TBXT

Summary

TBXT (T-box transcription factor T, HGNC:11515) is a protein-coding gene on chromosome 6q27, encoding T-box transcription factor T (O15178). Involved in the transcriptional regulation of genes required for mesoderm formation and differentiation.

The protein encoded by this gene is an embryonic nuclear transcription factor that binds to a specific DNA element, the palindromic T-site. It binds through a region in its N-terminus, called the T-box, and effects transcription of genes required for mesoderm formation and differentiation. The protein is localized to notochord-derived cells. Variation in this gene was associated with susceptibility to neural tube defects and chordoma. A mutation in this gene was found in a family with sacral agenesis with vertebral anomalies.

Source: NCBI Gene 6862 — RefSeq curated summary.

At a glance

• Gene–disease (curated): chordoma (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 58 total — 1 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 20
• Druggable target: yes
• Transcription factor: yes — 99 downstream targets (CollecTRI)
• MANE Select transcript: NM_001366285

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11515
Approved symbol	TBXT
Name	T-box transcription factor T
Location	6q27
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000164458
Ensembl biotype	protein_coding
OMIM	601397
Entrez	6862

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 6 protein_coding

ENST00000296946, ENST00000366871, ENST00000366876, ENST00000461348, ENST00000922033, ENST00000922034

RefSeq mRNA: 4 — MANE Select: NM_001366285 NM_001270484, NM_001366285, NM_001366286, NM_003181

CCDS: CCDS5290, CCDS59045, CCDS94030

Canonical transcript exons

ENST00000366876 — 8 exons

Exon	Start	End
ENSE00001084540	166164605	166164666
ENSE00001084542	166160837	166160966
ENSE00001084545	166164800	166164861
ENSE00001442878	166167386	166167851
ENSE00002282159	166157656	166158588
ENSE00002493193	166166592	166166856
ENSE00002523055	166165706	166165840
ENSE00002553803	166162447	166162623

Expression profiles

Bgee: expression breadth broad, 42 present calls, max score 84.50.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.7424 / max 412.7902, expressed in 94 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
76653	0.4736	77
76658	0.1475	1
76655	0.0379	7
76654	0.0175	7
76652	0.0160	6
76656	0.0143	6
76660	0.0090	2
76651	0.0087	1
76650	0.0071	2
76657	0.0069	1

Top tissues by expression

235 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	84.50	gold quality
pancreatic ductal cell	CL:0002079	79.67	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	73.78	gold quality
buccal mucosa cell	CL:0002336	71.18	silver quality
triceps brachii	UBERON:0001509	71.02	gold quality
gluteal muscle	UBERON:0002000	68.64	gold quality
myocardium	UBERON:0002349	68.60	gold quality
diaphragm	UBERON:0001103	68.21	gold quality
endometrium epithelium	UBERON:0004811	67.95	gold quality
oocyte	CL:0000023	66.45	silver quality
vastus lateralis	UBERON:0001379	66.32	gold quality
quadriceps femoris	UBERON:0001377	66.31	gold quality
heart right ventricle	UBERON:0002080	64.71	gold quality
cardiac muscle of right atrium	UBERON:0003379	63.86	gold quality
cerebellar vermis	UBERON:0004720	63.76	gold quality
left ventricle myocardium	UBERON:0006566	63.33	gold quality
nasal cavity epithelium	UBERON:0005384	63.09	gold quality
olfactory bulb	UBERON:0002264	63.04	gold quality
male germ cell	CL:0000015	62.77	gold quality
type B pancreatic cell	CL:0000169	62.77	gold quality
superficial temporal artery	UBERON:0001614	62.53	gold quality
sperm	CL:0000019	62.44	gold quality
upper arm skin	UBERON:0004263	62.26	gold quality
decidua	UBERON:0002450	62.12	gold quality
mucosa of urinary bladder	UBERON:0001259	61.80	gold quality
cranial nerve II	UBERON:0000941	61.73	silver quality
deltoid	UBERON:0001476	61.73	gold quality
vena cava	UBERON:0004087	60.30	gold quality
substantia nigra pars reticulata	UBERON:0001966	59.73	silver quality
nipple	UBERON:0002030	59.64	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-9388	yes	637.98
E-GEOD-109979	yes	258.64
E-GEOD-36552	no	3.98
E-ANND-3	no	2.28

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

99 targets.

Target	Regulation
ADM
AOX1
B3GNT9
B4GALT1
BAG6
BDNF
BGLAP
BLMH
BMP4
BMPR2
CAD
CCNT1
CD4
CD74
CDH1	Repression
CDK9
CDKN1A
CDKN1B
CDKN2A
CEACAM5
COL2A1
COMP
CSF2
CXCR4
DAB1
DES
DIAPH1
DKK1
DMC1
DNMT1

JASPAR motifs

Motif	Name	Family
MA0009.2	TBXT	Brachyury-related factors

JASPAR matrix evidence (PMIDs): PMID:7588606

Upstream regulators (CollecTRI, top): AHR, AP1, ATF4, BATF, BCL3, BHLHE23, CDX1, CREB1, CTCFL, CTNNB1, CUX1, DNMT1, EBF1, EGR1, EGR2, ELF3, ELK4, ERG, ESR1, ETS1, ETV4, EWSR1, EZH2, FLI1, FOS, FOXP1, FOXP3, GATA3, GATA4, GFI1, HIF1A, HMGB2, HNF1A, IRF1, IRF8, JDP2, JUN, KDM6B, KLF12, KLF9

miRNA regulators (miRDB)

38 targeting TBXT, 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-196A-1-3P	99.99	72.15	2772
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-219A-5P	99.91	73.36	735
HSA-MIR-4782-3P	99.88	73.31	735
HSA-MIR-6766-3P	99.88	73.38	732
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-448	99.79	72.37	2103
HSA-MIR-4517	99.76	69.19	1867
HSA-MIR-5580-3P	99.70	69.41	2052
HSA-MIR-4470	99.66	69.35	1767
HSA-MIR-4804-3P	99.65	67.78	866
HSA-MIR-217-5P	99.49	69.93	1419
HSA-MIR-324-3P	99.26	66.31	1034
HSA-MIR-6071	99.16	67.77	1780
HSA-MIR-452-3P	99.01	66.25	1241
HSA-MIR-4699-5P	98.99	67.50	1210
HSA-MIR-511-5P	98.97	70.94	2268
HSA-MIR-4801	98.96	69.42	2096
HSA-MIR-606	98.72	67.34	960
HSA-MIR-4700-5P	98.63	67.43	1915
HSA-MIR-6868-3P	98.63	69.64	2259
HSA-MIR-4731-3P	98.56	68.60	1860
HSA-MIR-6852-3P	98.54	67.60	1468
HSA-MIR-4720-3P	98.50	68.88	988
HSA-MIR-93-3P	98.15	66.65	1309
HSA-MIR-6880-5P	98.08	65.59	1282
HSA-MIR-1285-5P	98.01	68.71	779

Literature-anchored findings (GeneRIF, showing 40)

• Human T and risk for neural tube defects. (PMID:11897834)
• Describe brachyury expression in a series of extra-axial skeletal chordomas and in two soft tissue chordomas. (PMID:18301055)
• infer that the c.1013C>T substitution is pathogenic and represents the first report of an association between a missense mutation in the T gene and the occurrence of sporadic vertebral malformations in humans (PMID:18466071)
• brachyury was entirely specific for chordoma; however, not as sensitive as cytokeratin. (PMID:18820665)
• duplicated region contains only the T (brachyury) gene, which is important in notochord development and is expressed in most sporadic chordomas. (PMID:19801981)
• Exclusive brachyury expression in more than 90% of chordomas indicates its value as a unique, specific marker. (PMID:20670140)
• brachyury expressed in chordoma tumor cells, but not in benign notochoral cell rests that were coexistent. (PMID:20855213)
• This study confirms the specificity of brachyury for chordoma in the differential diagnostic distinction from the potential genitourinary mimics, germ cell tumors and metastatic clear cell renal cell carcinoma. (PMID:21102418)
• findings show chromosomal aberrations resulting in gain of the T locus are common in sporadic chordomas and expression of this gene is critical for proliferation of chordoma cells in vitro (PMID:21171078)
• Brachyury expression predicts poor prognosis at early stages of colorectal cancer (PMID:21220197)
• BRACHYURY may regulate NANOG in mesenchymal-like CRC cells to impose a ‘plastic-state’, allowing competence of cells to respond to signals prompting invasion or metastasis. (PMID:21365650)
• The tumor cells were diffusely positive for brachyury and cytokeratin 19 on immunohistochemistry, suggesting that the tumor was extra-axial soft tissue chordoma. (PMID:21397407)
• Loss of p27(Kip)(1) causes an elongated/scatter cell-like phenotype involving up-regulation of Brachyury and Twist gene expression. (PMID:21478681)
• BRA was necessary for and preceded CDX2 expression. (PMID:21816365)
• DeltaNP63 is not expressed and is therefore rarely, if ever, a transcriptional regulator of brachyury in human osteosarcomas and chordomas. (PMID:22007675)
• Brachyury and related Tbx proteins interact with the Mixl1 homeodomain protein and negatively regulate Mixl1 transcriptional activity (PMID:22164283)
• Propose the use of brachyury as an additional helpful immunohistochemical marker to resolve the differential diagnosis of hemangioblastoma and histologic mimics. (PMID:22446946)
• Genom-wide association identifies the T gene as a novel asthma pharmacogenetic locus. (PMID:22538805)
• Functional significance of Brachyury in the developmental program of hematopoietic differentiation from embryonic stem cells. (PMID:22548442)
• Data show a combination of only five genes (-BCL6, T (BRACHYURY), c-MYC, MITF and BAF60C (SMARCD3) rapidly and efficiently convert postnatal chorion and decidual cells into chondrocytes. (PMID:22833560)
• An integrated functional genomics approach identifies the regulatory network directed by brachyury (T) in chordoma. (PMID:22847733)
• Our findings present clinical evidence for an important role of Brachyury in EMT in oral SCC, and suggest that Brachyury and EMT patterns are useful prognostic markers. (PMID:23076115)
• heterochromatin-specific nonhistone chromosomal protein HP-1 (PMID:23218904)
• High expression of Brachyury gene is associated with lung carcinoma. (PMID:23456319)
• We report two cases of recurrent EAC confirmed by the expression of brachyury arising from the distal femur and distal tibia and describe the imaging findings from radiography and MRI at initial diagnosis and at recurrence. (PMID:23653219)
• results show that Brachyury expression is enhanced during TGF-beta1-induced epithelial-mesenchymal transition in human cancer cell lines and that a positive feedback loop is established between Brachyury and TGF-beta1 in mesenchymal-like tumor cells (PMID:23783250)
• Brachyury expression may attenuate cell cycle progression, enabling tumor cells to become less susceptible to chemotherapy and radiation in human carcinomas. (PMID:23788039)
• Common variants of PAX3 and T are associated with spina bifida. (PMID:23913553)
• The results of this study suggested that brachyury-negative chordomas are biologically distinct from brachyury-positive chordomas and that T/brachyury might be an appropriate molecular therapeutic target for chordoma. (PMID:23965741)
• Multiple abnormalities, consisting of sacral agenesis, abnormal ossification of the vertebral bodies and a persistent notochordal canal, are associated with mutations in the T (brachyury) gene. (PMID:24253444)
• Activated brachury is associated with chordoma. (PMID:24445144)
• Brachyury knockdown reduces invasiveness and chemoresistance and radioresistance of cancer stem cells in vivo. (PMID:24504414)
• Brachyury separates chordoma from cytomorphologic mimics with high sensitivity and specificity in small biopsies. (PMID:24554551)
• Brachyury expression may useful for the differential diagnosis of renal hemangioblastoma from other neoplastic histological mimickers. [Review] (PMID:24591762)
• The level of brachyury expression in breast cancer cells was positively associated with their ability to invade the extracellular matrix, efficiently form mammospheres in vitro, and resist the cytotoxic effect of docetaxel (PMID:24815864)
• Importance of the T gene in the pathogenesis of both familial and sporadic chordoma. (PMID:24990759)
• the present study suggests that Brachyury plays an important role in prostate cancer aggressiveness and points, for the first time, to Brachyury as a significant predictor of poor prostate cancer prognosis (PMID:25009296)
• Brachyury plays an important role in regulating TGF beta 1-mediated renal epithelial mesenchymal transition and could be an attractive target for progression of renal disease therapies (PMID:25433496)
• Elevated Brachyury facilitates hepatocellular carcinoma metastasis by promoting EMT via PTEN/Akt/Snail-dependent pathway. (PMID:25499255)
• Brachyury expression promotes lung cancer cell proliferation and invasion, and correlates with reduced patient survival. (PMID:25683840)

Cross-species orthologs

14 orthologs

Organism	Symbol	Gene ID
danio_rerio	tbxtb	ENSDARG00000039806
mus_musculus	T	ENSMUSG00000062327
rattus_norvegicus	Tbxt	ENSRNOG00000012229
drosophila_melanogaster	H15	FBGN0016660
drosophila_melanogaster	mid	FBGN0261963
drosophila_melanogaster	ocm	FBGN0266083
caenorhabditis_elegans		WBGENE00003106
caenorhabditis_elegans		WBGENE00004750
caenorhabditis_elegans		WBGENE00006545
caenorhabditis_elegans		WBGENE00006546
caenorhabditis_elegans		WBGENE00006556
caenorhabditis_elegans		WBGENE00006557
caenorhabditis_elegans		WBGENE00006559
caenorhabditis_elegans		WBGENE00044798

Paralogs (16): TBX21 (ENSG00000073861), TBX5 (ENSG00000089225), TBX15 (ENSG00000092607), TBX18 (ENSG00000112837), TBX2 (ENSG00000121068), TBX4 (ENSG00000121075), TBX22 (ENSG00000122145), TBX3 (ENSG00000135111), TBR1 (ENSG00000136535), TBX19 (ENSG00000143178), TBX6 (ENSG00000149922), EOMES (ENSG00000163508), TBX20 (ENSG00000164532), TBX10 (ENSG00000167800), MGA (ENSG00000174197), TBX1 (ENSG00000184058)

Protein

Protein identifiers

T-box transcription factor T — O15178 (reviewed: O15178)

Alternative names: Brachyury protein, Protein T

All UniProt accessions (3): O15178, H0YM91, J3KP65

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the transcriptional regulation of genes required for mesoderm formation and differentiation. Binds to a palindromic T site 5’-TTCACACCTAGGTGTGAA-3’ DNA sequence and activates gene transcription when bound to such a site.

Subunit / interactions. Monomer.

Subcellular location. Nucleus.

Tissue specificity. Detected in testis, but not in other, normal tissues. Detected in lung tumors (at protein level).

Disease relevance. Neural tube defects (NTD) [MIM:182940] Congenital malformations of the central nervous system and adjacent structures related to defective neural tube closure during the first trimester of pregnancy. Failure of neural tube closure can occur at any level of the embryonic axis. Common NTD forms include anencephaly, myelomeningocele and spina bifida, which result from the failure of fusion in the cranial and spinal region of the neural tube. NTDs have a multifactorial etiology encompassing both genetic and environmental components. Disease susceptibility is associated with variants affecting the gene represented in this entry. Chordoma (CHDM) [MIM:215400] Rare, clinically malignant tumors derived from notochordal remnants. They occur along the length of the spinal axis, predominantly in the sphenooccipital, vertebral and sacrococcygeal regions. They are characterized by slow growth, local destruction of bone, extension into adjacent soft tissues and rarely, distant metastatic spread. Disease susceptibility is associated with variants affecting the gene represented in this entry. Susceptibility to development of chordomas is due to a T gene duplication. Sacral agenesis with vertebral anomalies (SAVA) [MIM:615709] A disorder characterized by abnormalities of the spine, including sacral agenesis, abnormal ossification of all vertebral bodies, and a persistent notochordal canal during development. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (2)

UniProt ID	Names	Canonical?
O15178-1	1	yes
O15178-2	2

RefSeq proteins (4): NP_001257413, NP_001353214, NP_001353215, NP_003172 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001699	TF_T-box	Family
IPR002070	TF_Brachyury	Family
IPR008967	p53-like_TF_DNA-bd_sf	Homologous_superfamily
IPR018186	TF_T-box_CS	Conserved_site
IPR036960	T-box_sf	Homologous_superfamily
IPR046360	T-box_DNA-bd	Domain

Pfam: PF00907

UniProt features (33 total): strand 14, sequence variant 8, helix 6, chain 1, DNA-binding region 1, region of interest 1, compositionally biased region 1, splice variant 1

Structure

Experimental structures (PDB)

56 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
7HI9	X-RAY DIFFRACTION	1.42
5QS9	X-RAY DIFFRACTION	1.43
5QS8	X-RAY DIFFRACTION	1.47
5QSJ	X-RAY DIFFRACTION	1.49
7ZKF	X-RAY DIFFRACTION	1.49
7HI8	X-RAY DIFFRACTION	1.54
5QRM	X-RAY DIFFRACTION	1.55
5QSA	X-RAY DIFFRACTION	1.55
5QSK	X-RAY DIFFRACTION	1.55
5QRY	X-RAY DIFFRACTION	1.58
5QS0	X-RAY DIFFRACTION	1.6
7ZK2	X-RAY DIFFRACTION	1.6
5QRO	X-RAY DIFFRACTION	1.61
5QRN	X-RAY DIFFRACTION	1.62
5QSC	X-RAY DIFFRACTION	1.62
5QRK	X-RAY DIFFRACTION	1.63
5QSI	X-RAY DIFFRACTION	1.64
5QS4	X-RAY DIFFRACTION	1.65
5QS1	X-RAY DIFFRACTION	1.66
5QS7	X-RAY DIFFRACTION	1.66
5QRP	X-RAY DIFFRACTION	1.67
5QRV	X-RAY DIFFRACTION	1.67
5QS6	X-RAY DIFFRACTION	1.67
5QS2	X-RAY DIFFRACTION	1.68
5QRR	X-RAY DIFFRACTION	1.69
5QS3	X-RAY DIFFRACTION	1.71
5QRW	X-RAY DIFFRACTION	1.74
5QRL	X-RAY DIFFRACTION	1.76
5QRU	X-RAY DIFFRACTION	1.76
5QRT	X-RAY DIFFRACTION	1.77

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15178-F1	65.71	0.36

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-9733709	Cardiogenesis
R-HSA-9754189	Germ layer formation at gastrulation
R-HSA-9758919	Epithelial-Mesenchymal Transition (EMT) during gastrulation
R-HSA-9793380	Formation of paraxial mesoderm
R-HSA-9796292	Formation of axial mesoderm
R-HSA-9823730	Formation of definitive endoderm
R-HSA-1266738	Developmental Biology
R-HSA-9758941	Gastrulation

MSigDB gene sets: 233 (showing top): GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, MORF_FLT1, BENPORATH_ES_WITH_H3K27ME3, GOBP_AXIS_SPECIFICATION, GOBP_EMBRYONIC_AXIS_SPECIFICATION, GOBP_FORMATION_OF_PRIMARY_GERM_LAYER, MORF_BRCA1, GOBP_PRIMITIVE_STREAK_FORMATION, GOBP_GASTRULATION_WITH_MOUTH_FORMING_SECOND, MORF_RAD51L3, TCF4_Q5, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_MUSCLE_STRUCTURE_DEVELOPMENT, MODULE_379

GO Biological Process (32): negative regulation of transcription by RNA polymerase II (GO:0000122), mesoderm formation (GO:0001707), cell fate specification (GO:0001708), somitogenesis (GO:0001756), heart morphogenesis (GO:0003007), regulation of transcription by RNA polymerase II (GO:0006357), signal transduction (GO:0007165), mesoderm development (GO:0007498), anterior/posterior axis specification, embryo (GO:0008595), positive regulation of transcription by RNA polymerase II (GO:0045944), cardiac muscle cell myoblast differentiation (GO:0060379), primitive streak formation (GO:0090009), vasculogenesis (GO:0001570), neural plate morphogenesis (GO:0001839), neural tube closure (GO:0001843), regulation of DNA-templated transcription (GO:0006355), transcription by RNA polymerase II (GO:0006366), penetration of zona pellucida (GO:0007341), mesoderm migration involved in gastrulation (GO:0007509), cell population proliferation (GO:0008283), positive regulation of cell population proliferation (GO:0008284), anatomical structure morphogenesis (GO:0009653), anterior/posterior pattern specification (GO:0009952), notochord formation (GO:0014028), signal transduction involved in regulation of gene expression (GO:0023019), notochord development (GO:0030903), post-anal tail morphogenesis (GO:0036342), positive regulation of DNA-templated transcription (GO:0045893), embryonic skeletal system development (GO:0048706), bone morphogenesis (GO:0060349), determination of heart left/right asymmetry (GO:0061371), cellular response to retinoic acid (GO:0071300)

GO Molecular Function (8): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription factor activity (GO:0003700), transcription corepressor activity (GO:0003714), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (4): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Gastrulation	5
Developmental Biology	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of transcription by RNA polymerase II	3
transcription by RNA polymerase II	3
cellular anatomical structure	3
negative regulation of DNA-templated transcription	2
anatomical structure formation involved in morphogenesis	2
regulation of DNA-templated transcription	2
cellular process	2
anterior/posterior axis specification	2
DNA-templated transcription	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
formation of primary germ layer	1
mesoderm morphogenesis	1
cell fate commitment	1
cellular developmental process	1
anterior/posterior pattern specification	1
segmentation	1
chordate embryonic development	1
somite development	1
heart development	1
animal organ morphogenesis	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
tissue development	1
embryonic axis specification	1
tripartite regional subdivision	1
positive regulation of DNA-templated transcription	1
cardioblast differentiation	1
myoblast differentiation	1
gastrulation with mouth forming second	1
cell differentiation	1
blood vessel morphogenesis	1
neural plate development	1
morphogenesis of embryonic epithelium	1
primary neural tube formation	1
tube closure	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
single fertilization	1

Protein interactions and networks

STRING

894 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TBXT	CENPT	Q96BT3	760
TBXT	POU3F3	P20264	603
TBXT	MIXL1	Q9H2W2	575
TBXT	SOX17	Q9H6I2	536
TBXT	BMP4	P12644	531
TBXT	FOXA2	Q9Y261	514
TBXT	KDM6B	O15054	491
TBXT	FOXF1	Q12946	477
TBXT	POU5F1	P31359	441
TBXT	SETD7	Q8WTS6	431
TBXT	CENPU	Q71F23	430
TBXT	CENPN	Q96H22	429
TBXT	CENPM	Q9NSP4	425
TBXT	SMARCA4	P51532	420
TBXT	PAX6	P26367	412

IntAct

15 interactions, top by confidence:

A	B	Type	Score
NFIA	TBXT	psi-mi:“MI:0915”(physical association)	0.470
NFIB	TBXT	psi-mi:“MI:0915”(physical association)	0.470
MIXL1	TBXT	psi-mi:“MI:0915”(physical association)	0.400
NFIC	TBXT	psi-mi:“MI:0915”(physical association)	0.400
CXCL11	TBXT	psi-mi:“MI:0915”(physical association)	0.370
IFNA16	TBXT	psi-mi:“MI:0915”(physical association)	0.370
IFNA17	TBXT	psi-mi:“MI:0915”(physical association)	0.370
IFNA21	TBXT	psi-mi:“MI:0915”(physical association)	0.370
IFNA7	TBXT	psi-mi:“MI:0915”(physical association)	0.370
IL37	TBXT	psi-mi:“MI:0915”(physical association)	0.370
XCL1	TBXT	psi-mi:“MI:0915”(physical association)	0.370
TBXT	CAD	psi-mi:“MI:0914”(association)	0.350
KLHL22	TRAV18	psi-mi:“MI:0914”(association)	0.350
TBXT	BCL9	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (119): KDM6A (Proximity Label-MS), MNX1 (Proximity Label-MS), SMARCA2 (Proximity Label-MS), SMARCA4 (Proximity Label-MS), AES (Proximity Label-MS), SMARCD2 (Proximity Label-MS), SMARCD1 (Proximity Label-MS), TCF7L2 (Proximity Label-MS), CHD7 (Proximity Label-MS), ZNF703 (Proximity Label-MS), BCL9 (Proximity Label-MS), NFIB (Proximity Label-MS), ARID1A (Proximity Label-MS), KMT2D (Proximity Label-MS), ZNF609 (Proximity Label-MS)

ESM2 similar proteins: A0A1L8GWK2, A0JMA8, A2BGA0, A4IIG7, B5DF21, E7F187, O00482, O15178, P16375, P19793, P24781, P28700, P28701, P28705, P43354, P45448, P48443, P51128, P51129, P70302, P83093, P84903, Q05343, Q06219, Q07917, Q08E53, Q09555, Q0GFF6, Q0IHW3, Q0VC20, Q13586, Q26622, Q33E94, Q5BJR8, Q5FWP2, Q5R5Y4, Q5REL6, Q6DHP9, Q7SYN5, Q7TNK1

Diamond homologs: A1YF56, A2AWL7, D3ZJK7, E1BEA8, O01409, O13161, O15119, O15178, O17212, O43435, O54839, O60806, O70306, O73718, O75333, O95935, O95936, O95947, P20293, P24781, P55965, P56158, P57082, P70323, P70324, P70325, P70326, P70327, P79742, P79777, P79778, P79779, P79944, P80492, P87377, P90971, Q07998, Q13207, Q16650, Q17134

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
POU5F1	“down-regulates quantity by repression”	TBXT	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 15 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.

GO biological processes:

GO term	Partners	Fold	FDR
defense response to virus	5	24.8×	2e-05

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	39
Likely benign	7
Benign	7

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
126564	NM_001366285.2(TBXT):c.512A>G (p.His171Arg)	Pathogenic
1176844	NM_001366285.2(TBXT):c.816dup (p.Ser273fs)	Likely pathogenic

SpliceAI

1658 predictions. Top by Δscore:

Variant	Effect	Δscore
6:166158585:CTGA:C	acceptor_gain	1.0000
6:166158589:C:CC	acceptor_gain	1.0000
6:166160962:ATAGG:A	acceptor_gain	1.0000
6:166160963:TAGG:T	acceptor_gain	1.0000
6:166160963:TAGGC:T	acceptor_loss	1.0000
6:166160964:AGG:A	acceptor_gain	1.0000
6:166160964:AGGC:A	acceptor_loss	1.0000
6:166160965:GG:G	acceptor_gain	1.0000
6:166160965:GGCTA:G	acceptor_loss	1.0000
6:166160966:GCT:G	acceptor_loss	1.0000
6:166160967:C:CC	acceptor_gain	1.0000
6:166160967:CT:C	acceptor_loss	1.0000
6:166160968:T:A	acceptor_loss	1.0000
6:166164516:C:CA	donor_gain	1.0000
6:166164539:T:TA	donor_gain	1.0000
6:166164540:C:A	donor_gain	1.0000
6:166165599:T:TA	donor_gain	1.0000
6:166166588:CTA:C	donor_loss	1.0000
6:166166589:TA:T	donor_loss	1.0000
6:166166591:C:CT	donor_loss	1.0000
6:166158586:TGA:T	acceptor_gain	0.9900
6:166164496:C:A	donor_gain	0.9900
6:166165530:A:AC	donor_gain	0.9900
6:166165531:A:C	donor_gain	0.9900
6:166165546:T:A	donor_gain	0.9900
6:166165555:T:TA	donor_gain	0.9900
6:166165707:T:TA	donor_gain	0.9900
6:166166756:T:TA	donor_gain	0.9900
6:166167382:CCA:C	donor_loss	0.9900
6:166167383:CAC:C	donor_loss	0.9900

AlphaMissense

2864 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:166164817:G:C	F217L	1.000
6:166164817:G:T	F217L	1.000
6:166164818:A:C	F217C	1.000
6:166164818:A:G	F217S	1.000
6:166164819:A:C	F217V	1.000
6:166164819:A:G	F217L	1.000
6:166164823:T:A	K215N	1.000
6:166164823:T:G	K215N	1.000
6:166164824:T:A	K215I	1.000
6:166164825:T:C	K215E	1.000
6:166164827:G:A	A214V	1.000
6:166164827:G:T	A214E	1.000
6:166164828:C:T	A214T	1.000
6:166164829:A:C	F213L	1.000
6:166164829:A:T	F213L	1.000
6:166164830:A:C	F213C	1.000
6:166164830:A:G	F213S	1.000
6:166164831:A:C	F213V	1.000
6:166164831:A:G	F213L	1.000
6:166164831:A:T	F213I	1.000
6:166164835:A:C	N211K	1.000
6:166164835:A:T	N211K	1.000
6:166164836:T:A	N211I	1.000
6:166164837:T:C	N211D	1.000
6:166164845:A:C	I208S	1.000
6:166164845:A:G	I208T	1.000
6:166164845:A:T	I208N	1.000
6:166164847:T:A	K207N	1.000
6:166164847:T:G	K207N	1.000
6:166164848:T:A	K207I	1.000

dbSNP variants (sampled 300 via entrez): RS1000362183 (6:166160280 T>C), RS1000457722 (6:166157220 C>T), RS1000536960 (6:166165080 G>A), RS1000592440 (6:166165370 G>A), RS1000719636 (6:166169931 A>G), RS1001020589 (6:166162999 C>T), RS1001474103 (6:166159917 G>A,C,T), RS1001474647 (6:166163209 GC>G), RS1001581675 (6:166168899 G>A), RS1001926210 (6:166169063 C>A,G), RS1001929684 (6:166169876 C>G,T), RS1002648287 (6:166162284 T>C,G), RS1002861233 (6:166166178 T>A), RS1003144597 (6:166158562 C>T), RS1003247218 (6:166164986 C>T)

Disease associations

OMIM: gene MIM:601397 | disease phenotypes: MIM:615709, MIM:615599, MIM:182940

GenCC curated gene-disease

Disease	Classification	Inheritance
chordoma	Strong	Autosomal dominant
sacral agenesis-abnormal ossification of the vertebral bodies-persistent notochordal canal syndrome	Supportive	Autosomal recessive

Mondo (5): sacral agenesis-abnormal ossification of the vertebral bodies-persistent notochordal canal syndrome (MONDO:0014314), microcephaly-thin corpus callosum-intellectual disability syndrome (MONDO:0014273), neural tube defect (MONDO:0018075), neural tube defects, susceptibility to (MONDO:0020705), chordoma (MONDO:0008978)

Orphanet (4): Sacral agenesis-abnormal ossification of the vertebral bodies-persistent notochordal canal syndrome (Orphanet:397927), Microcephaly-thin corpus callosum-intellectual disability syndrome (Orphanet:397951), Neural tube defect (Orphanet:3388), Spina bifida and other spinal dysraphisms (Orphanet:823)

HPO phenotypes

20 total (20 of 20 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000020	Urinary incontinence
HP:0000122	Unilateral renal agenesis
HP:0000238	Hydrocephalus
HP:0000960	Sacral dimple
HP:0001012	Multiple lipomas
HP:0002023	Anal atresia
HP:0002323	Anencephaly
HP:0002475	Myelomeningocele
HP:0003298	Spina bifida occulta
HP:0003468	Abnormal vertebral morphology
HP:0003811	Neonatal death
HP:0008428	Vertebral clefting
HP:0008482	Asymmetry of spinal facet joints
HP:0010305	Absence of the sacrum
HP:0012032	Lipoma
HP:0012621	Persistent cloaca
HP:0034198	Second trimester onset
HP:0034199	Late first trimester onset

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001495_1	Asthma	6.000000e-06
GCST001524_8	Visceral adipose tissue/subcutaneous adipose tissue ratio	4.000000e-06
GCST005986_10	Blood urea nitrogen levels	3.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004767	visceral:subcutaneous adipose tissue ratio

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D002817	Chordoma	C04.557.465.220
D009436	Neural Tube Defects	C10.500.680; C16.131.666.680

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5169062 (PROTEIN-PROTEIN INTERACTION)

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2305089	Efficacy	3	flunisolide	Asthma

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2305089	TBXT	3	3.00	1	flunisolide

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — T-box transcription factors

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
compound 10 [PMID: 39952925]	Inhibition	5.1	pKd

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, decreases reaction, affects methylation	2
Arsenic	increases response to substance, affects methylation	2
Valproic Acid	affects expression	2
bisphenol A	increases expression	1
beta-lapachone	decreases expression	1
arsenite	increases methylation	1
monoisoamyl-2,3-dimercaptosuccinate	decreases reaction, affects expression, decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects expression	1
bisphenol S	affects methylation	1
(+)-JQ1 compound	decreases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	decreases expression	1
Carbamazepine	affects expression	1
Cisplatin	increases expression	1
Estradiol	increases expression	1
Lead	decreases expression	1
Tretinoin	affects expression	1
Raloxifene Hydrochloride	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5129897	Binding	TRAFTAC activity at VHL/Brachyury in human HeLa cells expressing NT-dCas9HT7 co-transfected with brachyury-TRAFTAC assessed as reduction in endogenous brachyury level at 10 uM measured after 15 hrs by Western blot analysis	Nucleic-Acid-Based Targeted Degradation in Drug Discovery. — J Med Chem

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A6W3	SEES3-1V human T, clone1	Embryonic stem cell	Male
CVCL_A6W4	SEES3-1V human T, clone2	Embryonic stem cell	Male
CVCL_A6W5	SEES3-1V human T, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01182779	PHASE3	UNKNOWN	Trial of Proton Versus Carbon Ion Radiation Therapy in Patients With Chordoma of the Skull Base
NCT00301587	PHASE3	WITHDRAWN	A Study to Evaluate Folate Levels in Women Taking Oral Contraceptives
NCT00468481	PHASE3	COMPLETED	Efficacy and Safety Study for an Oral Contraceptive Containing Folate
NCT00150072	PHASE2	COMPLETED	Efficacy and Safety of Imatinib in Chordoma
NCT00464620	PHASE2	COMPLETED	Trial of Dasatinib in Advanced Sarcomas
NCT00496119	PHASE2	ACTIVE_NOT_RECRUITING	Proton Beam Therapy for Chordoma Patients
NCT02383498	PHASE2	COMPLETED	QUILT-3.011 Phase 2 Yeast-Brachyury Vaccine Chordoma
NCT02834013	PHASE2	ACTIVE_NOT_RECRUITING	Nivolumab and Ipilimumab in Treating Patients With Rare Tumors
NCT03083678	PHASE2	COMPLETED	Afatinib in Locally Advanced and Metastatic Chordoma
NCT03110744	PHASE2	COMPLETED	CDK4/6 Inhibition in Locally Advanced/Metastatic Chordoma
NCT03242382	PHASE2	UNKNOWN	Trial of Palbociclib in Second Line of Advanced Sarcomas With CDK4 Overexpression.
NCT03595228	PHASE2	COMPLETED	BN Brachyury and Radiation in Chordoma
NCT03623854	PHASE2	COMPLETED	Nivolumab and Relatlimab in Treating Participants With Advanced Chordoma
NCT04042597	PHASE2	UNKNOWN	Anlotinib Hydrochloride Versus Imatinib Mesylate in Locally Advanced, Unresectable or Metastatic Chordoma
NCT04416568	PHASE2	ACTIVE_NOT_RECRUITING	Study of Nivolumab and Ipilimumab in Children and Young Adults With INI1-Negative Cancers
NCT05041127	PHASE2	ACTIVE_NOT_RECRUITING	Cetuximab for the Treatment of Advanced Unresectable or Metastatic Chordoma
NCT06140732	PHASE2	UNKNOWN	Apatinib Combined With Camrelizumab in Treating Participants With Advanced Chordoma
NCT06787664	PHASE2	ACTIVE_NOT_RECRUITING	A Study of BL-B01D1 in Patients With Locally Advanced or Metastatic Chordoma
NCT06794645	PHASE2	RECRUITING	Pembrolizumab and Pemetrexed for Progressive Chordoma
NCT01392989	PHASE2	COMPLETED	Post T-plant Infusion of Allogeneic Cytokine Induced Killer (CIK) Cells as Consolidative Therapy in Myelodysplastic Syndromes/Myeloproliferative Disorders
NCT00003926	PHASE1	TERMINATED	Amifostine to Protect From Side Effects of PSCT in Treating Patients With Solid Tumors
NCT01175109	PHASE1	UNKNOWN	Study of Imatinib, a Platelet-derived Growth Factor Receptor Inhibitor, and LBH589, a Histone Deacetylase Inhibitor, in the Treatment of Newly Diagnosed and Recurrent Chordoma
NCT01407198	PHASE1	COMPLETED	Nilotinib With Radiation for High Risk Chordoma
NCT02989636	PHASE1	ACTIVE_NOT_RECRUITING	Nivolumab With or Without Stereotactic Radiosurgery in Treating Patients With Recurrent, Advanced, or Metastatic Chordoma
NCT03955042	PHASE1	COMPLETED	Pemetrexed for the Treatment of Chordoma
NCT04246671	PHASE1	COMPLETED	TAEK-VAC-HerBy Vaccine for Brachyury and HER2 Expressing Cancer
NCT02230072	PHASE1	COMPLETED	Fetoscopic Meningomyelocele Repair Study
NCT00452829	PHASE1	COMPLETED	Prevention of Neural Tube Defects by Inositol in Conjunction With Folic Acid (PONTI Study)
NCT03794011	PHASE1	ACTIVE_NOT_RECRUITING	Patch vs. No Patch Fetoscopic Meningomyelocele Repair Study
NCT00592748	PHASE1/PHASE2	COMPLETED	Charged Particle RT for Chordomas and Chondrosarcomas of the Base of Skull or Cervical Spine
NCT03190174	PHASE1/PHASE2	COMPLETED	Nivolumab (Opdivo®) Plus ABI-009 (Nab-rapamycin) for Advanced Sarcoma and Certain Cancers
NCT03647423	PHASE1/PHASE2	WITHDRAWN	QUILT-3.091 NANT Chordoma Vaccine vs Radiation in Subjects With Unresectable Chordoma.
NCT05286801	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Tiragolumab and Atezolizumab for the Treatment of Relapsed or Refractory SMARCB1 or SMARCA4 Deficient Tumors
NCT05407441	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Tazemetostat+Nivo/Ipi in INI1-Neg/SMARCA4-Def Tumors
NCT06625190	PHASE1/PHASE2	RECRUITING	Alpha/Beta T and B Cell Depletion With Zoledronic Acid for Solid Tumors
NCT06957327	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Study of ERAS-601 in People With Chordoma
NCT00341627	Not specified	COMPLETED	Genetic Aspects of Chordoma: A Collaboration With SEER Registries to Identify Chordoma Families
NCT00349024	Not specified	UNKNOWN	Polyvinylpyrrolidone-Sodium Hyaluronate Gel in Reducing Pain From Oral Mucositis in Young Patients With Cancer
NCT00410670	Not specified	COMPLETED	Chordoma Family Study
NCT00713037	Not specified	COMPLETED	Hypoxia-positron Emission Tomography (PET) and Intensity Modulated Proton Therapy (IMPT) Dose Painting in Patients With Chordomas