BEX4

Summary

BEX4 (brain expressed X-linked 4, HGNC:25475) is a protein-coding gene on chromosome Xq22.1, encoding Protein BEX4 (Q9NWD9). May play a role in microtubule deacetylation by negatively regulating the SIRT2 deacetylase activity toward alpha-tubulin and thereby participate in the control of cell cycle progression and genomic stability.

This gene is a member of the brain expressed X-linked gene family. The proteins encoded by some of the other members of this family act as transcription elongation factors which allow RNA polymerase II to escape pausing during elongation. Multiple alternatively spliced variants, encoding the same protein, have been identified.

Source: NCBI Gene 56271 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 33 total
• MANE Select transcript: NM_001080425

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25475
Approved symbol	BEX4
Name	brain expressed X-linked 4
Location	Xq22.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ10097
Ensembl gene	ENSG00000102409
Ensembl biotype	protein_coding
OMIM	300692
Entrez	56271

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 18 protein_coding

ENST00000372691, ENST00000372695, ENST00000906428, ENST00000906429, ENST00000906430, ENST00000906431, ENST00000906432, ENST00000934077, ENST00000934078, ENST00000934079, ENST00000934080, ENST00000934081, ENST00000934082, ENST00000934083, ENST00000934084, ENST00000934085, ENST00000934086, ENST00000962075

RefSeq mRNA: 2 — MANE Select: NM_001080425 NM_001080425, NM_001127688

CCDS: CCDS35355

Canonical transcript exons

ENST00000372695 — 3 exons

Exon	Start	End
ENSE00000674092	103215682	103215764
ENSE00001458401	103215108	103215238
ENSE00001458417	103216149	103217246

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 99.11.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 87.6348 / max 1194.0314, expressed in 1687 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
197004	87.6348	1687

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
prefrontal cortex	UBERON:0000451	99.11	gold quality
Brodmann (1909) area 9	UBERON:0013540	99.09	gold quality
frontal pole	UBERON:0002795	99.00	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	99.00	gold quality
nucleus accumbens	UBERON:0001882	98.98	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.87	gold quality
hypothalamus	UBERON:0001898	98.83	gold quality
pons	UBERON:0000988	98.81	gold quality
caudate nucleus	UBERON:0001873	98.81	gold quality
amygdala	UBERON:0001876	98.79	gold quality
right frontal lobe	UBERON:0002810	98.78	gold quality
cingulate cortex	UBERON:0003027	98.77	gold quality
anterior cingulate cortex	UBERON:0009835	98.76	gold quality
cerebellar cortex	UBERON:0002129	98.71	gold quality
spinal cord	UBERON:0002240	98.71	gold quality
frontal cortex	UBERON:0001870	98.70	gold quality
cerebellar hemisphere	UBERON:0002245	98.70	gold quality
neocortex	UBERON:0001950	98.64	gold quality
right hemisphere of cerebellum	UBERON:0014890	98.60	gold quality
cortical plate	UBERON:0005343	98.58	gold quality
putamen	UBERON:0001874	98.56	gold quality
Brodmann (1909) area 10	UBERON:0013541	98.55	gold quality
lateral nuclear group of thalamus	UBERON:0002736	98.53	gold quality
cerebral cortex	UBERON:0000956	98.51	gold quality
cerebellar vermis	UBERON:0004720	98.50	gold quality
telencephalon	UBERON:0001893	98.49	gold quality
cerebellum	UBERON:0002037	98.49	gold quality
forebrain	UBERON:0001890	98.47	gold quality
adenohypophysis	UBERON:0002196	98.46	gold quality
paraflocculus	UBERON:0005351	98.45	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-GEOD-134144	yes	29.76
E-MTAB-7316	yes	16.38
E-MTAB-5061	yes	11.31
E-MTAB-8410	yes	8.68
E-GEOD-84465	yes	6.59
E-CURD-112	yes	6.26
E-GEOD-83139	yes	4.26
E-MTAB-10290	no	129.71
E-CURD-114	no	18.03
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

55 targeting BEX4, 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-8485	100.00	77.57	4731
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-8068	99.98	73.85	2376
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548J-5P	99.94	71.14	3489

Literature-anchored findings (GeneRIF, showing 5)

• Study provides evidence that BEX4 functions as tumor suppressor by inhibiting proliferation and growth of oral squamous cell carcinoma (OSCC). Decreased BEX4 contributes to the increased proliferative propensity of OSCC. (PMID:27297407)
• BEX4 overexpression causes an imbalance between TUB acetylation and deacetylation by SIRT2 inhibition and induces oncogenic aneuploidy transformation. (PMID:27512957)
• BEX4 positively regulated the expression of OCT4, silencing of which reduced the proliferation of A549 and H1975cells with over-expressed BEX4. (PMID:29660335)
• these results suggest that the oncogenicity of BEX4 is conferred by PLK1-mediated phosphorylation, and thus, the BEX4-PLK1 interaction is a novel oncogenic signal that enables the acquisition of chromosomal aneuploidy. (PMID:30367032)
• Aberrant brain-expressed X-linked 4 (BEX4) expression is a novel prognostic biomarker in gastric cancer. (PMID:33217815)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Bex4	ENSMUSG00000047844
mus_musculus	Bex6	ENSMUSG00000075269
rattus_norvegicus	Bex4	ENSRNOG00000062806

Protein

Protein identifiers

Protein BEX4 — Q9NWD9 (reviewed: Q9NWD9)

Alternative names: BEX1-like protein 1, Brain-expressed X-linked protein 4, Nerve growth factor receptor-associated protein 3

All UniProt accessions (1): Q9NWD9

UniProt curated annotations — full annotation on UniProt →

Function. May play a role in microtubule deacetylation by negatively regulating the SIRT2 deacetylase activity toward alpha-tubulin and thereby participate in the control of cell cycle progression and genomic stability. In absence of reductive stress, acts as a pseudosubstrate for the CRL2(FEM1B) complex: associates with FEM1B via zinc, thereby preventing association between FEM1B and its substrates.

Subunit / interactions. Interacts with alpha-tubulin. Interacts with SIRT2.

Subcellular location. Cytoplasm. Cytoskeleton. Spindle pole. Nucleus.

Tissue specificity. Very high expression in heart, skeletal muscle, liver, and kidney. The levels of expression are uniform throughout the brain.

Post-translational modifications. Ubiquitinated and degraded by the proteasome.

Similarity. Belongs to the BEX family.

RefSeq proteins (2): NP_001073894, NP_001121160 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007623	BEX	Family
IPR021156	TF_A-like/BEX	Family

Pfam: PF04538

UniProt features (6 total): region of interest 3, chain 1, compositionally biased region 1, binding site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NWD9-F1	64.35	0.08

Functional residue map

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

Ligand- & substrate-binding residues (1): 117

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 194 (showing top): WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, GOBP_REGULATION_OF_PROTEIN_DEACETYLATION, MODULE_418, GOZGIT_ESR1_TARGETS_DN, GOBP_MACROMOLECULE_DEACYLATION, TRAYNOR_RETT_SYNDROM_DN, KOYAMA_SEMA3B_TARGETS_UP, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_5, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, ONDER_CDH1_TARGETS_2_UP, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_METABOLIC_PROCESS, HELLER_HDAC_TARGETS_SILENCED_BY_METHYLATION_UP, FLECHNER_BIOPSY_KIDNEY_TRANSPLANT_REJECTED_VS_OK_DN, ONDER_CDH1_SIGNALING_VIA_CTNNB1, IVANOVA_HEMATOPOIESIS_EARLY_PROGENITOR

GO Biological Process (5): chromosome segregation (GO:0007059), regulation of cell migration (GO:0030334), negative regulation of protein ubiquitination (GO:0031397), regulation of cell population proliferation (GO:0042127), negative regulation of tubulin deacetylation (GO:1904428)

GO Molecular Function (5): histone deacetylase binding (GO:0042826), alpha-tubulin binding (GO:0043014), metal ion binding (GO:0046872), molecular function inhibitor activity (GO:0140678), protein binding (GO:0005515)

GO Cellular Component (7): spindle pole (GO:0000922), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), microtubule (GO:0005874), cytoskeleton (GO:0005856)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cell cycle process	1
cell migration	1
regulation of cell motility	1
protein ubiquitination	1
regulation of protein ubiquitination	1
negative regulation of protein modification by small protein conjugation or removal	1
cell population proliferation	1
regulation of cellular process	1
negative regulation of protein modification process	1
tubulin deacetylation	1
regulation of tubulin deacetylation	1
enzyme binding	1
tubulin binding	1
cation binding	1
molecular function regulator activity	1
binding	1
spindle	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
microtubule cytoskeleton	1
polymeric cytoskeletal fiber	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

360 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BEX4	TCEAL7	Q9BRU2	433
BEX4	TCEAL2	Q9H3H9	380
BEX4	RITA1	Q96K30	376
BEX4	TCEAL4	Q96EI5	371
BEX4	FAM47B	Q8NA70	367
BEX4	SATL1	Q86VE3	358
BEX4	C1orf53	Q5VUE5	349
BEX4	ITIH6	Q6UXX5	305
BEX4	SIMC1	Q8NDZ2	302
BEX4	BEX5	Q5H9J7	297
BEX4	CYTL1	Q9NRR1	296
BEX4	TCEAL1	Q15170	290
BEX4	TCEAL5	Q5H9L2	288
BEX4	DHX33	Q9H6R0	276
BEX4	TCEAL8	Q8IYN2	275

IntAct

8 interactions, top by confidence:

A	B	Type	Score
MPPED2	BEX4	psi-mi:“MI:0915”(physical association)	0.560
HSPB2	BEX4	psi-mi:“MI:0915”(physical association)	0.370
BEX4	FMR1	psi-mi:“MI:0915”(physical association)	0.370
BEX4	KLHL41	psi-mi:“MI:0914”(association)	0.350
MPPED2	BEX4	psi-mi:“MI:0915”(physical association)	0.000
PKNOX1	BEX4	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (21): BEX4 (Two-hybrid), BEX4 (Two-hybrid), BEX4 (Two-hybrid), GFM2 (Affinity Capture-MS), PPP2R2D (Affinity Capture-MS), ALDH6A1 (Affinity Capture-MS), CDKN2C (Affinity Capture-MS), GNB1L (Affinity Capture-MS), KIF3A (Affinity Capture-MS), KLHL41 (Affinity Capture-MS), HSD17B8 (Affinity Capture-MS), MTMR1 (Affinity Capture-MS), LYPLA1 (Affinity Capture-MS), PRKCD (Affinity Capture-MS), MAPK14 (Affinity Capture-MS)

ESM2 similar proteins: B3LVF9, B3P0Q4, B4HEN5, B4JTS9, B4K843, B4LY66, B4N943, B4PST7, B4QZV5, D5LWW7, F5HE12, F5HH39, F5HIC6, O55438, O91087, P03238, P03270, P0A3T0, P0A3T1, P0C1P3, P12541, P16766, P21186, P21277, P27556, P36715, P48313, Q07286, Q09230, Q17QW4, Q2PG52, Q3MKQ2, Q5R590, Q5SC49, Q64752, Q65947, Q6S6P9, Q6UDG4, Q77IS8, Q7M6R1

Diamond homologs: Q00994, Q2PG52, Q2TBV0, Q3MKP9, Q3MKQ1, Q3MKQ2, Q3ZBJ6, Q3ZBJ9, Q5H9J7, Q5R590, Q6PDU5, Q9BXY8, Q9CWT2, Q9HBH7, Q9NWD9, Q9R224, Q9WTZ8, Q9WTZ9, Q3TZW7

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PLK1	“up-regulates activity”	BEX4	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	17
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

345 predictions. Top by Δscore:

Variant	Effect	Δscore
X:103215754:GA:G	donor_gain	1.0000
X:103216145:CTA:C	acceptor_loss	1.0000
X:103216146:TA:T	acceptor_loss	1.0000
X:103216147:A:AG	acceptor_gain	1.0000
X:103216147:AG:A	acceptor_gain	1.0000
X:103216148:G:GG	acceptor_gain	1.0000
X:103216148:G:T	acceptor_loss	1.0000
X:103216148:GG:G	acceptor_gain	1.0000
X:103216148:GGA:G	acceptor_gain	1.0000
X:103216148:GGAGT:G	acceptor_gain	1.0000
X:103215235:GCAG:G	donor_gain	0.9900
X:103215236:CAGGT:C	donor_loss	0.9900
X:103215237:AGG:A	donor_loss	0.9900
X:103215239:GT:G	donor_loss	0.9900
X:103215240:T:A	donor_loss	0.9900
X:103215680:A:AG	acceptor_gain	0.9900
X:103215681:G:GG	acceptor_gain	0.9900
X:103215763:AGG:A	donor_loss	0.9900
X:103215764:GGTC:G	donor_loss	0.9900
X:103216139:T:A	acceptor_gain	0.9900
X:103215189:G:GT	donor_gain	0.9800
X:103215221:G:GT	donor_gain	0.9800
X:103215239:G:GG	donor_gain	0.9800
X:103215676:C:CA	acceptor_gain	0.9700
X:103215755:A:G	donor_gain	0.9700
X:103215755:A:T	donor_gain	0.9700
X:103215740:G:GT	donor_gain	0.9600
X:103215763:AGGTC:A	donor_gain	0.9600
X:103215466:C:T	donor_gain	0.9500
X:103215164:G:GA	donor_gain	0.9400

AlphaMissense

805 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:103216499:T:C	F116L	0.992
X:103216501:T:A	F116L	0.992
X:103216501:T:G	F116L	0.992
X:103216504:C:G	C117W	0.972
X:103216502:T:C	C117R	0.970
X:103216512:C:A	P120H	0.967
X:103216506:T:A	L118H	0.965
X:103216506:T:C	L118P	0.963
X:103216509:T:C	I119T	0.963
X:103216500:T:C	F116S	0.958
X:103216511:C:T	P120S	0.951
X:103216503:G:A	C117Y	0.948
X:103216500:T:G	F116C	0.943
X:103216512:C:T	P120L	0.941
X:103216512:C:G	P120R	0.939
X:103216511:C:A	P120T	0.938
X:103216337:T:C	F62L	0.937
X:103216339:T:A	F62L	0.937
X:103216339:T:G	F62L	0.937
X:103216489:C:A	N112K	0.932
X:103216489:C:G	N112K	0.932
X:103216502:T:A	C117S	0.931
X:103216503:G:C	C117S	0.931
X:103216466:T:C	F105L	0.914
X:103216468:C:A	F105L	0.914
X:103216468:C:G	F105L	0.914
X:103216497:A:T	D115V	0.912
X:103216503:G:T	C117F	0.911
X:103216497:A:G	D115G	0.908
X:103216502:T:G	C117G	0.903

dbSNP variants (sampled 300 via entrez): RS1000558680 (X:103217020 C>G), RS1002500324 (X:103216379 G>A), RS1004220666 (X:103214367 G>A), RS1004553294 (X:103214813 A>T), RS1005427643 (X:103215836 G>T), RS1006230329 (X:103217152 TATA>T), RS1006341572 (X:103216500 T>G), RS1008015231 (X:103215342 A>G), RS1008185094 (X:103217716 G>A,T), RS1008358556 (X:103213249 C>T), RS1009223651 (X:103216398 G>T), RS1010900108 (X:103214670 T>G), RS1011460687 (X:103213141 C>A), RS1012443106 (X:103214314 G>A), RS1012494037 (X:103213822 T>G)

Disease associations

OMIM: gene MIM:300692 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	2
Air Pollutants	decreases expression, increases abundance, increases expression	2
Valproic Acid	affects expression, increases expression, increases methylation	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
propionaldehyde	increases expression	1
bisphenol A	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	increases expression	1
perfluorooctanoic acid	increases expression	1
rutecarpine	increases expression	1
nickel sulfate	decreases expression	1
pentanal	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
nutlin 3	affects cotreatment, increases expression	1
abrine	increases expression	1
jinfukang	affects cotreatment, increases expression	1
Temozolomide	decreases expression	1
Aldehydes	increases expression	1
Benzo(a)pyrene	affects methylation	1
Cadmium	increases expression	1
Camptothecin	increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Dactinomycin	affects cotreatment, increases expression	1
Doxorubicin	increases expression	1
Estradiol	decreases expression	1
Nickel	decreases expression	1
Silicon Dioxide	increases expression	1
Testosterone	decreases expression	1

Clinical trials (associated diseases)

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