Pubs
located_in nuclear speck IDA
Inferred from Direct Assay
more info
  
located_in nucleoplasm TAS
Traceable Author Statement
more info
  
is_active_in nucleus IBA
Inferred from Biological aspect of Ancestor
more info
  

General protein information

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Preferred Names
methyl-CpG-binding domain protein 4
Names
3,N(4)-ethenocytosine glycosylase
G/5-fluorouracil mismatch glycosylase with biphasic kinetics
G/T mismatch glycosylase
G/U mismatch glycosylase
methyl-CpG binding domain protein 4
methyl-CpG-binding endonuclease 1
methyl-CpG-binding protein MBD4
mismatch-specific DNA N-glycosylase
putative methyl-CpG binding protein

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

  1. NG_033106.1 RefSeqGene

    Range
    5232..14233
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. NM_001276270.2 → NP_001263199.1  methyl-CpG-binding domain protein 4 isoform 2

    See identical proteins and their annotated locations for NP_001263199.1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (2) uses an alternate in-frame splice site in the 5' coding region, compared to variant 1. This results in a shorter protein (isoform 2), compared to isoform 1.
    Source sequence(s)
    BC011752, BP370521, DB568237
    Consensus CDS
    CCDS63768.1
    UniProtKB/Swiss-Prot
    O95243
    Related
    ENSP00000394080.2, ENST00000429544.7
    Conserved Domains (2) summary
    smart00391
    Location:79 → 155
    MBD; Methyl-CpG binding domain
    cl23768
    Location:444 → 514
    ENDO3c; endonuclease III; includes endonuclease III (DNA-(apurinic or apyrimidinic site) lyase), alkylbase DNA glycosidases (Alka-family) and other DNA glycosidases

  2. NM_001276271.2 → NP_001263200.1  methyl-CpG-binding domain protein 4 isoform 3

    Status: REVIEWED

    Description
    Transcript Variant: This variant (3) lacks an exon and its transcription extends past a splice site that is used in variant 1, resulting in a novel 3' coding region and 3' UTR compared to variant 1. It encodes isoform 3 which is shorter and has a distinct C-terminus, compared to isoform 1.
    Source sequence(s)
    AL449212
    Consensus CDS
    CCDS63766.1
    UniProtKB/Swiss-Prot
    O95243
    Related
    ENSP00000422327.1, ENST00000507208.1
    Conserved Domains (2) summary
    smart00391
    Location:79 → 155
    MBD; Methyl-CpG binding domain
    COG0177
    Location:453 → 518
    Nth; Endonuclease III [Replication, recombination and repair]

  3. NM_001276272.2 → NP_001263201.1  methyl-CpG-binding domain protein 4 isoform 4

    See identical proteins and their annotated locations for NP_001263201.1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (4) uses an alternate in-frame splice site in the 3' coding region, compared to variant 1. This results in a shorter protein (isoform 4), compared to isoform 1.
    Source sequence(s)
    AF532602, DB568237
    Consensus CDS
    CCDS63767.1
    UniProtKB/Swiss-Prot
    O95243
    Related
    ENSP00000424873.1, ENST00000503197.5
    Conserved Domains (2) summary
    smart00391
    Location:79 → 155
    MBD; Methyl-CpG binding domain
    cl23768
    Location:450 → 520
    ENDO3c; endonuclease III; includes endonuclease III (DNA-(apurinic or apyrimidinic site) lyase), alkylbase DNA glycosidases (Alka-family) and other DNA glycosidases

  4. NM_001276273.2 → NP_001263202.1  methyl-CpG-binding domain protein 4 isoform 5

    See identical proteins and their annotated locations for NP_001263202.1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (5) uses an alternate in-frame splice site and lacks an exon in the 5' coding region, compared to variant 1. The encoded isoform (5) is shorter, compared to isoform 1.
    Source sequence(s)
    AM180876, BP370521, CD678412, DB568237
    Consensus CDS
    CCDS63769.1
    UniProtKB/Swiss-Prot
    O95243
    Related
    ENSP00000376959.2, ENST00000393278.6
    Conserved Domains (1) summary
    cl23768
    Location:132 → 202
    ENDO3c; endonuclease III; includes endonuclease III (DNA-(apurinic or apyrimidinic site) lyase), alkylbase DNA glycosidases (Alka-family) and other DNA glycosidases

  5. NM_003925.3 → NP_003916.1  methyl-CpG-binding domain protein 4 isoform 1

    See identical proteins and their annotated locations for NP_003916.1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (1) encodes the longest isoform (1).
    Source sequence(s)
    AF072250, BY997577, DB568237
    Consensus CDS
    CCDS3058.1
    UniProtKB/Swiss-Prot
    B4DZN2, D3DNC3, D3DNC4, E9PEE4, O95243, Q2MD36, Q7Z4T3, Q96F09
    Related
    ENSP00000249910.1, ENST00000249910.5
    Conserved Domains (2) summary
    smart00391
    Location:79 → 155
    MBD; Methyl-CpG binding domain
    cl23768
    Location:450 → 520
    ENDO3c; endonuclease III; includes endonuclease III (DNA-(apurinic or apyrimidinic site) lyase), alkylbase DNA glycosidases (Alka-family) and other DNA glycosidases

RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2023_10

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh38.p14 Primary Assembly

Genomic

  1. NC_000003.12 Reference GRCh38.p14 Primary Assembly

    Range
    129430947..129439948 complement
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. XM_047449153.1 → XP_047305109.1  methyl-CpG-binding domain protein 4 isoform X2

  2. XM_024453810.2 → XP_024309578.1  methyl-CpG-binding domain protein 4 isoform X1

    Conserved Domains (2) summary
    smart00391
    Location:79 → 155
    MBD; Methyl-CpG binding domain
    cl27658
    Location:447 → 512
    HHH; Helix-hairpin-helix motif

Alternate T2T-CHM13v2.0

Genomic

  1. NC_060927.1 Alternate T2T-CHM13v2.0

    Range
    132175773..132184774 complement
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. XM_054348285.1 → XP_054204260.1  methyl-CpG-binding domain protein 4 isoform X2

  2. XM_054348284.1 → XP_054204259.1  methyl-CpG-binding domain protein 4 isoform X1

Nucleotide Protein
Heading Accession and Version
Protein Accession Links
GenPept Link UniProtKB Link
O95243.1 GenPept UniProtKB/Swiss-Prot:O95243

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