GBX2

Summary

GBX2 (gastrulation brain homeobox 2, HGNC:4186) is a protein-coding gene on chromosome 2q37.2, encoding Homeobox protein GBX-2 (P52951). May act as a transcription factor for cell pluripotency and differentiation in the embryo.

Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of nervous system development and regulation of transcription by RNA polymerase II. Predicted to act upstream of or within several processes, including branching involved in blood vessel morphogenesis; nervous system development; and neural crest cell migration. Predicted to be located in chromatin. Predicted to be active in nucleus.

Source: NCBI Gene 2637 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 50 total
• MANE Select transcript: NM_001485

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4186
Approved symbol	GBX2
Name	gastrulation brain homeobox 2
Location	2q37.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000168505
Ensembl biotype	protein_coding
OMIM	601135
Entrez	2637

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000306318, ENST00000465889, ENST00000551105

RefSeq mRNA: 2 — MANE Select: NM_001485 NM_001301687, NM_001485

CCDS: CCDS2515, CCDS77545

Canonical transcript exons

ENST00000306318 — 2 exons

Exon	Start	End
ENSE00001874089	236167449	236168386
ENSE00001958948	236165236	236166437

Expression profiles

Bgee: expression breadth broad, 53 present calls, max score 80.39.

FANTOM5 (CAGE): breadth broad, TPM avg 0.5974 / max 37.1410, expressed in 211 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
34657	0.5974	211

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	80.39	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	75.80	gold quality
tendon of biceps brachii	UBERON:0008188	66.07	gold quality
putamen	UBERON:0001874	65.16	gold quality
stromal cell of endometrium	CL:0002255	63.16	gold quality
pancreatic ductal cell	CL:0002079	62.86	silver quality
caudate nucleus	UBERON:0001873	61.09	gold quality
gingival epithelium	UBERON:0001949	61.00	gold quality
gluteal muscle	UBERON:0002000	60.40	gold quality
triceps brachii	UBERON:0001509	60.35	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	60.01	gold quality
vena cava	UBERON:0004087	59.74	gold quality
gingiva	UBERON:0001828	58.81	gold quality
parotid gland	UBERON:0001831	58.44	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	58.34	gold quality
hypothalamus	UBERON:0001898	56.77	gold quality
spinal cord	UBERON:0002240	56.74	gold quality
myocardium	UBERON:0002349	55.84	gold quality
nasal cavity epithelium	UBERON:0005384	55.65	gold quality
medial globus pallidus	UBERON:0002477	55.23	gold quality
nucleus accumbens	UBERON:0001882	54.79	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	54.41	gold quality
decidua	UBERON:0002450	54.16	gold quality
mucosa of sigmoid colon	UBERON:0004993	54.02	gold quality
male germ cell	CL:0000015	52.70	gold quality
sperm	CL:0000019	52.62	gold quality
pericardium	UBERON:0002407	52.61	gold quality
substantia nigra	UBERON:0002038	52.27	gold quality
globus pallidus	UBERON:0001875	51.98	gold quality
epithelial cell of pancreas	CL:0000083	51.69	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.81

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

9 targets.

Target	Regulation
BMP4
EEF1A1
FGF8	Unknown
GBX2
HMGB1
IL6	Activation
LMO3
OTX2	Repression
WNT1	Unknown

JASPAR motifs

Motif	Name	Family
MA0890.1	GBX2	HOX
MA0890.2	GBX2	HOX

JASPAR matrix evidence (PMIDs): PMID:18585359

Upstream regulators (CollecTRI, top): DLX5, GBX2, MYB, PAX2

miRNA regulators (miRDB)

53 targeting GBX2, 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-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-23A-5P	99.94	65.39	468
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-7978	99.86	66.90	856
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-369-3P	99.85	70.52	2264
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-12129	99.72	67.45	1311
HSA-MIR-6762-3P	99.66	66.94	1188
HSA-MIR-875-3P	99.63	69.47	2548
HSA-MIR-4499	99.62	67.29	1470
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-12123	99.52	71.79	2990

Literature-anchored findings (GeneRIF, showing 9)

• Altered expression is associated with therapy failure and death in patients with multiple types of cancer. (PMID:15931389)
• Gbx2 and Otx2 interact with the WD40 domain of Groucho/Tle corepressors (PMID:17060451)
• Data established a seven-gene (AR, ESR2, GATA3, GBX2, KRT16, MMP28 and WNT11) prognostic signature to define a subset of triple-negative breast cancer (TNBC). (PMID:23549873)
• Gastrulation brain homeobox 2 (GBX2) methylation is associated with Gleason score (GS), pathologic stage (pT), and biochemical recurrence (BCR) in prostate cancer (PCa). Among intraductal carcinoma/cribriform architecture (IDC/C)-negative patients, GBX2 methylation improves prediction of BCR. Loss of TET2 in prostate cells results in greater GBX2 methylation. (PMID:31200836)
• GBX2, as a tumor promoter in lung adenocarcinoma, enhances cells viability, invasion and migration by regulating the AKT/ERK signaling pathway. (PMID:31758726)
• NCBP3/SNHG6 inhibits GBX2 transcription in a histone modification manner to facilitate the malignant biological behaviour of glioma cells. (PMID:32618493)
• LncRNA FEZF1-AS1 accelerates the migration and invasion of laryngeal squamous cell carcinoma cells through miR-4497 targeting GBX2. (PMID:33550476)
• circRERE regulates the expression of GBX2 through miR-1299 and ZC3H13/N(6)-methyladenosine (m(6)A) to promote growth and invasion of hepatocellular carcinoma cells. (PMID:36222159)
• The accession number for the cDNA listed for the sequence data at the bottom of page 335 on the left side is incorrect. It should read U31468 instead of U31458. (PMID:8838315)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	gbx2	ENSDARG00000002933
mus_musculus	Gbx2	ENSMUSG00000034486
rattus_norvegicus	Gbx2	ENSRNOG00000019495
drosophila_melanogaster	unpg	FBGN0015561

Paralogs (1): GBX1 (ENSG00000164900)

Protein

Protein identifiers

Homeobox protein GBX-2 — P52951 (reviewed: P52951)

Alternative names: Gastrulation and brain-specific homeobox protein 2

All UniProt accessions (2): P52951, F8VY47

UniProt curated annotations — full annotation on UniProt →

Function. May act as a transcription factor for cell pluripotency and differentiation in the embryo.

Subcellular location. Nucleus.

RefSeq proteins (2): NP_001288616, NP_001476* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR017970	Homeobox_CS	Conserved_site
IPR020479	HD_metazoa	Domain
IPR042982	GBX-1/2	Family

Pfam: PF00046

UniProt features (10 total): region of interest 3, compositionally biased region 3, sequence conflict 2, chain 1, DNA-binding region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P52951-F1	63.07	0.17

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-9823739	Formation of the anterior neural plate
R-HSA-9832991	Formation of the posterior neural plate
R-HSA-9834899	Specification of the neural plate border

MSigDB gene sets: 213 (showing top): GOBP_FOREBRAIN_NEURON_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_HINDBRAIN_DEVELOPMENT, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_METENCEPHALON_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, HNF3ALPHA_Q6, TATTATA_MIR374, GOBP_NEUROGENESIS, GOBP_NEURAL_TUBE_DEVELOPMENT, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GOBP_FOREBRAIN_DEVELOPMENT, GOBP_AMEBOIDAL_TYPE_CELL_MIGRATION, TANG_SENESCENCE_TP53_TARGETS_UP

GO Biological Process (19): branching involved in blood vessel morphogenesis (GO:0001569), neural crest cell migration (GO:0001755), regulation of transcription by RNA polymerase II (GO:0006357), nervous system development (GO:0007399), axon guidance (GO:0007411), cerebellum development (GO:0021549), midbrain-hindbrain boundary morphogenesis (GO:0021555), rhombomere 2 development (GO:0021568), thalamus development (GO:0021794), forebrain neuron development (GO:0021884), cerebellar granule cell precursor proliferation (GO:0021930), inner ear morphogenesis (GO:0042472), autonomic nervous system development (GO:0048483), regulation of nervous system development (GO:0051960), regulation of DNA-templated transcription (GO:0006355), hindbrain development (GO:0030902), midbrain-hindbrain boundary development (GO:0030917), tube morphogenesis (GO:0035239), positive regulation of transcription by RNA polymerase II (GO:0045944)

GO Molecular Function (8): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), RNA polymerase II core promoter sequence-specific DNA binding (GO:0000979), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA-binding transcription factor activity (GO:0003700), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677)

GO Cellular Component (2): chromatin (GO:0000785), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Gastrulation	3

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
anatomical structure development	4
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
regulation of DNA-templated transcription	2
transcription by RNA polymerase II	2
system development	2
embryonic morphogenesis	2
nervous system development	2
brain development	2
regulation of transcription by RNA polymerase II	2
transcription cis-regulatory region binding	2
angiogenesis	1
blood vessel morphogenesis	1
branching morphogenesis of an epithelial tube	1
neural crest cell development	1
mesenchymal cell migration	1
axonogenesis	1
neuron projection guidance	1
metencephalon development	1
midbrain-hindbrain boundary development	1
rhombomere development	1
diencephalon development	1
forebrain neuron differentiation	1
central nervous system neuron development	1
cell proliferation in external granule layer	1
ear morphogenesis	1
inner ear development	1
regulation of multicellular organismal development	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
rostrocaudal neural tube patterning	1
anatomical structure morphogenesis	1
tube development	1
positive regulation of DNA-templated transcription	1
core promoter sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1

Protein interactions and networks

STRING

1318 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GBX2	WNT1	P04628	881
GBX2	FGF8	P55075	822
GBX2	PAX2	Q02962	818
GBX2	OTX2	P32243	723
GBX2	SHH	Q15465	695
GBX2	WNT3A	P56704	626
GBX2	NEUROG1	Q92886	618
GBX2	AGAP1	Q9UPQ3	617
GBX2	FOXG1	P55315	602
GBX2	ZIC1	Q15915	566
GBX2	OLIG3	Q7RTU3	560
GBX2	IRX3	P78415	553
GBX2	LMX1A	Q8TE12	553
GBX2	SIX3	O95343	549
GBX2	TFCP2L1	Q9NZI6	547
GBX2	EFNA5	P52803	547

IntAct

2 interactions, top by confidence:

A	B	Type	Score
GBX2	FHL3	psi-mi:“MI:0914”(association)	0.350

BioGRID (6): CHD4 (Affinity Capture-MS), GBX1 (Affinity Capture-MS), FHL3 (Affinity Capture-MS), GBX2 (Affinity Capture-RNA), GBX2 (Proximity Label-MS), GBX2 (Proximity Label-MS)

ESM2 similar proteins: A0A8V0YY16, A0JPN1, A7MB54, A8MTJ6, O35762, O42115, O57601, O88181, O95096, P09065, P23683, P28356, P31311, P31315, P32443, P39020, P42581, P42586, P43697, P48031, P49640, P50222, P50476, P52951, P52954, P52955, P78426, P81067, P81068, P97334, Q14549, Q14774, Q1KKY1, Q1XID0, Q2NKI2, Q2VL76, Q2VL80, Q4V5A3, Q5SQQ9, Q60554

Diamond homologs: A2RU54, A5PKG8, A5YC49, A6NHT5, A6NMT0, A6YP92, A8XJD0, E7FDX5, F1R2J1, O08686, O35085, O42230, O43711, O43763, O55144, O57601, O70218, O88181, O93366, O93367, O97039, P15142, P15858, P19601, P20009, P20269, P22544, P22807, P26797, P29454, P31314, P42580, P42581, P43345, P43687, P48031, P52950, P52951, P52954, P52955

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	46
Likely benign	1
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

194 predictions. Top by Δscore:

Variant	Effect	Δscore
2:236166433:CCCGA:C	acceptor_gain	1.0000
2:236166434:CCGA:C	acceptor_gain	1.0000
2:236166434:CCGAC:C	acceptor_gain	1.0000
2:236166435:CGA:C	acceptor_gain	1.0000
2:236166435:CGAC:C	acceptor_gain	1.0000
2:236166436:GA:G	acceptor_gain	1.0000
2:236166437:ACT:A	acceptor_loss	1.0000
2:236166438:C:CC	acceptor_gain	1.0000
2:236166438:C:T	acceptor_loss	1.0000
2:236166439:T:C	acceptor_loss	1.0000
2:236166445:C:CT	acceptor_gain	1.0000
2:236167446:CA:C	donor_loss	1.0000
2:236167447:A:AC	donor_gain	1.0000
2:236167448:C:CC	donor_gain	1.0000
2:236167448:CCGAG:C	donor_gain	1.0000
2:236166446:A:T	acceptor_gain	0.9900
2:236167448:CCG:C	donor_gain	0.9900
2:236166451:C:CT	acceptor_gain	0.9800
2:236166451:C:T	acceptor_gain	0.9800
2:236167447:AC:A	donor_gain	0.9800
2:236167448:CC:C	donor_gain	0.9800
2:236167448:CCGA:C	donor_gain	0.9800
2:236166436:G:T	acceptor_gain	0.9700
2:236166452:A:T	acceptor_gain	0.9100
2:236167136:AC:A	donor_gain	0.8900
2:236167137:CC:C	donor_gain	0.8900
2:236167442:GAC:G	donor_loss	0.8700
2:236166439:T:A	acceptor_gain	0.8600
2:236167131:AACCT:A	donor_loss	0.8600
2:236167132:ACCTA:A	donor_loss	0.8600

AlphaMissense

2262 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:236165963:C:A	R333M	1.000
2:236165965:G:C	S332R	1.000
2:236165965:G:T	S332R	1.000
2:236165967:T:G	S332R	1.000
2:236165969:A:T	V331D	1.000
2:236165975:A:T	V329D	1.000
2:236165978:G:C	P328R	1.000
2:236165978:G:T	P328H	1.000
2:236165979:G:A	P328S	1.000
2:236165981:A:C	I327S	1.000
2:236165981:A:G	I327T	1.000
2:236165981:A:T	I327N	1.000
2:236165984:G:C	P326R	1.000
2:236165984:G:T	P326H	1.000
2:236165985:G:A	P326S	1.000
2:236165985:G:T	P326T	1.000
2:236165987:A:G	V325A	1.000
2:236165987:A:T	V325D	1.000
2:236165990:A:T	V324D	1.000
2:236165993:A:C	I323S	1.000
2:236165993:A:G	I323T	1.000
2:236165993:A:T	I323N	1.000
2:236166050:C:G	R304P	1.000
2:236166052:T:A	K303N	1.000
2:236166052:T:G	K303N	1.000
2:236166053:T:A	K303I	1.000
2:236166054:T:C	K303E	1.000
2:236166055:C:A	W302C	1.000
2:236166055:C:G	W302C	1.000
2:236166056:C:G	W302S	1.000

dbSNP variants (sampled 300 via entrez): RS1000056972 (2:236161247 G>T), RS1000167521 (2:236164395 C>T), RS1000765688 (2:236164171 C>T), RS1000845033 (2:236164610 C>T), RS1001120963 (2:236170363 C>T), RS1001284865 (2:236168431 C>T), RS1001290705 (2:236167128 T>C), RS1001442332 (2:236161837 C>T), RS1001846896 (2:236163390 G>A), RS1001875347 (2:236161298 G>A), RS1002011537 (2:236165251 C>G,T), RS1002287084 (2:236169331 T>A,G), RS1002294603 (2:236165530 T>C), RS1002517440 (2:236160987 G>A,T), RS1002913809 (2:236161940 G>C)

Disease associations

OMIM: gene MIM:601135 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST004412_3	Craniofacial microsomia	5.000000e-13
GCST008396_1	Educational attainment (years of education)	3.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004784	self reported educational attainment

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, affects cotreatment, increases expression	6
entinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
aristolochic acid I	increases expression	1
bisphenol F	increases expression	1
methylmercuric chloride	increases expression	1
propionaldehyde	increases expression	1
bisphenol A	increases expression	1
geraniol	decreases expression	1
trichostatin A	increases expression	1
arsenite	increases methylation	1
butyraldehyde	increases expression	1
tetrabromobisphenol A	increases expression	1
pentanal	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
dorsomorphin	affects cotreatment, increases expression	1
licochalcone B	increases expression	1
jinfukang	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Aldehydes	increases expression	1
Benzo(a)pyrene	increases methylation	1
Cisplatin	decreases expression	1
Estradiol	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Particulate Matter	increases abundance, increases expression	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A2G3	SEES3-1V human GBX2, clone1	Embryonic stem cell	Male
CVCL_A2G4	SEES3-1V human GBX2, clone2	Embryonic stem cell	Male
CVCL_A2G5	SEES3-1V human GBX2, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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