MBD4

Summary

MBD4 (methyl-CpG binding domain 4, DNA glycosylase, HGNC:6919) is a protein-coding gene on chromosome 3q21.3, encoding Methyl-CpG-binding domain protein 4 (O95243). Mismatch-specific DNA N-glycosylase involved in DNA repair.

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.

Source: NCBI Gene 8930 — RefSeq curated summary.

At a glance

• Gene–disease (curated): tumor predisposition syndrome 2 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 9
• Clinical variants (ClinVar): 1,293 total — 107 pathogenic, 14 likely-pathogenic
• Phenotypes (HPO): 13
• Druggable target: yes
• MANE Select transcript: NM_001276270

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6919
Approved symbol	MBD4
Name	methyl-CpG binding domain 4, DNA glycosylase
Location	3q21.3
Locus type	gene with protein product
Status	Approved
Aliases	MED1
Ensembl gene	ENSG00000129071
Ensembl biotype	protein_coding
OMIM	603574
Entrez	8930

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 10 protein_coding, 2 protein_coding_CDS_not_defined, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000249910, ENST00000393278, ENST00000429544, ENST00000503197, ENST00000505883, ENST00000507208, ENST00000509587, ENST00000509828, ENST00000511009, ENST00000515266, ENST00000853349, ENST00000853350, ENST00000853351, ENST00000915033, ENST00000915034

RefSeq mRNA: 5 — MANE Select: NM_001276270 NM_001276270, NM_001276271, NM_001276272, NM_001276273, NM_003925

CCDS: CCDS3058, CCDS63766, CCDS63767, CCDS63768, CCDS63769

Canonical transcript exons

ENST00000429544 — 8 exons

Exon	Start	End
ENSE00000885773	129433850	129433984
ENSE00001754317	129436461	129437308
ENSE00002025791	129439730	129439948
ENSE00002053870	129430947	129431578
ENSE00003498281	129437720	129437950
ENSE00003523769	129434062	129434136
ENSE00003636660	129432503	129432606
ENSE00003694104	129433098	129433247

Expression profiles

Bgee: expression breadth ubiquitous, 299 present calls, max score 99.70.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 30.8178 / max 376.2600, expressed in 1820 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
44522	15.1349	1793
44521	11.0372	1762
44523	4.2645	1407
44520	0.3812	175

Top tissues by expression

299 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	99.70	gold quality
oocyte	CL:0000023	99.27	gold quality
pylorus	UBERON:0001166	98.74	gold quality
visceral pleura	UBERON:0002401	98.11	gold quality
trabecular bone tissue	UBERON:0002483	97.92	gold quality
caput epididymis	UBERON:0004358	97.91	gold quality
epithelium of nasopharynx	UBERON:0001951	97.73	gold quality
cranial nerve II	UBERON:0000941	97.62	gold quality
cardia of stomach	UBERON:0001162	97.59	gold quality
renal medulla	UBERON:0000362	97.36	gold quality
corpus epididymis	UBERON:0004359	97.19	gold quality
pericardium	UBERON:0002407	97.16	gold quality
cauda epididymis	UBERON:0004360	97.13	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.68	gold quality
parietal pleura	UBERON:0002400	96.61	gold quality
pleura	UBERON:0000977	96.59	gold quality
superior surface of tongue	UBERON:0007371	96.57	gold quality
hair follicle	UBERON:0002073	96.32	gold quality
nipple	UBERON:0002030	96.26	gold quality
bone element	UBERON:0001474	96.22	gold quality
lymph node	UBERON:0000029	96.12	gold quality
jejunal mucosa	UBERON:0000399	96.12	gold quality
bone marrow	UBERON:0002371	95.91	gold quality
mammary duct	UBERON:0001765	95.66	gold quality
oral cavity	UBERON:0000167	95.62	gold quality
tendon of biceps brachii	UBERON:0008188	95.62	gold quality
superficial temporal artery	UBERON:0001614	95.51	gold quality
epithelium of mammary gland	UBERON:0003244	95.44	gold quality
jejunum	UBERON:0002115	95.25	gold quality
urethra	UBERON:0000057	95.05	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.74
E-MTAB-6379	no	1024.38

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): DNMT3A, DNMT3B, MBD1

miRNA regulators (miRDB)

36 targeting MBD4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-3616-5P	99.55	67.02	989
HSA-MIR-573	99.55	67.44	955
HSA-MIR-5004-3P	99.54	68.27	1371
HSA-MIR-3147	99.52	66.34	388
HSA-MIR-216A-5P	99.50	68.02	1288
HSA-MIR-208A-5P	99.42	70.83	1913
HSA-MIR-208B-5P	99.42	70.83	1952
HSA-MIR-889-5P	99.41	68.75	1025
HSA-MIR-504-3P	99.30	67.18	1745
HSA-MIR-4478	99.07	65.16	2320
HSA-MIR-7151-3P	99.04	69.72	2370
HSA-MIR-222-5P	98.75	69.17	1242
HSA-MIR-6755-3P	98.61	66.90	834
HSA-MIR-6842-3P	98.07	66.33	1325
HSA-MIR-3670	97.88	64.39	763
HSA-MIR-3920	97.75	69.02	1168
HSA-MIR-3652	97.71	65.43	1890

Literature-anchored findings (GeneRIF, showing 40)

• MBD4 expression is associated with grade of malignancy in gliomas (PMID:11836615)
• results indicate the formation of a complex with the estradiol receptor (PMID:12220634)
• Frameshift mutations were found in 29% of gastric and 20% of colon MSI-H cancers, but not in any low-frequency microsatellite instability/microsatellite stable cancers. (PMID:12430186)
• MBD4 mutations were found in 15% MSI but not in MSS colrectal tumors. (PMID:12926109)
• MBD4 acts as a repressor protein binding to hypermethylated promoters of the p16(INK4a) and hMLH1 genes. (PMID:15899845)
• MBD4 Glu346Lys polymorphism could be used as a marker for genetic susceptibility to adenocarcinoma of the lung. (PMID:16803845)
• Mutations in MBD4 are unlikely to be implicated in HPS. (PMID:16831587)
• These results suggest that RFP is a mediator connecting several MBD proteins and allowing the formation of a more potent transcriptional repressor complex. (PMID:17049487)
• The overexpression of MBD4(tru) in Big Blue (lacI)-transfected, MSI human colorectal carcinoma cells doubled mutation frequency, indicating that the modest dominant negative effect on DNA repair can occur in living cells in short-term experiments. (PMID:17285135)
• MBD2 and MBD4 transcript overexpression and inverse correlations with DNA methylation indices indicate that both enzymes may really have a direct and active role on the genome-wide DNA hypomethylation observed in CD4+ T cells from SLE patients. (PMID:17360956)
• Truncation of MBD4 predisposes to reciprocal chromosomal translocations and alters the response to therapeutic agents in colon cancer cells. (PMID:18162445)
• Single nucleotide polymorphisms in MBD4 are associated with lung cancer. (PMID:18495292)
• MBD4 efficiently processed T/G mismatches within the nucleosome. (PMID:18519584)
• The methyl binding domain of MBD4/MED1 was found to specifically inhibit the activity of MBD4/MED1 as well as the glycosylase domain, when the G:IU mispairs were located in a methylated CpG context. (PMID:19395862)
• The Glu346Lys polymorphism and frameshift mutations of the Methyl-CpG Binding Domain 4 gene is associated with gastrointestinal cancer (PMID:19469655)
• Data suggest that methyl-CpG binding domain 4 polymorphism may not be a stratification marker to predict the susceptibility to immune thrombocytopenic purpura, at least in the Chinese population. (PMID:20100009)
• MBD4-8666 and MBD4-9229, but not MBD4-1057, gene polymorphisms are related to rheumatoid arthritis in Chinese patients in Taiwan. (PMID:20676650)
• decreased expression in patients with primary immune thrombocytopenia (PMID:21377502)
• the crystal structure of C-terminal glycosylase domain of human MBD4 was determined. (PMID:21820404)
• MBD 4–a potential substrate for protein kinase X (PMID:21971312)
• specificity of MBD4 for acting at CpG sites depends largely on its methyl-CpG-binding domain, which binds preferably to G.T mispairs in a methylated CpG site (PMID:22560993)
• Crystal structures of human MBD4(catalytic domain) reveal that MBD4 uses a base flipping mechanism to specifically recognize thymine and 5-hydroxymethyluracil. (PMID:22848106)
• MBD4 Glu346Lys polymorphism is associated with the risk of cervical cancer in a Chinese population. (PMID:23027038)
• the crystal structure of MBD4 bound to 5-hydroxymethylcytosine further demonstrates that MBDMBD4 is able to recognize a wide range of 5-methylcytosine modifications (PMID:23316048)
• ERCC4 rs1800124 and MBD4 rs10342 non-synonymous single nucleotide polymorphism variants were associated with DNA repair capacity. (PMID:24004570)
• Interaction between DNMT1 and MBD4 is involved in controlling gene expression and responding to oxidative stress. (PMID:24434851)
• MBD4 rs3138373 A>G and rs2005618 T>C single nucleotide polymorphisms were not associated with esophageal squamous cell carcinoma (ESCC) risk. rs3138355 GG genotype was associated with a decreased risk of ESCC among male patients and the elderly. (PMID:25162968)
• The ability of MBD4 to directly interact with and recruit USP7 to chromocenters implicates it as an additional factor that can potentially regulate Dnmt1 activity during cell proliferation. (PMID:25358258)
• these data suggest that MBD4 inactivation may contribute to tumorigenesis, acting as a modifier of mismatch repair-deficient cancer phenotype. (PMID:26503472)
• a novel molecular mechanism by which MBD4 inhibits GITR expression in a DNMT1-dependent manner (PMID:28542810)
• Results demonstrated that MBD4 was downregulated, which lead to the overexpression and promoter hypomethylation of CD70 in CD4+ T cells from patients from systemic lupus erythematosus (SLE). This study preliminarily revealed the role and mechanism of MBD4 in the pathogenesis of SLE. (PMID:29018507)
• These findings suggest that RNF144A is epigenetically silenced in breast cancer cells by promoter hypermethylation and MBD4. (PMID:29473320)
• Germ line MBD4 deficiency stimulates clonal hematopoiesis and guides the development of leukemia via recurrent mutations in DNMT3A. (PMID:30049810)
• MBD4 is sumoylated in vivo in a DNA damage-specific manner (PMID:31476572)
• Meta-analysis of the association between MBD4 Glu346Lys polymorphism and cancer risk. (PMID:31891275)
• Germline MBD4 Mutations and Predisposition to Uveal Melanoma. (PMID:32239153)
• Germline loss-of-function variants in MBD4 are rare in Finnish patients with uveal melanoma. (PMID:32421892)
• [Comparative Analysis of the Activity of the Polymorphic Variants of Human Uracil-DNA-Glycosylases SMUG1 and MBD4]. (PMID:33871441)
• Structural Insights into the Mechanism of Base Excision by MBD4. (PMID:34107280)
• MBD4 deficiency is predictive of response to immune checkpoint inhibitors in metastatic uveal melanoma patients. (PMID:35863105)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Mbd4	ENSMUSG00000030322
rattus_norvegicus	Mbd4	ENSRNOG00000010919

Paralogs (1): MECP2 (ENSG00000169057)

Protein

Protein identifiers

Methyl-CpG-binding domain protein 4 — O95243 (reviewed: O95243)

Alternative names: Methyl-CpG-binding endonuclease 1, Methyl-CpG-binding protein MBD4, Mismatch-specific DNA N-glycosylase

All UniProt accessions (2): O95243, D6RBI7

UniProt curated annotations — full annotation on UniProt →

Function. Mismatch-specific DNA N-glycosylase involved in DNA repair. Has thymine glycosylase activity and is specific for G:T mismatches within methylated and unmethylated CpG sites. Can also remove uracil or 5-fluorouracil in G:U mismatches. Has no lyase activity. Was first identified as methyl-CpG-binding protein.

Subunit / interactions. Interacts with MLH1.

Subcellular location. Nucleus.

Disease relevance. Tumor predisposition syndrome 2 (TPDS2) [MIM:619975] An autosomal recessive condition characterized by predisposition to develop a variety of tumors or malignancies, including acute myeloid leukemia, myelodysplastic syndrome, colorectal adenomatous polyposis and carcinoma, and uveal melanoma. The disease is caused by variants affecting the gene represented in this entry. Melanoma, uveal, 1 (UVM1) [MIM:606660] Most common intraocular malignancy, arising from melanocytes in the iris, ciliary body, or choroid. Metastases develop in more than 30% of case patients, almost invariably in the liver, with poor prognosis. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Miscellaneous. Possesses uracil DNA glycosylase but not thymine DNA glycosylase activity.

Isoforms (5)

UniProt ID	Names	Canonical?
O95243-1	1	yes
O95243-2	2
O95243-3	3
O95243-5	5
O95243-6	4

RefSeq proteins (5): NP_001263199, NP_001263200, NP_001263201, NP_001263202, NP_003916 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001739	Methyl_CpG_DNA-bd	Domain
IPR011257	DNA_glycosylase	Homologous_superfamily
IPR016177	DNA-bd_dom_sf	Homologous_superfamily
IPR017352	MBD4	Family
IPR045138	MeCP2/MBD4	Family

Pfam: PF01429

UniProt features (48 total): sequence variant 16, helix 13, splice variant 5, sequence conflict 3, strand 2, turn 2, modified residue 2, chain 1, domain 1, region of interest 1, mutagenesis site 1, active site 1

Structure

Experimental structures (PDB)

18 structures.

PDB	Method	Resolution (Å)
4OFA	X-RAY DIFFRACTION	1.55
7KZ0	X-RAY DIFFRACTION	1.57
7KZ1	X-RAY DIFFRACTION	1.62
7KZG	X-RAY DIFFRACTION	1.68
4E9F	X-RAY DIFFRACTION	1.79
5CHZ	X-RAY DIFFRACTION	1.83
4E9E	X-RAY DIFFRACTION	1.9
4EA4	X-RAY DIFFRACTION	2
6VJW	X-RAY DIFFRACTION	2.02
4EA5	X-RAY DIFFRACTION	2.14
4OFE	X-RAY DIFFRACTION	2.15
4OFH	X-RAY DIFFRACTION	2.22
4E9G	X-RAY DIFFRACTION	2.35
4LG7	X-RAY DIFFRACTION	2.5
3IHO	X-RAY DIFFRACTION	2.7
4DK9	X-RAY DIFFRACTION	2.76
4E9H	X-RAY DIFFRACTION	3
2MOE	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95243-F1	60.67	0.33

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 560

Post-translational modifications (2): 318, 428

Mutagenesis-validated functional residues (1):

Position	Phenotype
560	loss of dna n-glycosylase activity.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-110328	Recognition and association of DNA glycosylase with site containing an affected pyrimidine
R-HSA-110329	Cleavage of the damaged pyrimidine
R-HSA-110357	Displacement of DNA glycosylase by APEX1
R-HSA-73884	Base Excision Repair
R-HSA-73894	DNA Repair
R-HSA-73928	Depyrimidination
R-HSA-73929	Base-Excision Repair, AP Site Formation
R-HSA-73933	Resolution of Abasic Sites (AP sites)

MSigDB gene sets: 769 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, GOBP_MYELOID_CELL_DIFFERENTIATION, GSE45365_NK_CELL_VS_CD11B_DC_UP, GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_EPITHELIAL_CELL_DIFFERENTIATION, GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_PROLIFERATION, REACTOME_TRANSCRIPTIONAL_REGULATION_OF_WHITE_ADIPOCYTE_DIFFERENTIATION, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_REGULATION_OF_HEPATOCYTE_PROLIFERATION, GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_EMBRYONIC_HEMOPOIESIS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, AAGCAAT_MIR137, GOBP_EPITHELIUM_DEVELOPMENT

GO Biological Process (4): DNA repair (GO:0006281), response to estradiol (GO:0032355), depyrimidination (GO:0045008), DNA damage response (GO:0006974)

GO Molecular Function (8): DNA binding (GO:0003677), satellite DNA binding (GO:0003696), DNA endonuclease activity (GO:0004520), pyrimidine-specific mismatch base pair DNA N-glycosylase activity (GO:0008263), DNA N-glycosylase activity (GO:0019104), catalytic activity (GO:0003824), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (3): nucleus (GO:0005634), nucleoplasm (GO:0005654), nuclear speck (GO:0016607)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Depyrimidination	2
Base Excision Repair	2
Resolution of Abasic Sites (AP sites)	1
DNA Repair	1
Base-Excision Repair, AP Site Formation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA metabolic process	1
DNA damage response	1
response to lipid	1
response to oxygen-containing compound	1
base-excision repair, AP site formation	1
DNA modification	1
pyrimidine deoxyribonucleotide catabolic process	1
cellular response to stress	1
nucleic acid binding	1
sequence-specific double-stranded DNA binding	1
endonuclease activity	1
DNA nuclease activity	1
mismatch base pair DNA N-glycosylase activity	1
hydrolase activity, hydrolyzing N-glycosyl compounds	1
catalytic activity, acting on DNA	1
molecular_function	1
binding	1
catalytic activity	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
nuclear ribonucleoprotein granule	1

Protein interactions and networks

STRING

1210 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MBD4	DNMT3B	Q9UBC3	946
MBD4	DNMT1	P26358	925
MBD4	MLH1	P40692	921
MBD4	TDG	Q13569	897
MBD4	DNMT3A	Q9Y6K1	896
MBD4	SMUG1	Q53HV7	860
MBD4	TRDMT1	O14717	806
MBD4	MBD2	Q9UBB5	779
MBD4	ZBTB33	Q86T24	745
MBD4	UHRF1	Q96T88	690
MBD4	UNG	P13051	684
MBD4	MPG	P29372	669
MBD4	CYP27B1	O15528	651
MBD4	NTHL1	P78549	646
MBD4	NEIL1	Q96FI4	644

IntAct

34 interactions, top by confidence:

A	B	Type	Score
FADD	MBD4	psi-mi:“MI:0915”(physical association)	0.580
MBD4	FADD	psi-mi:“MI:0915”(physical association)	0.580
MBD4	PSMD1	psi-mi:“MI:0915”(physical association)	0.400
MBD4	TFG	psi-mi:“MI:0915”(physical association)	0.400
FAS	MBD4	psi-mi:“MI:0915”(physical association)	0.370
ECE1	MBD4	psi-mi:“MI:0915”(physical association)	0.370
HTT	MBD4	psi-mi:“MI:0915”(physical association)	0.370
MBD4	CDCA2	psi-mi:“MI:0915”(physical association)	0.370
SUV39H1	MBD4	psi-mi:“MI:0915”(physical association)	0.370
KDM1A	MBD4	psi-mi:“MI:0915”(physical association)	0.370
MBD4	TRIM27	psi-mi:“MI:0915”(physical association)	0.370
Prkci	LLGL2	psi-mi:“MI:0914”(association)	0.350
Cep78	ING5	psi-mi:“MI:0914”(association)	0.350
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
GATA3	HNRNPDL	psi-mi:“MI:0914”(association)	0.350
MBD4	A2ML1	psi-mi:“MI:0914”(association)	0.350
HNRNPCL2	SMCHD1	psi-mi:“MI:0914”(association)	0.350
AGGF1	BLTP3B	psi-mi:“MI:2364”(proximity)	0.270
HNRNPC	SBNO1	psi-mi:“MI:2364”(proximity)	0.270
ILF3	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
TRA2A	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
ZRANB2	SBNO1	psi-mi:“MI:2364”(proximity)	0.270
NSUN2	RPSA2	psi-mi:“MI:2364”(proximity)	0.270
NPM1	SBNO1	psi-mi:“MI:2364”(proximity)	0.270
APP	MBD4	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (118): MBD4 (Affinity Capture-RNA), MBD4 (Affinity Capture-RNA), MBD4 (Affinity Capture-RNA), UHRF1 (Affinity Capture-MS), USP7 (Affinity Capture-MS), UHRF1 (Affinity Capture-Western), USP7 (Affinity Capture-Western), MBD4 (Affinity Capture-Western), MLH1 (Affinity Capture-Western), Uhrf1 (Affinity Capture-Western), MLH1 (Reconstituted Complex), UHRF1 (Reconstituted Complex), MBD4 (Reconstituted Complex), MBD4 (Two-hybrid), MBD4 (Two-hybrid)

ESM2 similar proteins: A0P8Z5, A6H8Y1, A7MBJ2, B2RX14, E2QTD3, F4KIX0, O15151, O35618, O95243, P28715, P48785, P61590, P61591, P61592, P61593, P61594, P93831, Q10MI4, Q15361, Q2HJ21, Q336N8, Q588V7, Q5IFK1, Q5TAX3, Q5VN06, Q5XIN1, Q60GC1, Q68FE8, Q69Z69, Q6N043, Q6P7W0, Q6YU88, Q84UI6, Q8BSV3, Q8L6Z7, Q8N7W2, Q8NAT2, Q8NEM0, Q8RXD4, Q8S4P4

Diamond homologs: O95243, O95983, P51608, Q00566, Q0IGK1, Q95LG8, Q9UBB5, Q9YDP0, Q9Z2D6, Q9Z2D7, Q9Z2D8, Q9Z2E1, A0A1B0GVZ6, A6NDZ8, A6NE82, A6NJ08, Q8NHZ7, Q8WWY6, Q9D9H3, Q9UIS9, Q9Z2E2, Q9VGA4, Q9FZP6, Q9LTJ1, Q9LYB9, A0R567, P17802, P29588, P44320, P46230, P46303, P57617, P73715, P83847, P9WQ08, P9WQ09, Q05869, Q7LX22, Q8R5G2, Q99P21

SIGNOR signaling

16 interactions.

A	Effect	B	Mechanism
ERBB2	“up-regulates activity”	MBD4	phosphorylation
CDK7	“down-regulates activity”	MBD4	phosphorylation
PRKCA	“up-regulates activity”	MBD4	phosphorylation
PKC	“up-regulates activity”	MBD4	phosphorylation
UBE2I	“up-regulates activity”	MBD4	sumoylation
“SAE1/SAE2 complex”	“up-regulates activity”	MBD4	sumoylation
MBD4	“up-regulates quantity by expression”	CYP27B1	“transcriptional regulation”
MBD4	up-regulates	DNA_repair
MBD4	up-regulates	Base-excision_repair

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

1293 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	107
Likely pathogenic	14
Uncertain significance	741
Likely benign	342
Benign	15

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1700250	NM_003925.2:c.1699_1701del	Pathogenic
1700253	NM_001276270.2(MBD4):c.217C>T (p.Gln73Ter)	Pathogenic
1879590	NM_001276270.2(MBD4):c.803_804del (p.Val267_Cys268insTer)	Pathogenic
1976297	NM_001276270.2(MBD4):c.1213_1216del (p.Arg405fs)	Pathogenic
2033330	NM_001276270.2(MBD4):c.846_849del (p.Gln283fs)	Pathogenic
2107332	NM_001276270.2(MBD4):c.614_615del (p.Leu204_Ser205insTer)	Pathogenic
2654123	NM_001276270.2(MBD4):c.1253_1254del (p.Lys418fs)	Pathogenic
2697830	NM_001276270.2(MBD4):c.615dup (p.Asn206Ter)	Pathogenic
2702357	NM_001276270.2(MBD4):c.300del (p.Lys101fs)	Pathogenic
2702363	NM_001276270.2(MBD4):c.364del (p.Ser122fs)	Pathogenic
2704947	NM_001276270.2(MBD4):c.512_524del (p.Ser171fs)	Pathogenic
2705642	NM_001276270.2(MBD4):c.943_946dup (p.Ser316Ter)	Pathogenic
2706994	NM_001276270.2(MBD4):c.1447G>T (p.Glu483Ter)	Pathogenic
2708635	NM_001276270.2(MBD4):c.1254_1257del (p.Glu419fs)	Pathogenic
2725154	NM_001276270.2(MBD4):c.1425del (p.Leu476fs)	Pathogenic
2776110	NM_001276270.2(MBD4):c.1183+12_1183+16del	Pathogenic
2783108	NM_001276270.2(MBD4):c.541C>T (p.Arg181Ter)	Pathogenic
2785228	NM_001276270.2(MBD4):c.1002_1005del (p.Lys335fs)	Pathogenic
2798240	NM_001276270.2(MBD4):c.229dup (p.Thr77fs)	Pathogenic
2800545	NM_001276270.2(MBD4):c.938_939dup (p.Glu314fs)	Pathogenic
2802466	NM_001276270.2(MBD4):c.1131dup (p.Arg378fs)	Pathogenic
2878853	NM_001276270.2(MBD4):c.249dup (p.Lys84Ter)	Pathogenic
2884001	NM_001276270.2(MBD4):c.1273C>T (p.Arg425Ter)	Pathogenic
3029610	NM_001276270.2(MBD4):c.1469G>A (p.Trp490Ter)	Pathogenic
3246992	NC_000003.11:g.(?129150344)(129158676_?)del	Pathogenic
3543766	NM_001276270.2(MBD4):c.587C>G (p.Ser196Ter)	Pathogenic
3638594	NM_001276270.2(MBD4):c.1248T>A (p.Tyr416Ter)	Pathogenic
3639803	NM_001276270.2(MBD4):c.249_250insCT (p.Lys84fs)	Pathogenic
3642431	NM_001276270.2(MBD4):c.1376_1377del (p.Phe459fs)	Pathogenic
3642839	NM_001276270.2(MBD4):c.947C>G (p.Ser316Ter)	Pathogenic

SpliceAI

3179 predictions. Top by Δscore:

Variant	Effect	Δscore
17:39410717:TACAT:T	acceptor_gain	1.0000
17:39410718:ACAT:A	acceptor_gain	1.0000
17:39410719:CAT:C	acceptor_gain	1.0000
17:39410719:CATC:C	acceptor_gain	1.0000
17:39410720:AT:A	acceptor_gain	1.0000
17:39410720:ATCTG:A	acceptor_loss	1.0000
17:39410721:TC:T	acceptor_loss	1.0000
17:39410722:C:CC	acceptor_gain	1.0000
17:39410729:A:AC	acceptor_gain	1.0000
17:39410729:A:C	acceptor_gain	1.0000
17:39415127:TACCA:T	acceptor_gain	1.0000
17:39415128:ACCA:A	acceptor_gain	1.0000
17:39415129:CCA:C	acceptor_gain	1.0000
17:39415129:CCAC:C	acceptor_gain	1.0000
17:39415130:CA:C	acceptor_gain	1.0000
17:39415130:CAC:C	acceptor_gain	1.0000
17:39415132:C:CC	acceptor_gain	1.0000
17:39419711:CAGTA:C	donor_loss	1.0000
17:39419712:AGTAC:A	donor_loss	1.0000
17:39419713:GTACC:G	donor_loss	1.0000
17:39419714:TA:T	donor_loss	1.0000
17:39419715:A:T	donor_loss	1.0000
17:39419716:C:CT	donor_loss	1.0000
17:39419716:CCTT:C	donor_gain	1.0000
17:39419748:T:TA	donor_gain	1.0000
17:39419919:C:CC	acceptor_gain	1.0000
17:39419919:CT:C	acceptor_loss	1.0000
17:39423321:ACTT:A	donor_loss	1.0000
17:39423323:TTA:T	donor_loss	1.0000
17:39423324:TACAG:T	donor_loss	1.0000

AlphaMissense

3798 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:129432511:A:G	W553R	0.999
3:129432511:A:T	W553R	0.999
3:129432531:C:G	R546P	0.999
3:129432586:A:G	W528R	0.999
3:129432586:A:T	W528R	0.999
3:129433892:A:G	W457R	0.999
3:129433892:A:T	W457R	0.999
3:129433949:A:G	W438R	0.999
3:129433949:A:T	W438R	0.999
3:129432524:A:C	F548L	0.998
3:129432524:A:T	F548L	0.998
3:129432526:A:G	F548L	0.998
3:129432584:C:A	W528C	0.998
3:129432584:C:G	W528C	0.998
3:129433217:A:G	F481S	0.998
3:129433876:G:T	A462D	0.998
3:129431535:A:G	L570P	0.997
3:129431539:A:G	W569R	0.997
3:129431539:A:T	W569R	0.997
3:129431556:A:G	L563S	0.997
3:129432509:C:A	W553C	0.997
3:129432509:C:G	W553C	0.997
3:129432567:A:G	L534P	0.997
3:129432601:A:C	Y523D	0.997
3:129433226:A:G	L478P	0.997
3:129433864:A:G	L466P	0.997
3:129433885:A:G	L459P	0.997
3:129433890:C:A	W457C	0.997
3:129433890:C:G	W457C	0.997
3:129433947:C:A	W438C	0.997

dbSNP variants (sampled 300 via entrez): RS1000109196 (3:129433626 G>C,T), RS1000984886 (3:129438884 T>C), RS1001035935 (3:129441930 C>G), RS1001165805 (3:129431389 C>T), RS1001269015 (3:129436849 T>A,C,G), RS1001333395 (3:129435190 G>A,T), RS1001668940 (3:129438318 T>C), RS1001721355 (3:129438006 A>C), RS1001882534 (3:129431606 G>A,C), RS1002000976 (3:129439967 A>ACGC), RS1002055066 (3:129439749 C>A,G), RS1002107477 (3:129439477 G>A), RS1002119229 (3:129437376 C>T), RS1002669170 (3:129433589 G>A), RS1004127545 (3:129440610 C>T)

Disease associations

OMIM: gene MIM:603574 | disease phenotypes: MIM:606660, MIM:619975, MIM:618512

GenCC curated gene-disease

Disease	Classification	Inheritance
tumor predisposition syndrome 2	Strong	Autosomal recessive
melanoma, uveal, susceptibility to, 1	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
tumor predisposition syndrome 2	Moderate	AR

Mondo (4): melanoma, uveal, susceptibility to, 1 (MONDO:0011695), tumor predisposition syndrome 2 (MONDO:0859267), hereditary neoplastic syndrome (MONDO:0015356), O’Donnell-Luria-Rodan syndrome (MONDO:0032793)

Orphanet (3): Uveal melanoma (Orphanet:39044), MBD4-related tumor predisposition syndrome (Orphanet:661526), Inherited cancer-predisposing syndrome (Orphanet:140162)

HPO phenotypes

13 total (13 of 13 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0002858	Meningioma
HP:0003003	Colon cancer
HP:0003581	Adult onset
HP:0003596	Middle age onset
HP:0003621	Juvenile onset
HP:0004808	Acute myeloid leukemia
HP:0005227	Adenomatous colonic polyposis
HP:0007716	Uveal melanoma
HP:0011462	Young adult onset
HP:0030075	Ductal carcinoma in situ
HP:0031919	Juvenile type ovarian granulosa cell tumor
HP:0100008	Schwannoma

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST002875_11	Diisocyanate-induced asthma	2.000000e-06
GCST002875_143	Diisocyanate-induced asthma	3.000000e-06
GCST005551_4	Systemic sclerosis (anti-topoisomerase-positive)	3.000000e-06
GCST005956_82	Waist-to-hip ratio adjusted for BMI	2.000000e-07
GCST005958_5	Waist-to-hip ratio adjusted for BMI (age >50)	4.000000e-10
GCST005962_16	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	2.000000e-11
GCST90020025_598	Waist-to-hip ratio adjusted for BMI	3.000000e-08
GCST90020025_599	Waist-to-hip ratio adjusted for BMI	1.000000e-26
GCST90020027_375	Waist-hip index	2.000000e-26

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0006995	response to diisocyanate
EFO:0008537	anti-topoisomerase-I-antibody-positive systemic scleroderma
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5723573 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

54 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases reaction, affects expression, affects methylation, increases expression, affects cotreatment (+3 more)	5
Estradiol	increases methylation, decreases expression, increases reaction, increases expression, affects cotreatment (+1 more)	3
Acetaminophen	decreases expression, increases expression	2
Doxorubicin	decreases expression	2
Hydrogen Peroxide	affects expression, increases expression	2
Valproic Acid	decreases expression, decreases methylation, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	2
Cadmium Chloride	increases expression, decreases expression, increases abundance	2
FR900359	decreases phosphorylation	1
TAK-243	increases sumoylation	1
dicrotophos	decreases expression	1
testosterone enanthate	affects expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	increases expression, affects binding, increases activity	1
lead acetate	decreases expression	1
VX-agent	increases expression	1
beta-lapachone	increases expression	1
3,N(4)-ethenocytosine	affects glycosylation	1
quinoline yellow	increases expression	1
coumarin	decreases phosphorylation	1
testosterone-3-carboxymethyloxime-bovine serum albumin conjugate	affects expression	1
di-n-butylphosphoric acid	affects expression	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
riccardin D	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5665444	Functional	Inhibition of MBD4 by quantifying inhibition of MBD4-mediated cleavage and dissociation of quenched duplex DNA oligonucleotides, measured as fluorescence at 594 nm. To generate a functional strand incision and increase turn-over this assay	Enzyme Inhibitor Single Concentration assay results for EUbOPEN Chemogenomics Library

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1WU	Abcam HeLa MBD4 KO	Cancer cell line	Female
CVCL_SX48	HAP1 MBD4 (-) 1	Cancer cell line	Male
CVCL_SX49	HAP1 MBD4 (-) 2	Cancer cell line	Male
CVCL_SX50	HAP1 MBD4 (-) 3	Cancer cell line	Male
CVCL_SX51	HAP1 MBD4 (-) 4	Cancer cell line	Male

Clinical trials (associated diseases)

29 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00001496	Not specified	COMPLETED	Establishment of Normal Breast Epithelial Cell Lines From Patients at High Risk for Breast Cancer
NCT00001898	Not specified	COMPLETED	Microarray Analysis for Human Genetic Disease
NCT00026884	Not specified	RECRUITING	Collection of Serum and Tissue Samples From Patients With Biopsy-Proved or Suspected Malignant Disease
NCT02289326	Not specified	COMPLETED	Biomarker Monitoring in TP53 Mutation Carriers
NCT02958462	Not specified	RECRUITING	Pre-myeloid Cancer and Bone Marrow Failure Clinic Study
NCT03160274	Not specified	RECRUITING	Genetic Analysis of Pheochromocytomas, Paragangliomas and Associated Conditions
NCT03426878	Not specified	COMPLETED	Cancer Health Assessments Reaching Many
NCT03857594	Not specified	ACTIVE_NOT_RECRUITING	Integrative Sequencing In Germline and Hereditary Tumours
NCT03973450	Not specified	UNKNOWN	Epidemiology of Pituitary Tumours: Prevalence of Associated Neoplasia
NCT03979612	Not specified	UNKNOWN	Evaluation of the Adhesion to the GENEPY Network
NCT04261972	Not specified	ACTIVE_NOT_RECRUITING	Cell-free DNA in Hereditary And High-Risk Malignancies 1
NCT04494945	Not specified	RECRUITING	Identifying and Caring for Individuals With Inherited Cancer Syndrome
NCT04541654	Not specified	RECRUITING	Li-Fraumeni & TP53 (LiFT UP): Understanding and Progress
NCT04763915	Not specified	ACTIVE_NOT_RECRUITING	Improving Care After Inherited Cancer Testing
NCT05562778	Not specified	RECRUITING	Chatbot to Maximize Hereditary Cancer Genetic Risk Assessment
NCT05664867	Not specified	RECRUITING	Implementation of Population Cancer Genetic Services in Federally Qualified Health Centers (FQHC)
NCT05721326	Not specified	COMPLETED	Sequential EHR Based Interventions to Increase Genetic Testing for Breast and Ovarian Cancer Predisposition
NCT06096688	Not specified	RECRUITING	Discovering New Targets for Colorectal and Endometrial Cancer Risk Reduction
NCT06654466	Not specified	RECRUITING	Closing the GAPS: Guideline Adherence, Prevention and Surveillance in Hereditary Cancer
NCT06708429	Not specified	RECRUITING	Lynch Syndrome X-Talk of Enteral Mucosa With Immune System
NCT06726642	Not specified	RECRUITING	CfDNA in Hereditary And High-risk Malignancies 2
NCT06914726	Not specified	ENROLLING_BY_INVITATION	Patient Centered Clinical Decision Support for Hereditary Cancer Syndromes
NCT06927947	Not specified	RECRUITING	Navigation Interventions to Improve Cascade Genetic Testing Among Relatives of Patients With Hereditary Cancer Syndromes
NCT06999954	Not specified	RECRUITING	Shwachman-Diamond Syndrome Global Patient Survey and Partnering Platform
NCT07052266	Not specified	RECRUITING	Trial of Combined Obstetric Carrier Screening and Hereditary Cancer Screening
NCT07195071	Not specified	RECRUITING	Feasibility Trial of Combination of Obstetrical Carrier Screening and Hereditary Cancer Screening
NCT07378423	Not specified	RECRUITING	Questionnaire on Congenital Cancer Signs Through Self-Assessment
NCT07381985	Not specified	ENROLLING_BY_INVITATION	Strategy for Management of Patients With Hereditary Cancer Syndromes (HCS) in a Rural Environment
NCT07542405	Not specified	NOT_YET_RECRUITING	A Web-Based Program (Kindred) to Improve the Understanding of Genetic Cancer Risk and Cancer Genetic Testing in African American Families