MXD4

Summary

MXD4 (MAX dimerization protein 4, HGNC:13906) is a protein-coding gene on chromosome 4p16.3, encoding Max dimerization protein 4 (Q14582). Transcriptional repressor.

This gene is a member of the MAD gene family . The MAD genes encode basic helix-loop-helix-leucine zipper proteins that heterodimerize with MAX protein, forming a transcriptional repression complex. The MAD proteins compete for MAX binding with MYC, which heterodimerizes with MAX forming a transcriptional activation complex. Studies in rodents suggest that the MAD genes are tumor suppressors and contribute to the regulation of cell growth in differentiating tissues.

Source: NCBI Gene 10608 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 35 total
• MANE Select transcript: NM_006454

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13906
Approved symbol	MXD4
Name	MAX dimerization protein 4
Location	4p16.3
Locus type	gene with protein product
Status	Approved
Aliases	MAD4, MSTP149, MST149, bHLHc12
Ensembl gene	ENSG00000123933
Ensembl biotype	protein_coding
OMIM	620016
Entrez	10608

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 4 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000337190, ENST00000510822, ENST00000513372, ENST00000513380, ENST00000515378, ENST00000854675, ENST00000925217, ENST00000942649

RefSeq mRNA: 1 — MANE Select: NM_006454 NM_006454

CCDS: CCDS3361

Canonical transcript exons

ENST00000337190 — 6 exons

Exon	Start	End
ENSE00001348585	2247432	2250701
ENSE00002067789	2261917	2262109
ENSE00003554927	2251084	2251246
ENSE00003578150	2252408	2252522
ENSE00003622197	2261725	2261824
ENSE00003624012	2257982	2258011

Expression profiles

Bgee: expression breadth ubiquitous, 242 present calls, max score 98.51.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 42.3687 / max 877.6138, expressed in 1820 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
51112	36.5513	1816
51113	4.7623	1671
51111	0.6999	443
51114	0.3394	151
51110	0.0159	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	98.51	gold quality
cerebellar hemisphere	UBERON:0002245	98.44	gold quality
cerebellar cortex	UBERON:0002129	98.39	gold quality
cerebellum	UBERON:0002037	97.56	gold quality
adenohypophysis	UBERON:0002196	97.38	gold quality
right lung	UBERON:0002167	96.81	gold quality
pituitary gland	UBERON:0000007	96.67	gold quality
apex of heart	UBERON:0002098	96.49	gold quality
metanephros cortex	UBERON:0010533	96.23	gold quality
right adrenal gland cortex	UBERON:0035827	95.84	gold quality
descending thoracic aorta	UBERON:0002345	95.69	gold quality
right adrenal gland	UBERON:0001233	95.63	gold quality
tibial nerve	UBERON:0001323	95.59	gold quality
thoracic aorta	UBERON:0001515	95.51	gold quality
ascending aorta	UBERON:0001496	95.47	gold quality
right coronary artery	UBERON:0001625	95.46	gold quality
right lobe of thyroid gland	UBERON:0001119	95.07	gold quality
aorta	UBERON:0000947	94.98	gold quality
left adrenal gland cortex	UBERON:0035825	94.84	gold quality
left adrenal gland	UBERON:0001234	94.82	gold quality
left coronary artery	UBERON:0001626	94.82	gold quality
left lobe of thyroid gland	UBERON:0001120	94.81	gold quality
spleen	UBERON:0002106	94.78	gold quality
right uterine tube	UBERON:0001302	94.74	gold quality
popliteal artery	UBERON:0002250	94.72	gold quality
tibial artery	UBERON:0007610	94.71	gold quality
stromal cell of endometrium	CL:0002255	94.69	gold quality
body of uterus	UBERON:0009853	94.56	gold quality
sural nerve	UBERON:0015488	94.48	gold quality
coronary artery	UBERON:0001621	94.45	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-HCAD-13	yes	24.92
E-ANND-3	yes	11.01
E-MTAB-9689	no	171.84
E-MTAB-7037	no	74.80
E-ENAD-27	no	3.23

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
ID2
ODC1	Unknown

Upstream regulators (CollecTRI, top): MYC, ZBTB17

miRNA regulators (miRDB)

106 targeting MXD4, 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-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4713-3P	100.00	65.92	505
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-3682-5P	99.93	67.97	1163
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-4659A-3P	99.80	72.62	4248

Literature-anchored findings (GeneRIF, showing 7)

• regulation by a transcriptional repressor complex that contains Miz-1 and c-Myc (PMID:12418961)
• Data suggest that the biological function of the interaction between T-complex protein 10-like and MAD4 may be to maintain the differentiation state in liver cells. (PMID:15469726)
• replicative senescence-specific factors may block c-Myc inhibition of Miz-1 activation of hMad4 expression, and the continual presence of hMad4 protein may transcriptionally repress selected c-Myc target genes (PMID:16167342)
• The E3 ligase activity of c-IAP1 was not required for downregulation of Mad4 expression. (PMID:22895069)
• NUTM1-rearranged colorectal sarcoma: a clinicopathologically and genetically distinctive malignant neoplasm with a poor prognosis. (PMID:33714983)
• MXD4/MAD4 Regulates Human Keratinocyte Precursor Fate. (PMID:36007550)
• Targeting UHRF1-SAP30-MXD4 axis for leukemia initiating cell eradication in myeloid leukemia. (PMID:36302855)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	mxd4	ENSDARG00000054031
mus_musculus	Mxd4	ENSMUSG00000037235
rattus_norvegicus	Mxd4	ENSRNOG00000015033
caenorhabditis_elegans		WBGENE00003163

Paralogs (4): MXD1 (ENSG00000059728), MNT (ENSG00000070444), MXI1 (ENSG00000119950), MXD3 (ENSG00000213347)

Protein

Protein identifiers

Max dimerization protein 4 — Q14582 (reviewed: Q14582)

Alternative names: Class C basic helix-loop-helix protein 12, Max-associated protein 4, Max-interacting transcriptional repressor MAD4

All UniProt accessions (2): Q14582, H0Y8Z5

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional repressor. Binds with MAX to form a sequence-specific DNA-binding protein complex which recognizes the core sequence 5’-CAC[GA]TG-3’. Antagonizes MYC transcriptional activity by competing for MAX and suppresses MYC dependent cell transformation.

Subunit / interactions. Efficient DNA binding requires dimerization with another bHLH protein. Binds DNA as a heterodimer with MAX. Interacts with SIN3A AND SIN3B. Interacts with RNF17.

Subcellular location. Nucleus.

RefSeq proteins (1): NP_006445* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011598	bHLH_dom	Domain
IPR036638	HLH_DNA-bd_sf	Homologous_superfamily

Pfam: PF00010

UniProt features (6 total): region of interest 2, compositionally biased region 2, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14582-F1	73.22	0.35

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-1251985	Nuclear signaling by ERBB4
R-HSA-1236394	Signaling by ERBB4
R-HSA-162582	Signal Transduction
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases

MSigDB gene sets: 238 (showing top): RRAGTTGT_UNKNOWN, PAX4_01, GCANCTGNY_MYOD_Q6, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, LINDGREN_BLADDER_CANCER_CLUSTER_3_DN, CACCAGC_MIR138, USF_C, SP1_Q2_01, PATIL_LIVER_CANCER, MODULE_66, GTGCCTT_MIR506, MISSIAGLIA_REGULATED_BY_METHYLATION_UP, MYCMAX_01

GO Biological Process (2): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of transcription by RNA polymerase II (GO:0006357)

GO Molecular Function (5): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), protein dimerization activity (GO:0046983), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (3): chromatin (GO:0000785), nucleoplasm (GO:0005654), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Signaling by ERBB4	1
Signaling by Receptor Tyrosine Kinases	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
cellular anatomical structure	2
negative regulation of DNA-templated transcription	1
regulation of DNA-templated transcription	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
protein binding	1
nucleic acid binding	1
binding	1
chromosome	1
nuclear lumen	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

772 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MXD4	MLXIPL	Q9NP71	931
MXD4	MLX	Q9UH92	927
MXD4	MNT	Q99583	895
MXD4	MLXIP	Q9HAP2	895
MXD4	NIF3L1	Q9GZT8	765
MXD4	PKLR	P11973	680
MXD4	HSD17B1	P14061	650
MXD4	SIN3A	Q96ST3	627
MXD4	XPO1	O14980	565
MXD4	MAX	P25912	512
MXD4	MGA	Q8IWI9	478
MXD4	ZNF532	Q9HCE3	453
MXD4	NUTM1	Q86Y26	446
MXD4	KIAA1191	Q96A73	437
MXD4	MYC	P01106	403

IntAct

14 interactions, top by confidence:

A	B	Type	Score
MAX	E2F6	psi-mi:“MI:0914”(association)	0.710
TCP10L	MXD4	psi-mi:“MI:0915”(physical association)	0.660
MXD4	TCP10L	psi-mi:“MI:0915”(physical association)	0.660
MXD4	TCP10L	psi-mi:“MI:0403”(colocalization)	0.660
IFNA14	MXD4	psi-mi:“MI:0915”(physical association)	0.370
Max	PABPN1	psi-mi:“MI:0914”(association)	0.350
Trappc11	TRAPPC3	psi-mi:“MI:0914”(association)	0.350
MAX	SMARCA5	psi-mi:“MI:0914”(association)	0.350
MAX	AGRN	psi-mi:“MI:0914”(association)	0.350

BioGRID (24): MXD4 (Affinity Capture-MS), MXD4 (Affinity Capture-MS), MXD4 (Affinity Capture-MS), MXD4 (Affinity Capture-MS), MXD4 (Affinity Capture-MS), MXD4 (Affinity Capture-Western), MXD4 (Affinity Capture-MS), MXD4 (Affinity Capture-MS), MXD4 (Two-hybrid), MLX (Two-hybrid), MAX (Two-hybrid), MXD4 (Affinity Capture-MS), MXD4 (Two-hybrid), MXD4 (Affinity Capture-Western), MXD4 (Two-hybrid)

ESM2 similar proteins: A0A804C8T0, A2X9L8, A2XD15, A2XK00, A2XY47, A2YAW8, A2Z730, A7YY73, B8APB5, B8BLA3, F4JCN9, O54791, P13097, P43273, Q00P32, Q01069, Q03062, Q07816, Q0DDF6, Q0DUR2, Q0VH33, Q10R47, Q14582, Q28DB3, Q2R1J3, Q338G6, Q39140, Q5FWT9, Q5K4R0, Q60948, Q6ASS9, Q6IVC3, Q6Q9H6, Q6YUX0, Q7SX95, Q7X742, Q7X993, Q7XJU2, Q8GW32, Q90595

Diamond homologs: G5EG44, O09015, P50538, P50539, P50540, P50541, Q05195, Q0VFI9, Q0VH33, Q0VH34, Q14582, Q28DB3, Q60948, Q62912, Q7SX95, Q80US8, Q9BW11, O08789, Q0VH32, Q99583, P49709, P52160, Q7ZVS9, Q90342, A1YG22, A2T7L5, B8XIA5, G5EEH5, P01106, P01108, P01109, P01110, P03966, P04198, P06171, P06295, P06646, P09416, P0C0N8, P0C0N9

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
MAX	“up-regulates activity”	MXD4	binding
SMC3	“down-regulates activity”	MXD4	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	23
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1520 predictions. Top by Δscore:

Variant	Effect	Δscore
4:2250699:CTT:C	acceptor_gain	1.0000
4:2250702:C:CC	acceptor_gain	1.0000
4:2251080:CCA:C	donor_loss	1.0000
4:2251081:CAC:C	donor_loss	1.0000
4:2251083:CCTTG:C	donor_gain	1.0000
4:2251098:T:TA	donor_gain	1.0000
4:2251242:AGTTT:A	acceptor_gain	1.0000
4:2251243:GTTT:G	acceptor_gain	1.0000
4:2251244:TTT:T	acceptor_gain	1.0000
4:2251245:TT:T	acceptor_gain	1.0000
4:2251246:TCT:T	acceptor_loss	1.0000
4:2251247:C:CC	acceptor_gain	1.0000
4:2251248:T:G	acceptor_loss	1.0000
4:2252406:A:AC	donor_gain	1.0000
4:2252406:AC:A	donor_gain	1.0000
4:2252407:C:A	donor_loss	1.0000
4:2252407:C:CC	donor_gain	1.0000
4:2252407:CC:C	donor_gain	1.0000
4:2252407:CCTTG:C	donor_gain	1.0000
4:2252518:CTCGT:C	acceptor_gain	1.0000
4:2252519:TCGT:T	acceptor_gain	1.0000
4:2252520:CGT:C	acceptor_gain	1.0000
4:2252520:CGTC:C	acceptor_gain	1.0000
4:2252521:GT:G	acceptor_gain	1.0000
4:2252522:TC:T	acceptor_loss	1.0000
4:2252523:C:CC	acceptor_gain	1.0000
4:2252523:C:T	acceptor_loss	1.0000
4:2250697:CACTT:C	acceptor_gain	0.9900
4:2250700:TT:T	acceptor_gain	0.9900
4:2250700:TTCTA:T	acceptor_loss	0.9900

AlphaMissense

1350 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:2252433:A:G	L95P	1.000
4:2252490:A:G	L76P	1.000
4:2251200:A:G	L119P	0.999
4:2251242:A:G	L105P	0.999
4:2252424:G:T	A98D	0.999
4:2252425:C:G	A98P	0.999
4:2252433:A:T	L95Q	0.999
4:2252436:A:G	L94P	0.999
4:2252448:G:A	T90I	0.999
4:2252490:A:T	L76H	0.999
4:2252499:A:G	L73P	0.999
4:2252511:A:G	L69P	0.999
4:2252522:T:A	R65S	0.999
4:2252522:T:G	R65S	0.999
4:2257982:C:A	R65I	0.999
4:2257982:C:G	R65T	0.999
4:2257990:T:A	E62D	0.999
4:2257990:T:G	E62D	0.999
4:2252442:A:G	L92P	0.998
4:2252507:C:A	R70S	0.998
4:2252507:C:G	R70S	0.998
4:2252511:A:T	L69H	0.998
4:2257987:C:A	K63N	0.998
4:2257987:C:G	K63N	0.998
4:2257991:T:A	E62V	0.998
4:2258004:G:C	H58D	0.998
4:2261947:C:G	A12P	0.998
4:2251179:A:G	L126P	0.997
4:2252412:A:G	I102T	0.997
4:2252412:A:T	I102N	0.997

dbSNP variants (sampled 300 via entrez): RS1000048895 (4:2262504 T>C), RS1000203943 (4:2260668 G>A), RS1000311129 (4:2251022 G>A), RS1000353867 (4:2256511 GCA>G), RS1000395994 (4:2259556 C>T), RS1000489630 (4:2256734 A>G), RS1000653021 (4:2261672 C>CG), RS1000689276 (4:2257523 G>A), RS1000710254 (4:2256327 C>A,T), RS1000779407 (4:2255345 G>A), RS1000991980 (4:2248825 C>T), RS1001052847 (4:2251917 G>A), RS1001217012 (4:2250388 G>A), RS1001381829 (4:2254281 T>A,C), RS1001453343 (4:2248029 C>T)

Disease associations

OMIM: gene MIM:620016 | disease phenotypes: MIM:118400

GenCC curated gene-disease

Mondo (1): cherubism (MONDO:0007315)

Orphanet (1): Cherubism (Orphanet:184)

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST010242_184	HDL cholesterol levels	4.000000e-08
GCST90002393_216	Monocyte count	4.000000e-12

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0005091	monocyte count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D002636	Cherubism	C05.116.099.708.375.199; C05.500.174; C07.320.173; C16.131.621.207.540.170; C16.320.170

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression, increases expression	4
Valproic Acid	decreases expression, increases methylation	3
sodium arsenite	decreases expression, increases expression	2
bisphenol S	decreases expression, affects cotreatment	2
Estradiol	decreases expression	2
Smoke	decreases expression, increases expression	2
Particulate Matter	decreases expression, increases abundance, affects cotreatment	2
aristolochic acid I	increases expression	1
GSK-J4	increases expression	1
afuresertib	increases expression	1
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
geraniol	increases expression	1
lead acetate	decreases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
sulforaphane	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	decreases expression	1
potassium chromate(VI)	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
cupric chloride	decreases expression	1
CGP 52608	increases reaction, affects binding	1
2-palmitoylglycerol	increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
palbociclib	increases expression	1
jinfukang	affects cotreatment, increases expression	1
(+)-JQ1 compound	increases expression	1
bisphenol AF	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01630447	Not specified	RECRUITING	Genetic and Functional Analysis of Cherubism
NCT01916772	Not specified	COMPLETED	Natural History of Cherubism Observational Study