MBD6

Summary

MBD6 (methyl-CpG binding domain protein 6, HGNC:20445) is a protein-coding gene on chromosome 12q13.3, encoding Methyl-CpG-binding domain protein 6 (Q96DN6). Non-catalytic component of the polycomb repressive deubiquitinase (PR-DUB) complex, a complex that specifically mediates deubiquitination of histone H2A monoubiquitinated at ‘Lys-120’ (H2AK119ub1).

Enables chromatin binding activity. Located in chromocenter; fibrillar center; and nucleoplasm. Implicated in autism spectrum disorder.

Source: NCBI Gene 114785 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 208 total
• MANE Select transcript: NM_052897

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20445
Approved symbol	MBD6
Name	methyl-CpG binding domain protein 6
Location	12q13.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1887
Ensembl gene	ENSG00000166987
Ensembl biotype	protein_coding
OMIM	619458
Entrez	114785

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 11 protein_coding, 3 nonsense_mediated_decay, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000355673, ENST00000546632, ENST00000546805, ENST00000547545, ENST00000547844, ENST00000548550, ENST00000548887, ENST00000549042, ENST00000549231, ENST00000549623, ENST00000551351, ENST00000552163, ENST00000552255, ENST00000552659, ENST00000861014, ENST00000861015

RefSeq mRNA: 1 — MANE Select: NM_052897 NM_052897

CCDS: CCDS8944

Canonical transcript exons

ENST00000355673 — 13 exons

Exon	Start	End
ENSE00001108445	57527507	57527660
ENSE00001108448	57528147	57528560
ENSE00001108451	57527848	57528017
ENSE00001108452	57525348	57526388
ENSE00001108455	57528666	57528718
ENSE00001179559	57524029	57524092
ENSE00001267870	57528946	57529009
ENSE00001267896	57526566	57527227
ENSE00001412336	57529160	57530148
ENSE00002351580	57522824	57523011
ENSE00003627042	57524280	57524416
ENSE00003687689	57524953	57525115
ENSE00003694418	57524720	57524822

Expression profiles

Bgee: expression breadth ubiquitous, 251 present calls, max score 98.73.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 38.2534 / max 580.1176, expressed in 1819 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
126240	20.3451	1793
126239	9.6973	1760
126244	2.9068	1260
126245	1.6065	925
126236	0.7174	272
126246	0.6407	359
126247	0.5721	298
126235	0.4929	282
126237	0.4138	153
206752	0.3135	141

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oviduct epithelium	UBERON:0004804	98.73	gold quality
right lobe of thyroid gland	UBERON:0001119	98.56	gold quality
left lobe of thyroid gland	UBERON:0001120	98.45	gold quality
pituitary gland	UBERON:0000007	98.33	gold quality
adenohypophysis	UBERON:0002196	98.21	gold quality
thyroid gland	UBERON:0002046	98.01	gold quality
left testis	UBERON:0004533	97.16	gold quality
right testis	UBERON:0004534	97.14	gold quality
mucosa of stomach	UBERON:0001199	96.86	gold quality
right uterine tube	UBERON:0001302	96.81	gold quality
tendon of biceps brachii	UBERON:0008188	96.71	gold quality
metanephros cortex	UBERON:0010533	96.54	gold quality
blood	UBERON:0000178	96.00	gold quality
spleen	UBERON:0002106	95.89	gold quality
endocervix	UBERON:0000458	95.82	gold quality
body of uterus	UBERON:0009853	95.81	gold quality
testis	UBERON:0000473	95.66	gold quality
granulocyte	CL:0000094	95.58	gold quality
minor salivary gland	UBERON:0001830	95.16	gold quality
body of stomach	UBERON:0001161	95.12	gold quality
right ovary	UBERON:0002118	95.09	gold quality
left uterine tube	UBERON:0001303	95.04	gold quality
right adrenal gland	UBERON:0001233	94.97	gold quality
left ovary	UBERON:0002119	94.87	gold quality
small intestine Peyer’s patch	UBERON:0003454	94.84	gold quality
upper arm skin	UBERON:0004263	94.73	gold quality
right adrenal gland cortex	UBERON:0035827	94.73	gold quality
ectocervix	UBERON:0012249	94.57	gold quality
transverse colon	UBERON:0001157	94.47	gold quality
metanephros	UBERON:0000081	94.44	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.14

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR6A1

miRNA regulators (miRDB)

149 targeting MBD6, 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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-137-3P	99.87	74.74	2401

Literature-anchored findings (GeneRIF, showing 7)

• MBD5 and MBD6 are unlikely to be methyl-binding proteins, yet they may contribute to the formation or function of heterochromatin. (PMID:20700456)
• MBD6 is regulated by Ago2 via an interaction with Oct4, which alters self-renewal and gene expression in human adipose tissue-derived stem cells. (PMID:23052207)
• This study demonstrates examples of autistic patients carrying alterations in MBD6. (PMID:23055267)
• We studied and showed that both MBD5 and MBD6 interact with the mammalian PR-DUB Polycomb protein complex in a mutually exclusive manner, and that the MBD of MBD5 and MBD6 is both necessary and sufficient to mediate this interaction. (PMID:24634419)
• Frameshift mutations of MBD6 gene is associated with stomach and colorectal cancers. (PMID:25638327)
• Our findings imply that reduced stability and enhanced dynamics of MBD1 or MBD6 is the origin of ATP7B dysfunction in Wilson disease patients with the G85V or G591D mutation. (PMID:27744583)
• The decreased expression of the MBD6 protein was correlated with the tumor size of uterine leiomyomas (PMID:31313936)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	mbd6	ENSDARG00000086980
mus_musculus	Mbd6	ENSMUSG00000025409
rattus_norvegicus	Mbd6	ENSRNOG00000006209
drosophila_melanogaster	sba	FBGN0016754

Paralogs (1): MBD5 (ENSG00000204406)

Protein

Protein identifiers

Methyl-CpG-binding domain protein 6 — Q96DN6 (reviewed: Q96DN6)

Alternative names: Methyl-CpG-binding protein MBD6

All UniProt accessions (11): Q96DN6, A0A0C4DGJ6, F8VNX1, F8VPC4, F8VU14, F8VVK7, F8VW40, F8VZD7, H0YHD1, H0YHN1, H0YIU1

UniProt curated annotations — full annotation on UniProt →

Function. Non-catalytic component of the polycomb repressive deubiquitinase (PR-DUB) complex, a complex that specifically mediates deubiquitination of histone H2A monoubiquitinated at ‘Lys-120’ (H2AK119ub1). Important for stability of PR-DUB components and stimulating its ubiquitinase activity. As part of the PR-DUB complex, associates with chromatin enriched in histone marks H3K4me1, H3K4me3, and H3K27Ac, but not in H3K27me3. MBD5 and MBD6 containing complexes associate with distinct chromatin regions enriched in genes involved in different pathways. Heterochromatin recruitment is not mediated by DNA methylation. The PR-DUB complex is an epigenetic regulator of gene expression, including genes involved in development, cell communication, signaling, cell proliferation and cell viability; may promote cancer cell growth.

Subunit / interactions. Core component of the polycomb repressive deubiquitinase (PR-DUB) complex, at least composed of BAP1, one of ASXL1, ASXL2 or (probably) ASXL3, and one of MBD5 or MBD6. Distinct combinations of ASXL and MBD proteins may preferentially bind specific histone modification marks. The PR-DUB core associates with a number of accessory proteins, including FOXK1, FOXK2, KDM1B, HCFC1 and OGT; KDM1B specifically associates with ASXL2 PR-DUB complexes. Interacts (via MBD domain) with ASXL1, ASXL2 and ASXL3 (via PHD domain); the interaction is probably direct, mediates association with other PR-DUB complex core components.

Subcellular location. Nucleus. Chromosome.

Domain organisation. Possesses a methyl-binding domain (MBD) that is necessary for chromocentric localization. The MBD may lack methyl-binding activity.

Miscellaneous. Named ‘methyl-CpG-binding domain protein’ for homology to other methyl-CpG-binding domain proteins and the presence of an MBD domain, MBD5 and MBD6 may have evolutionarily lost the ability to bind methylated DNA and are recruited to heterochromatin by alternative signals.

RefSeq proteins (1): NP_443129* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001739	Methyl_CpG_DNA-bd	Domain
IPR016177	DNA-bd_dom_sf	Homologous_superfamily

UniProt features (35 total): compositionally biased region 25, region of interest 4, mutagenesis site 2, sequence conflict 2, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96DN6-F1	43.72	0.01

Functional residue map

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

Mutagenesis-validated functional residues (2):

Position	Phenotype
61	disrupts interaction with asxl1/2/3; when associated with a-66.
66	disrupts interaction with asxl1/2/3; when associated with a-61.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-5689603	UCH proteinases
R-HSA-392499	Metabolism of proteins
R-HSA-5688426	Deubiquitination
R-HSA-597592	Post-translational protein modification

MSigDB gene sets: 193 (showing top): RNGTGGGC_UNKNOWN, MYOGENIN_Q6, AAGCCAT_MIR135A_MIR135B, TGACCTY_ERR1_Q2, TAL1ALPHAE47_01, TTGGGAG_MIR150, CATTTCA_MIR203, ATF1_Q6, CCTGTGA_MIR513, TCCCCAC_MIR491, AAAGACA_MIR511, AACTTT_UNKNOWN, MYB_Q3, MAF_Q6, USF_02

GO Biological Process (0):

GO Molecular Function (3): chromatin binding (GO:0003682), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (5): fibrillar center (GO:0001650), nucleus (GO:0005634), nucleoplasm (GO:0005654), chromosome (GO:0005694), chromocenter (GO:0010369)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Deubiquitination	1
Post-translational protein modification	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
cellular anatomical structure	2
intracellular membraneless organelle	2
nucleic acid binding	1
nucleolus	1
intracellular membrane-bounded organelle	1
nuclear lumen	1

Protein interactions and networks

STRING

1184 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MBD6	MBD4	O95243	624
MBD6	ATP7B	P35670	582
MBD6	MBD5	Q9P267	575
MBD6	COMMD1	Q8N668	497
MBD6	Q08EI0	Q08EI0	475
MBD6	ASXL2	Q76L83	443
MBD6	ATOX1	O00244	435
MBD6	FOXK2	Q01167	399
MBD6	BAP1	Q92560	388
MBD6	OGT	O15294	374
MBD6	FOXK1	P85037	368
MBD6	OR5M11	Q96RB7	348
MBD6	HCFC1	P51610	343
MBD6	DNMT1	P26358	341
MBD6	MECP2	P51608	329

IntAct

22 interactions, top by confidence:

A	B	Type	Score
ASXL2	MBD6	psi-mi:“MI:0915”(physical association)	0.670
ZEB2	MTA2	psi-mi:“MI:0914”(association)	0.580
RBM10	MBD6	psi-mi:“MI:0915”(physical association)	0.560
NCK2	MBD6	psi-mi:“MI:0915”(physical association)	0.560
C1qbp		psi-mi:“MI:0914”(association)	0.350
ASXL2	FOXK1	psi-mi:“MI:0914”(association)	0.350
CHCHD2	RECQL4	psi-mi:“MI:0914”(association)	0.350
ASXL2	CTRL	psi-mi:“MI:0914”(association)	0.350
ASXL1	OGT	psi-mi:“MI:0914”(association)	0.350
ASXL2	OGT	psi-mi:“MI:0914”(association)	0.350
BAP1	PSMD11	psi-mi:“MI:0914”(association)	0.350
HNF1B	BCL9	psi-mi:“MI:2364”(proximity)	0.270
YY1	SMCHD1	psi-mi:“MI:2364”(proximity)	0.270
FHIP1B	MED19	psi-mi:“MI:2364”(proximity)	0.270
RBM10	MBD6	psi-mi:“MI:0915”(physical association)	0.000
ASXL2	MBD6	psi-mi:“MI:0915”(physical association)	0.000
NCK2	MBD6	psi-mi:“MI:0915”(physical association)	0.000
DUSP12	MBD6	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (107): MBD6 (Affinity Capture-MS), MBD6 (Affinity Capture-MS), MBD6 (Affinity Capture-MS), MBD6 (Affinity Capture-MS), MBD6 (Affinity Capture-MS), MBD6 (Affinity Capture-MS), MBD6 (Two-hybrid), MBD6 (Two-hybrid), MBD6 (Two-hybrid), RBM10 (Two-hybrid), MBD6 (Affinity Capture-MS), MBD6 (Affinity Capture-MS), MBD6 (Proximity Label-MS), MBD6 (Proximity Label-MS), MBD6 (Affinity Capture-Western)

ESM2 similar proteins: A0A2Z4LIS9, A2A9I7, A7X8B3, A7X8B5, A7X8B7, A7X8B9, A7X8C2, A7X8C4, A7X8C7, A7X8C9, A7X8D2, A7X8D4, A7XW16, A7XW20, A7XW25, A8WFF7, O08550, O15054, O15353, O43151, O43474, O55087, O94993, P08151, P19419, P82976, Q00175, Q00587, Q3TY92, Q5NCY0, Q5TGY3, Q60793, Q63449, Q66HC8, Q6NZN1, Q6PAL7, Q80U22, Q80WJ1, Q86UU5, Q8BG87

Diamond homologs: A8JR92, B1AYB6, O88508, Q1LZ53, Q3TY92, Q96DN6, Q9P267, Q9Y6K1

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 21 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
UCH proteinases	7	54.3×	3e-09

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	167
Likely benign	18
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

1759 predictions. Top by Δscore:

Variant	Effect	Δscore
12:57524718:A:AG	acceptor_gain	1.0000
12:57524719:G:GA	acceptor_gain	1.0000
12:57524948:TACAG:T	acceptor_loss	1.0000
12:57524950:CAGGT:C	acceptor_loss	1.0000
12:57524952:G:GC	acceptor_loss	1.0000
12:57525111:TCCTG:T	donor_gain	1.0000
12:57525116:G:GA	donor_loss	1.0000
12:57525117:T:A	donor_loss	1.0000
12:57528719:G:GG	donor_gain	1.0000
12:57528944:A:AG	acceptor_gain	1.0000
12:57528945:G:GA	acceptor_gain	1.0000
12:57528945:GCCC:G	acceptor_gain	1.0000
12:57528945:GCCCT:G	acceptor_gain	1.0000
12:57529005:CCCGA:C	donor_gain	1.0000
12:57529006:CCGA:C	donor_gain	1.0000
12:57529007:CGA:C	donor_gain	1.0000
12:57529007:CGAG:C	donor_loss	1.0000
12:57529008:GA:G	donor_gain	1.0000
12:57529008:GAG:G	donor_gain	1.0000
12:57529009:AGTA:A	donor_loss	1.0000
12:57529010:G:GG	donor_gain	1.0000
12:57529011:T:A	donor_loss	1.0000
12:57529014:G:GG	donor_gain	1.0000
12:57523008:CGCGG:C	donor_loss	0.9900
12:57523009:GCG:G	donor_gain	0.9900
12:57523009:GCGGT:G	donor_loss	0.9900
12:57523011:GGTG:G	donor_loss	0.9900
12:57523012:G:GG	donor_gain	0.9900
12:57523013:T:A	donor_loss	0.9900
12:57523014:GAGT:G	donor_loss	0.9900

AlphaMissense

6255 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:57524376:T:A	W25R	1.000
12:57524376:T:C	W25R	1.000
12:57524377:G:C	W25S	1.000
12:57524378:G:C	W25C	1.000
12:57524378:G:T	W25C	1.000
12:57524409:T:G	Y36D	1.000
12:57524737:T:C	L44P	1.000
12:57524763:T:G	Y53D	1.000
12:57524767:T:A	L54H	1.000
12:57524767:T:C	L54P	1.000
12:57524784:T:A	C60S	1.000
12:57524784:T:C	C60R	1.000
12:57524785:G:A	C60Y	1.000
12:57524785:G:C	C60S	1.000
12:57524786:C:G	C60W	1.000
12:57524789:G:C	K61N	1.000
12:57524789:G:T	K61N	1.000
12:57524790:T:A	C62S	1.000
12:57524790:T:C	C62R	1.000
12:57524791:G:A	C62Y	1.000
12:57524791:G:C	C62S	1.000
12:57524792:C:G	C62W	1.000
12:57524797:T:C	L64P	1.000
12:57524802:T:A	C66S	1.000
12:57524802:T:C	C66R	1.000
12:57524803:G:A	C66Y	1.000
12:57524803:G:C	C66S	1.000
12:57524804:T:G	C66W	1.000
12:57524956:T:C	F74L	1.000
12:57524957:T:C	F74S	1.000

dbSNP variants (sampled 300 via entrez): RS1000179989 (12:57519646 G>A,C), RS1000204759 (12:57519297 C>T), RS1000321044 (12:57518956 G>A,C,T), RS1000456414 (12:57525766 C>G,T), RS1000576589 (12:57520323 A>C,G), RS1000632053 (12:57519244 T>C), RS1001296847 (12:57523790 A>G), RS1001365699 (12:57531416 C>T), RS1001589905 (12:57525083 G>A), RS1001644872 (12:57523978 T>C), RS1001783325 (12:57518722 G>A), RS1002117148 (12:57520035 G>A,C), RS1002348631 (12:57530110 C>T), RS1002721497 (12:57531347 ACC>A), RS1002998215 (12:57523470 G>T)

Disease associations

OMIM: gene MIM:619458 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010703_209	Brain morphology (MOSTest)	2.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases expression	2
Air Pollutants	affects expression, increases abundance, increases expression	2
Valproic Acid	affects cotreatment, increases expression, affects expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
arsenite	affects expression	1
butyraldehyde	decreases expression	1
manganese chloride	increases abundance, increases expression	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
perfluoro-n-nonanoic acid	decreases expression	1
ICG 001	increases expression	1
abrine	increases expression	1
PCI 5002	increases expression, affects cotreatment	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
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Arsenic	increases abundance, increases expression	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Cadmium	decreases expression, increases abundance	1
Caffeine	affects phosphorylation	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Doxorubicin	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1
Hydralazine	affects cotreatment, increases expression	1
Manganese	increases abundance, increases expression	1
Methyl Methanesulfonate	increases expression	1

Clinical trials (associated diseases)

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