BEX3

Summary

BEX3 (brain expressed X-linked 3, HGNC:13388) is a protein-coding gene on chromosome Xq22.2, encoding Protein BEX3 (Q00994). May be a signaling adapter molecule involved in NGFR/p75NTR-mediated apoptosis induced by NGF.

Enables identical protein binding activity. Predicted to be involved in negative regulation of protein ubiquitination and signal transduction. Predicted to act upstream of or within extrinsic apoptotic signaling pathway via death domain receptors. Located in cytosol.

Source: NCBI Gene 27018 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 18 total — 1 pathogenic
• MANE Select transcript: NM_206917

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13388
Approved symbol	BEX3
Name	brain expressed X-linked 3
Location	Xq22.2
Locus type	gene with protein product
Status	Approved
Aliases	Bex, NADE, HGR74, Hero20, DXS6984E
Ensembl gene	ENSG00000166681
Ensembl biotype	protein_coding
OMIM	300361
Entrez	27018

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 19 protein_coding

ENST00000361298, ENST00000372634, ENST00000372635, ENST00000372645, ENST00000870967, ENST00000870968, ENST00000870969, ENST00000870970, ENST00000870971, ENST00000870972, ENST00000870973, ENST00000870974, ENST00000936275, ENST00000936276, ENST00000936277, ENST00000936278, ENST00000936279, ENST00000936280, ENST00000936281

RefSeq mRNA: 4 — MANE Select: NM_206917 NM_001282674, NM_014380, NM_206915, NM_206917

CCDS: CCDS14508, CCDS14509

Canonical transcript exons

ENST00000361298 — 3 exons

Exon	Start	End
ENSE00001375610	103376538	103376613
ENSE00001416044	103377028	103377106
ENSE00001458290	103377510	103378164

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 99.93.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 205.5566 / max 1796.5551, expressed in 1716 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
197018	172.9262	1712
197017	17.2647	1580
197016	6.1781	1436
197019	5.3713	1464
197022	1.8112	854
197020	1.1002	741
197015	0.4848	279
197021	0.4200	227

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pons	UBERON:0000988	99.93	gold quality
cerebellar vermis	UBERON:0004720	99.93	gold quality
middle temporal gyrus	UBERON:0002771	99.91	gold quality
superior vestibular nucleus	UBERON:0007227	99.91	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.88	gold quality
ventral tegmental area	UBERON:0002691	99.87	gold quality
renal medulla	UBERON:0000362	99.85	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.84	gold quality
substantia nigra pars compacta	UBERON:0001965	99.83	gold quality
dorsal plus ventral thalamus	UBERON:0001897	99.82	gold quality
medulla oblongata	UBERON:0001896	99.81	gold quality
substantia nigra pars reticulata	UBERON:0001966	99.81	gold quality
renal glomerulus	UBERON:0000074	99.79	gold quality
lateral globus pallidus	UBERON:0002476	99.79	gold quality
orbitofrontal cortex	UBERON:0004167	99.79	gold quality
inferior vagus X ganglion	UBERON:0005363	99.79	gold quality
superior frontal gyrus	UBERON:0002661	99.78	gold quality
entorhinal cortex	UBERON:0002728	99.78	gold quality
metanephric glomerulus	UBERON:0004736	99.78	gold quality
endothelial cell	CL:0000115	99.77	gold quality
parietal lobe	UBERON:0001872	99.77	gold quality
subthalamic nucleus	UBERON:0001906	99.77	gold quality
occipital lobe	UBERON:0002021	99.76	gold quality
corpus epididymis	UBERON:0004359	99.76	gold quality
germinal epithelium of ovary	UBERON:0001304	99.75	gold quality
postcentral gyrus	UBERON:0002581	99.75	gold quality
dorsal root ganglion	UBERON:0000044	99.74	gold quality
Brodmann (1909) area 46	UBERON:0006483	99.74	gold quality
prefrontal cortex	UBERON:0000451	99.73	gold quality
trigeminal ganglion	UBERON:0001675	99.72	gold quality

Single-cell (SCXA)

Detected in 38 experiment(s), a significant marker in 32.

Experiment	Marker?	Max mean expression
E-GEOD-134144	yes	2774.43
E-CURD-98	yes	1827.94
E-MTAB-7407	yes	1331.80
E-MTAB-7316	yes	1283.61
E-GEOD-81547	yes	788.93
E-GEOD-36552	yes	436.68
E-GEOD-76312	yes	236.56
E-GEOD-75688	yes	143.63
E-MTAB-6701	yes	135.28
E-HCAD-4	yes	85.30
E-HCAD-1	yes	81.59
E-MTAB-8410	yes	56.30
E-HCAD-35	yes	45.36
E-HCAD-10	yes	44.48
E-HCAD-31	yes	38.91

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

23 targeting BEX3, 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-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-545-5P	99.66	70.18	2308
HSA-MIR-216A-5P	99.50	68.02	1288
HSA-MIR-642A-3P	99.23	67.67	1258
HSA-MIR-642B-3P	99.23	67.67	1258
HSA-MIR-4717-3P	99.06	66.34	1072
HSA-MIR-452-3P	99.01	66.25	1241
HSA-MIR-6830-5P	99.01	68.73	1884
HSA-MIR-16-1-3P	98.70	69.23	1538
HSA-MIR-5581-3P	98.55	70.31	1161
HSA-MIR-302F	98.44	69.02	1776
HSA-MIR-9851-5P	97.57	67.49	1067
HSA-MIR-514A-3P	96.43	67.77	1048
HSA-MIR-514B-3P	96.43	67.77	1048
HSA-MIR-4330	95.44	66.39	993

Literature-anchored findings (GeneRIF, showing 5)

• Structure-function analysis of NADE: identification of regions that mediate nerve growth factor-induced apoptosis (PMID:11830582)
• suppresses cell growth in vivo, when expressed in cultured cells (PMID:12739005)
• DRG-1 may contribute to the dopamine-induced cell growth, which is negatively regulated by NADE (PMID:16777077)
• Results showed that BEX3 was overexpressed in nasopharyngeal carcinoma (NPC), and indicated a unique functional role of BEX3 in mediating the sensitivity of NPC cells to cisplatin. (PMID:28083995)
• Characterization of an eutherian gene cluster generated after transposon domestication identifies Bex3 as relevant for advanced neurological functions. (PMID:33100228)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Bex3	ENSMUSG00000046432
rattus_norvegicus	Bex3	ENSRNOG00000028822

Paralogs (3): BEX2 (ENSG00000133134), BEX1 (ENSG00000133169), BEX5 (ENSG00000184515)

Protein

Protein identifiers

Protein BEX3 — Q00994 (reviewed: Q00994)

Alternative names: Brain-expressed X-linked protein 3, Nerve growth factor receptor-associated protein 1, Ovarian granulosa cell 13.0 kDa protein HGR74, p75NTR-associated cell death executor

All UniProt accessions (1): Q00994

UniProt curated annotations — full annotation on UniProt →

Function. May be a signaling adapter molecule involved in NGFR/p75NTR-mediated apoptosis induced by NGF. Plays a role in zinc-triggered neuronal death. 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. Self-associates. Binds to the DEATH domain of p75NTR/NGFR. Interacts with 14-3-3 epsilon (YWHAE). Interacts with DIABLO/SMAC.

Subcellular location. Nucleus. Cytoplasm. Cytosol.

Tissue specificity. Found in ovarian granulosa cells, testis, prostate and seminal vesicle tissue. High levels also detected in liver.

Post-translational modifications. Ubiquitinated. Degraded by the proteasome.

Domain organisation. The nuclear export signal is required for export from the nucleus and the interactions with itself and NGFR/p75NTR. The histidine cluster (His cluster) and Cys-108 mediate zinc-binding.

Similarity. Belongs to the BEX family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q00994-1	1	yes
Q00994-2	2

RefSeq proteins (4): NP_001269603, NP_055195, NP_996798, NP_996800* (*=MANE)

Domains & families (InterPro)

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

Pfam: PF04538

UniProt features (8 total): region of interest 4, chain 1, short sequence motif 1, binding site 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q00994-F1	65.81	0.21

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): 108

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-205025	NADE modulates death signalling
R-HSA-162582	Signal Transduction
R-HSA-193704	p75 NTR receptor-mediated signalling
R-HSA-204998	Cell death signalling via NRAGE, NRIF and NADE
R-HSA-73887	Death Receptor Signaling

MSigDB gene sets: 246 (showing top): MULLIGHAN_NPM1_SIGNATURE_3_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, KYNG_DNA_DAMAGE_DN, GOBP_APOPTOTIC_SIGNALING_PATHWAY, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM3, DOANE_RESPONSE_TO_ANDROGEN_DN, MCBRYAN_PUBERTAL_BREAST_3_4WK_UP, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY_VIA_DEATH_DOMAIN_RECEPTORS, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_METABOLIC_PROCESS, HELLER_HDAC_TARGETS_SILENCED_BY_METHYLATION_UP, MAGRANGEAS_MULTIPLE_MYELOMA_IGG_VS_IGA_UP, KYNG_ENVIRONMENTAL_STRESS_RESPONSE_UP, DODD_NASOPHARYNGEAL_CARCINOMA_UP

GO Biological Process (5): signal transduction (GO:0007165), extrinsic apoptotic signaling pathway via death domain receptors (GO:0008625), negative regulation of protein ubiquitination (GO:0031397), regulation of apoptotic signaling pathway (GO:2001233), apoptotic process (GO:0006915)

GO Molecular Function (8): signaling receptor binding (GO:0005102), nerve growth factor receptor binding (GO:0005163), cysteine-type endopeptidase activator activity involved in apoptotic process (GO:0008656), identical protein binding (GO:0042802), metal ion binding (GO:0046872), molecular function inhibitor activity (GO:0140678), death receptor binding (GO:0005123), protein binding (GO:0005515)

GO Cellular Component (3): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Cell death signalling via NRAGE, NRIF and NADE	1
Death Receptor Signaling	1
p75 NTR receptor-mediated signalling	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
apoptotic signaling pathway	2
protein binding	2
cellular anatomical structure	2
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
extrinsic apoptotic signaling pathway	1
protein ubiquitination	1
regulation of protein ubiquitination	1
negative regulation of protein modification by small protein conjugation or removal	1
regulation of signal transduction	1
regulation of apoptotic process	1
programmed cell death	1
execution phase of apoptosis	1
death receptor binding	1
neurotrophin receptor binding	1
peptidase activator activity involved in apoptotic process	1
cysteine-type endopeptidase regulator activity involved in apoptotic process	1
cation binding	1
molecular function regulator activity	1
tumor necrosis factor receptor superfamily binding	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

452 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BEX3	TCEAL7	Q9BRU2	896
BEX3	NGFR	P08138	888
BEX3	TCEAL1	Q15170	852
BEX3	MAGED1	Q9Y5V3	677
BEX3	NGF	P01138	600
BEX3	TCEAL9	Q9UHQ7	594
BEX3	SMIM24	O75264	575
BEX3	CASP2	P42575	549
BEX3	CPXM1	Q96SM3	547
BEX3	TCEAL8	Q8IYN2	530
BEX3	DIABLO	Q9NR28	530
BEX3	NYNRIN	Q9P2P1	518
BEX3	MCF2L	O15068	505
BEX3	TSC2	P49815	502
BEX3	TCEAL3	Q969E4	498

IntAct

138 interactions, top by confidence:

A	B	Type	Score
FSD2	BEX3	psi-mi:“MI:0915”(physical association)	0.720
NECAB2	BEX3	psi-mi:“MI:0915”(physical association)	0.720
BEX3	USHBP1	psi-mi:“MI:0915”(physical association)	0.720
USHBP1	BEX3	psi-mi:“MI:0915”(physical association)	0.720
BEX3	FSD2	psi-mi:“MI:0915”(physical association)	0.720
BEX3	NECAB2	psi-mi:“MI:0915”(physical association)	0.720
CCDC116	BEX3	psi-mi:“MI:0915”(physical association)	0.670
BEX3	BEX3	psi-mi:“MI:0915”(physical association)	0.670
BEX3	CCDC116	psi-mi:“MI:0915”(physical association)	0.670
GOLGA8F	BEX3	psi-mi:“MI:0915”(physical association)	0.560
GOLGA8DP	BEX3	psi-mi:“MI:0915”(physical association)	0.560
BEX3	EMILIN1	psi-mi:“MI:0915”(physical association)	0.560
CTNNBL1	BEX3	psi-mi:“MI:0915”(physical association)	0.560
BEX3	GOLGA8F	psi-mi:“MI:0915”(physical association)	0.560
BEX3	GOLGA8DP	psi-mi:“MI:0915”(physical association)	0.560
EMILIN1	BEX3	psi-mi:“MI:0915”(physical association)	0.560
BEX3	CTNNBL1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (51): NGFRAP1 (Two-hybrid), NGFRAP1 (Two-hybrid), NECAB2 (Two-hybrid), CTNNBL1 (Two-hybrid), USHBP1 (Two-hybrid), FSD2 (Two-hybrid), CCDC116 (Two-hybrid), GOLGA8EP (Two-hybrid), GOLGA8F (Two-hybrid), NGFRAP1 (Two-hybrid), NGFRAP1 (Two-hybrid), NGFRAP1 (Two-hybrid), NGFRAP1 (Two-hybrid), NGFRAP1 (Two-hybrid), NGFRAP1 (Two-hybrid)

ESM2 similar proteins: A4GWX9, B9F4Q9, E9QAU8, O22197, O22283, O49500, O64836, O82239, P0CH30, P32828, P93758, Q00994, Q09463, Q1PFC2, Q3ZBJ6, Q3ZBJ9, Q5H9J7, Q5QLR5, Q5R590, Q5XI50, Q5Z8R1, Q6AVN2, Q6DIP3, Q6PDU5, Q7XKC5, Q7XTV7, Q8GXL7, Q8H1G0, Q8LPN7, Q8SV35, Q93YN8, Q93YV5, Q940T5, Q94AK4, Q9D0C1, Q9FJK3, Q9FKK2, Q9FMM4, Q9H992, Q9LM46

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

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	2
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
144469	GRCh38/hg38 Xq22.2(chrX:103350804-104033500)x2	Pathogenic

SpliceAI

341 predictions. Top by Δscore:

Variant	Effect	Δscore
X:103376612:AG:A	donor_loss	0.9900
X:103376613:GGTAA:G	donor_loss	0.9900
X:103376614:GT:G	donor_loss	0.9900
X:103376615:T:G	donor_loss	0.9900
X:103377096:GA:G	donor_gain	0.9900
X:103377452:T:A	acceptor_gain	0.9900
X:103377454:T:TA	acceptor_gain	0.9900
X:103377461:A:G	acceptor_gain	0.9900
X:103376610:GCAG:G	donor_gain	0.9800
X:103377103:CCAG:C	donor_loss	0.9800
X:103377104:CAG:C	donor_loss	0.9800
X:103377105:AG:A	donor_loss	0.9800
X:103377106:GGT:G	donor_loss	0.9800
X:103377449:A:AG	acceptor_gain	0.9800
X:103377449:ACTT:A	acceptor_gain	0.9800
X:103377462:G:GG	acceptor_gain	0.9800
X:103377105:AGGTC:A	donor_gain	0.9600
X:103377450:C:G	acceptor_gain	0.9600
X:103377459:A:AG	acceptor_gain	0.9600
X:103376694:G:GT	donor_gain	0.9500
X:103376835:G:GT	donor_gain	0.9500
X:103377097:A:G	donor_gain	0.9500
X:103377460:A:G	acceptor_gain	0.9500
X:103377462:GAAAA:G	acceptor_gain	0.9500
X:103376836:A:T	donor_gain	0.9400
X:103377097:A:T	donor_gain	0.9400
X:103377460:AAGA:A	acceptor_loss	0.9400
X:103377462:GAAA:G	acceptor_gain	0.9400
X:103377462:GA:G	acceptor_gain	0.9200
X:103377462:GAA:G	acceptor_gain	0.9200

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1001111129 (X:103375878 G>T), RS1003805127 (X:103378246 A>G), RS1006333809 (X:103376980 C>T), RS1008103704 (X:103378475 T>A), RS1009061057 (X:103377382 A>G), RS1009590432 (X:103376962 G>C), RS1009763244 (X:103378625 CT>C), RS1010711496 (X:103378659 C>T), RS1012860687 (X:103378178 C>A,G), RS1012978968 (X:103377574 A>G), RS1013342401 (X:103376697 G>A,C), RS1013361869 (X:103375736 C>A,T), RS1013664761 (X:103376043 C>A,T), RS1015175047 (X:103376993 C>T), RS1015230287 (X:103374366 T>C)

Disease associations

OMIM: gene MIM:300361 | 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

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	decreases expression	3
Particulate Matter	increases expression, decreases expression, increases abundance, affects cotreatment	3
cobaltous chloride	decreases expression	2
Air Pollutants	decreases expression, increases abundance	2
Valproic Acid	affects expression, increases methylation	2
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
sodium arsenite	decreases expression	1
aflatoxin B2	decreases methylation	1
beta-methylcholine	affects expression	1
polyhexamethyleneguanidine	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
ICG 001	increases expression	1
NSC 689534	affects binding, decreases expression	1
Sunitinib	decreases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	increases methylation, affects methylation	1
Copper	affects binding, decreases expression	1
Doxorubicin	increases expression	1
Estradiol	decreases expression	1
Gasoline	affects cotreatment, increases abundance, increases expression	1
Menthol	increases expression	1
Ozone	increases expression	1
Phenobarbital	affects expression	1
Polycyclic Aromatic Hydrocarbons	affects cotreatment, increases abundance, increases expression	1
Rotenone	increases expression	1
Sarin	decreases expression	1
Thiram	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2SS	Abcam HEK293T BEX3 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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