TBX2

Summary

TBX2 (T-box transcription factor 2, HGNC:11597) is a protein-coding gene on chromosome 17q23.2, encoding T-box transcription factor TBX2 (Q13207). Transcription factor which acts as a transcriptional repressor.

This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. This gene product is the human homolog of mouse Tbx2, and shares strong sequence similarity with Drosophila omb protein. Expression studies indicate that this gene may have a potential role in tumorigenesis as an immortalizing agent. Transcript heterogeneity due to alternative polyadenylation has been noted for this gene.

Source: NCBI Gene 6909 — RefSeq curated summary.

At a glance

• Gene–disease (curated): vertebral anomalies and variable endocrine and T-cell dysfunction (Strong, GenCC)
• GWAS associations: 39
• Clinical variants (ClinVar): 182 total — 3 likely-pathogenic
• Phenotypes (HPO): 40
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• Transcription factor: yes — 37 downstream targets (CollecTRI)
• MANE Select transcript: NM_005994

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11597
Approved symbol	TBX2
Name	T-box transcription factor 2
Location	17q23.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000121068
Ensembl biotype	protein_coding
OMIM	600747
Entrez	6909

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 3 protein_coding, 1 nonsense_mediated_decay, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000240328, ENST00000419047, ENST00000477081, ENST00000586986, ENST00000964761, ENST00000964762

RefSeq mRNA: 1 — MANE Select: NM_005994 NM_005994

CCDS: CCDS11627

Canonical transcript exons

ENST00000240328 — 7 exons

Exon	Start	End
ENSE00000820427	61399843	61400571
ENSE00001132011	61408054	61409466
ENSE00003516211	61404421	61404497
ENSE00003540908	61405202	61405836
ENSE00003542486	61403061	61403207
ENSE00003650326	61404606	61404769
ENSE00003692976	61401684	61401951

Expression profiles

Bgee: expression breadth ubiquitous, 236 present calls, max score 97.76.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 26.8529 / max 403.9544, expressed in 1201 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
162090	15.9511	1091
162089	4.9108	812
162092	2.4405	695
162094	1.8483	374
162093	1.1727	231
162091	0.3562	210
208299	0.1733	88

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lung	UBERON:0002167	97.76	gold quality
right coronary artery	UBERON:0001625	96.22	gold quality
upper lobe of left lung	UBERON:0008952	95.76	gold quality
upper lobe of lung	UBERON:0008948	95.68	gold quality
right uterine tube	UBERON:0001302	95.53	gold quality
left coronary artery	UBERON:0001626	94.86	gold quality
coronary artery	UBERON:0001621	94.57	gold quality
seminal vesicle	UBERON:0000998	94.44	gold quality
metanephros cortex	UBERON:0010533	94.01	gold quality
popliteal artery	UBERON:0002250	93.77	gold quality
tibial artery	UBERON:0007610	93.77	gold quality
endometrium epithelium	UBERON:0004811	93.41	gold quality
apex of heart	UBERON:0002098	93.04	gold quality
periodontal ligament	UBERON:0008266	92.95	gold quality
caput epididymis	UBERON:0004358	92.86	gold quality
lower lobe of lung	UBERON:0008949	92.77	gold quality
lung	UBERON:0002048	92.53	gold quality
corpus epididymis	UBERON:0004359	92.31	gold quality
aorta	UBERON:0000947	91.42	gold quality
adult mammalian kidney	UBERON:0000082	89.21	gold quality
ascending aorta	UBERON:0001496	88.63	gold quality
thoracic aorta	UBERON:0001515	88.48	gold quality
tibial nerve	UBERON:0001323	88.05	gold quality
sural nerve	UBERON:0015488	88.02	gold quality
descending thoracic aorta	UBERON:0002345	87.83	gold quality
stromal cell of endometrium	CL:0002255	87.78	gold quality
body of uterus	UBERON:0009853	87.65	gold quality
heart left ventricle	UBERON:0002084	86.95	gold quality
cardiac ventricle	UBERON:0002082	86.58	gold quality
placenta	UBERON:0001987	86.19	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	29.01
E-GEOD-135922	yes	25.76
E-ANND-3	yes	11.32

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

37 targets.

Target	Regulation
ADAM10	Repression
BAG6
BMP4
CCN4	Repression
CCND1	Activation
CDH1	Repression
CDH17
CDKN1A	Repression
CDKN2A	Repression
CEBPD	Repression
COL1A2	Repression
EIF3K
FN1
FRZB	Repression
GAPDH	Repression
GJA1	Repression
GJA5	Unknown
GJC1
IL33	Repression
MAPK14
MITF
MYCN	Repression
NDRG1	Unknown
NPPA	Unknown
OCA2	Repression
PDP1
SHH	Repression
SHISA3	Repression
SRF	Activation
TBX2

JASPAR motifs

Motif	Name	Family
MA0688.1	TBX2	TBX2-related factors
MA0688.2	TBX2	TBX2-related factors

JASPAR matrix evidence (PMIDs): PMID:16285859

Upstream regulators (CollecTRI, top): BMP2, E2F4, HEY2, MITF, PAX3, PITX2, SP1, SSRP1, TBX15, TBX20, TBX2, TBX3

miRNA regulators (miRDB)

57 targeting TBX2, 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-3662	99.99	73.82	5684
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-9-3P	99.96	70.88	2068
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-486-5P	99.51	70.39	707
HSA-MIR-4672	99.50	71.58	2893
HSA-MIR-21-5P	99.46	70.54	1035
HSA-MIR-520F-5P	99.34	70.40	1632
HSA-MIR-128-1-5P	99.33	60.46	332
HSA-MIR-128-2-5P	99.33	60.83	311
HSA-MIR-590-5P	99.25	70.76	930
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-4292	99.16	65.57	1767

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• identification of a variant T-site as the essential TBX2/TBX3-binding element in the human p14(ARF) promoter (PMID:12000749)
• upregulation of Tbx2 gene in response to tension downregulates CX43 in cranial sutures (PMID:14595187)
• In human melanoma cells, expression of dnTbx2 leads to severely reduced growth and induction of senescence-associated heterochromatin foci. (PMID:15781639)
• Results are consistent with Tbx2 playing a role in cell cycle progression and organization of subnuclear compartments. (PMID:16730707)
• Tbx2 in fibroblasts reduces expression of the COL1A2 gene (PMID:17407139)
• the ability of Tbx2 to repress the p21 gene is enhanced in response to a stress-induced senescence pathway, which leads to a better understanding of the regulation of the anti-senescence function of Tbx2. (PMID:18025091)
• identify a Sp1 element and a reverse CCAAT box to be essential for basal Tbx2 promoter activity (PMID:18640248)
• Tbx2 and Tbx3 may play a dual role during the radial to vertical growth phase transition by both inhibiting senescence via repression of p21(CIP1) expression, and enhancing melanoma invasiveness by decreasing E-cadherin levels. (PMID:18829543)
• TBX2 is a cell type-dependent survival factor under a p53-negative background. (PMID:19216023)
• Tbx2 protein might play an important role in the process of the development and metastasis of pancreatic cancers (PMID:19469638)
• Data reveal that TPA activates transcription of TBX2 through activating MSK1, which leads to an increase in phosphorylated histone H3 and the recruitment of Sp1 to the TBX2 gene. (PMID:19633291)
• This review presents a state of the art overview of the role and regulation of Tbx2 in early embryonic development and in cancer[review] (PMID:19960541)
• Data identify a novel mechanism for TBX2-driven oncogenesis and highlight the importance of NDRG1 as a growth control gene in breast tissue. (PMID:20348948)
• We report the first analysis of PSCA, PIWIL1, and TBX2 expression in EAC. Our findings suggest that PSCA and TBX2 might be candidate targets for cancer therapy. (PMID:20502058)
• Rb1 is an important determinant of Tbx2 functional specificity. (PMID:20534814)
• TBX2 gene duplication is associated with complex heart defect and skeletal malformations. (PMID:20635360)
• Microdeletion of 17q22q23.2 encompassing TBX2 and TBX4 in a patient with congenital microcephaly, thyroid duct cyst, sensorineural hearing loss, and pulmonary hypertension. (PMID:21271665)
• PML and TBX2 act in an autoregulatory loop to control the effective execution of the senescence program. (PMID:22002537)
• TBX2 CPG island methylation predicts progression in bladder cancer. (PMID:22284968)
• an unanticipated link between TBX2 deregulation in cancer and the acquisition of EMT and invasive features of epithelial tumor cells (PMID:22844464)
• The identification of TBX2 as a target for PAX3 provides a key insight into how PAX3 may contribute to melanoma evolution. (PMID:23020925)
• Coimmunoprecipitations and immunofluorescence analyses confirmed the L2-TBX2 interaction and revealed that human papillomavirus 16 L2 also interacts with human TBX3, another member of the T-box family. (PMID:23388722)
• DNA sequence variants within TBX2 gene promoter may contribute to ventricular septal defects ethiology (PMID:23727221)
• TBX2 was a significantly prognostic factor for decreased survival. (PMID:23959449)
• Knocking down TBX2 sensitises the cells to cisplatin by disrupting the ATM-CHK2-p53 signalling pathway. (PMID:24113180)
• The data suggested that the DNA sequence variants within the TBX2 gene promoter was implicated in the indirect inguinal hernia development as a rare cause. (PMID:24309999)
• deregulated TBX2 serves as an oncogene in rhabdomyosarcoma (PMID:24470334)
• High TBX2 expression is associated with breast cancer. (PMID:24742492)
• High TBX2 expression is associated with non-small cell lung cancer. (PMID:25027744)
• Our results suggest a conserved role of Tbx2-related proteins in cell invasion and metastasis-related processes (PMID:25344916)
• Data show that the down-regulation of T-box transcription factor TBX2 by transforming growth factor beta I (TGF-beta1) is mediated by T-box transcription factor TBX3. (PMID:25371204)
• this new molecular-grade based on the combination of TBX2 and TBX3 methylation is an excellent marker for predicting progression to muscle-invasive bladder cancer in patients with primary pTaG1/2 bladder cancer. (PMID:25394776)
• TBX2 is a central component of the PTEN/PI3K/AKT signaling pathway deregulation in RMS cells and that targeting TBX2 in RMS tumors may offer a novel therapeutic approach for RMS (PMID:26686089)
• The results indicated that the expression rates of TBX2 were significantly increased in the prostate cancerous tissues, compared with the healthy tumor adjacent tissue, and TBX2 increased staining was associated with the clinical stage and pathological grade. (PMID:28849151)
• We report four individuals with an overlapping spectrum of craniofacial dysmorphisms, cardiac anomalies, skeletal malformations, immune deficiency, endocrine abnormalities and developmental impairments, reminiscent of DiGeorge syndrome, who are heterozygotes for TBX2 variants. (PMID:29726930)
• Our results indicate that the R608W and R616Q variants of TBX2 as well as the A192T and A562V variants of TBX3 contribute to Conotruncal heart defects (CTDs)etiology; this was the first association of variants of TBX2 and TBX3 to CTDs based on a large population. (PMID:30223900)
• T allele of rs59382073 in TBX2 3’UTR contributes to greater congenital heart defects risk in the Han Chinese population (PMID:30262811)
• TBX2 is a neuroblastoma core regulatory circuitry component enhancing MYCN/FOXM1 reactivation of DREAM targets. (PMID:30451831)
• The minor C allele of rs4455026 in TBX2 promoter region was related with lower congenital heart disease susceptibility in the Han Chinese population via repressing its transcriptional activity. (PMID:30525309)
• transcription factor TBX2 is able to restrain ADAM10 gene expression and that this mechanism might play a role in regulating cellular processes in health, development and disease. (PMID:30599067)

Cross-species orthologs

15 orthologs

Organism	Symbol	Gene ID
danio_rerio	tbx2b	ENSDARG00000006120
danio_rerio	tbx2a	ENSDARG00000018025
mus_musculus	Tbx2	ENSMUSG00000000093
rattus_norvegicus	Tbx2	ENSRNOG00000003517
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), TBX4 (ENSG00000121075), TBX22 (ENSG00000122145), TBX3 (ENSG00000135111), TBR1 (ENSG00000136535), TBX19 (ENSG00000143178), TBX6 (ENSG00000149922), EOMES (ENSG00000163508), TBXT (ENSG00000164458), TBX20 (ENSG00000164532), TBX10 (ENSG00000167800), MGA (ENSG00000174197), TBX1 (ENSG00000184058)

Protein

Protein identifiers

T-box transcription factor TBX2 — Q13207 (reviewed: Q13207)

All UniProt accessions (2): Q13207, F8WCM9

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor which acts as a transcriptional repressor. May also function as a transcriptional activator. Binds to the palindromic T site 5’-TTCACACCTAGGTGTGAA-3’ DNA sequence, or a half-site, which are present in the regulatory region of several genes. Required for cardiac atrioventricular canal formation. May cooperate with NKX2.5 to negatively modulate expression of NPPA/ANF in the atrioventricular canal. May play a role as a positive regulator of TGFB2 expression, perhaps acting in concert with GATA4 in the developing outflow tract myocardium. Plays a role in limb pattern formation. Acts as a transcriptional repressor of ADAM10 gene expression, perhaps in concert with histone deacetylase HDAC1 as cofactor. Involved in branching morphogenesis in both developing lungs and adult mammary glands, via negative modulation of target genes; acting redundantly with TBX3. Required, together with TBX3, to maintain cell proliferation in the embryonic lung mesenchyme; perhaps acting downstream of SHH, BMP and TGFbeta signaling. Involved in modulating early inner ear development, acting independently of, and also redundantly with TBX3, in different subregions of the developing ear. Acts as a negative regulator of PML function in cellular senescence. Acts as a negative regulator of expression of CDKN1A/p21, IL33 and CCN4; repression of CDKN1A is enhanced in response to UV-induced stress, perhaps as a result of phosphorylation by p38 MAPK. Negatively modulates expression of CDKN2A/p14ARF and CDH1/E-cadherin. Plays a role in induction of the epithelial-mesenchymal transition (EMT). Plays a role in melanocyte proliferation, perhaps via regulation of cyclin CCND1. Involved in melanogenesis, acting via negative modulation of expression of DHICA oxidase/TYRP1 and P protein/OCA2. Involved in regulating retinal pigment epithelium (RPE) cell proliferation, perhaps via negatively modulating transcription of the transcription factor CEBPD.

Subunit / interactions. Binds DNA as a monomer. Interacts with PML (isoform PML-2, isoform PML-3 and isoform PML-4).

Subcellular location. Nucleus.

Tissue specificity. Expressed primarily in adult in kidney, lung, and placenta. Weak expression in heart and ovary.

Disease relevance. Vertebral anomalies and variable endocrine and T-cell dysfunction (VETD) [MIM:618223] An autosomal dominant syndrome characterized by skeletal malformations primarily involving the vertebrae, immunodeficiency, endocrine abnormalities such as hypoparathyroidism and growth hormone deficiency, craniofacial dysmorphism, congenital cardiac anomalies consisting of double-outlet right ventricle, pulmonary valve stenosis and atrial septal defect, and developmental impairments. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Repression domain 1 (RD1) is involved in transcriptional repression. RD1 is necessary for its interaction with PML.

RefSeq proteins (1): NP_005985* (*=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
IPR022582	TBX2/3_TAD	Domain
IPR036960	T-box_sf	Homologous_superfamily
IPR046360	T-box_DNA-bd	Domain
IPR048387	TBX2_3_RD	Domain

Pfam: PF00907, PF12598, PF20627

UniProt features (28 total): modified residue 7, sequence conflict 7, compositionally biased region 4, mutagenesis site 3, region of interest 3, sequence variant 2, chain 1, DNA-binding region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13207-F1	58.13	0.27

Functional residue map

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

Post-translational modifications (7): 342, 360, 622, 653, 657, 676, 336

Mutagenesis-validated functional residues (3):

Position	Phenotype
132–133	abolishes repression of tumor suppressor arf/p14arf expression.
132	abolishes binding to t site 5’-ttcacacctaggtgtgaa-3’ dna sequence.
282	severely impairs repression of tumor suppressor arf/p14arf expression.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-9825892	Regulation of MITF-M-dependent genes involved in cell cycle and proliferation
R-HSA-1266738	Developmental Biology
R-HSA-9730414	MITF-M-regulated melanocyte development
R-HSA-9856651	MITF-M-dependent gene expression

MSigDB gene sets: 431 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_DN, GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_MAMMARY_GLAND_MORPHOGENESIS, GOBP_MUSCLE_TISSUE_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_CARDIAC_SEPTUM_DEVELOPMENT, WWTAAGGC_UNKNOWN, GOBP_GLAND_MORPHOGENESIS, GOBP_OUTFLOW_TRACT_SEPTUM_MORPHOGENESIS, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_CARDIAC_CHAMBER_MORPHOGENESIS, GOBP_CELLULAR_RESPONSE_TO_LIPID

GO Biological Process (47): negative regulation of transcription by RNA polymerase II (GO:0000122), cell fate specification (GO:0001708), heart looping (GO:0001947), outflow tract septum morphogenesis (GO:0003148), outflow tract morphogenesis (GO:0003151), endocardial cushion morphogenesis (GO:0003203), endocardial cushion formation (GO:0003272), regulation of transcription by RNA polymerase II (GO:0006357), apoptotic process (GO:0006915), Notch signaling pathway (GO:0007219), muscle cell fate determination (GO:0007521), regulation of heart contraction (GO:0008016), fibroblast growth factor receptor signaling pathway (GO:0008543), neurogenesis (GO:0022008), response to retinoic acid (GO:0032526), embryonic heart tube development (GO:0035050), aorta morphogenesis (GO:0035909), atrioventricular canal development (GO:0036302), embryonic digit morphogenesis (GO:0042733), pigment metabolic process involved in pigmentation (GO:0043474), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of transcription by RNA polymerase II (GO:0045944), embryonic camera-type eye morphogenesis (GO:0048596), cardiac muscle tissue development (GO:0048738), smooth muscle cell differentiation (GO:0051145), roof of mouth development (GO:0060021), pharyngeal system development (GO:0060037), positive regulation of cardiac muscle cell proliferation (GO:0060045), cardiac muscle cell myoblast differentiation (GO:0060379), epithelial tube branching involved in lung morphogenesis (GO:0060441), developmental growth involved in morphogenesis (GO:0060560), mammary placode formation (GO:0060596), mesenchymal cell proliferation involved in lung development (GO:0060916), cellular response to dexamethasone stimulus (GO:0071549), ureteric peristalsis (GO:0072105), cochlea morphogenesis (GO:0090103), cellular senescence (GO:0090398), melanocyte proliferation (GO:0097325), negative regulation of heart looping (GO:1901208), negative regulation of cardiac chamber formation (GO:1901211)

GO Molecular Function (10): 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 repressor activity, RNA polymerase II-specific (GO:0001227), DNA binding (GO:0003677), histone deacetylase binding (GO:0042826), sequence-specific DNA binding (GO:0043565), DNA-binding transcription factor binding (GO:0140297), sequence-specific double-stranded DNA binding (GO:1990837), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515)

GO Cellular Component (5): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
MITF-M-dependent gene expression	1
Developmental Biology	1
MITF-M-regulated melanocyte development	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
cellular anatomical structure	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
heart morphogenesis	2
regulation of DNA-templated transcription	2
heart development	2
negative regulation of DNA-templated transcription	1
cell fate commitment	1
cellular developmental process	1
embryonic heart tube morphogenesis	1
determination of heart left/right asymmetry	1
outflow tract morphogenesis	1
cardiac septum morphogenesis	1
anatomical structure morphogenesis	1
endocardial cushion development	1
mesenchyme morphogenesis	1
endocardial cushion morphogenesis	1
anatomical structure formation involved in morphogenesis	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cell surface receptor signaling pathway	1
cell fate determination	1
muscle cell fate commitment	1
heart contraction	1
regulation of blood circulation	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to fibroblast growth factor stimulus	1
nervous system development	1
cell differentiation	1
response to lipid	1
response to oxygen-containing compound	1
tube development	1
embryonic organ development	1
epithelium development	1
aorta development	1
artery morphogenesis	1
anatomical structure development	1
embryonic limb morphogenesis	1

Protein interactions and networks

STRING

1822 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TBX2	NKX2-5	P52952	833
TBX2	HAND2	P61296	737
TBX2	GJA5	P36382	714
TBX2	NPPA	P01160	713
TBX2	ISL1	P20663	706
TBX2	H3-3A	P06351	665
TBX2	H3-5	Q6NXT2	665
TBX2	H3-7	Q5TEC6	662
TBX2	H3C14	Q71DI3	662
TBX2	H3C1	P02295	656
TBX2	H3-4	Q16695	656
TBX2	PHOX2B	Q99453	630
TBX2	BCAS3	Q9H6U6	628
TBX2	MSX2	P35548	612
TBX2	BMP2	P12643	611

IntAct

38 interactions, top by confidence:

A	B	Type	Score
TTC19	TBX2	psi-mi:“MI:0915”(physical association)	0.560
TBX2	CIDEB	psi-mi:“MI:0915”(physical association)	0.560
CNOT2	TBX2	psi-mi:“MI:0915”(physical association)	0.560
LMO2	TBX2	psi-mi:“MI:0915”(physical association)	0.560
CYSRT1	TBX2	psi-mi:“MI:0915”(physical association)	0.560
KRTAP6-3	TBX2	psi-mi:“MI:0915”(physical association)	0.560
TNPO2	TBX2	psi-mi:“MI:0915”(physical association)	0.560
ATXN1L	TBX2	psi-mi:“MI:0915”(physical association)	0.560
TBX2	TTC19	psi-mi:“MI:0915”(physical association)	0.560
MEIS2	TBX2	psi-mi:“MI:0915”(physical association)	0.560
TBX2	CNOT2	psi-mi:“MI:0915”(physical association)	0.560
TBX2	PML	psi-mi:“MI:0915”(physical association)	0.400
PML	TBX2	psi-mi:“MI:0915”(physical association)	0.400
CEBPE	TBX2	psi-mi:“MI:0915”(physical association)	0.370
TBX2	LZTR1	psi-mi:“MI:0915”(physical association)	0.370
TEAD2	DDX39A	psi-mi:“MI:0914”(association)	0.350
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
AFG3L2	TBX3	psi-mi:“MI:0914”(association)	0.350
TBX2	CYSRT1	psi-mi:“MI:0915”(physical association)	0.000
TBX2	KRTAP6-3	psi-mi:“MI:0915”(physical association)	0.000
TNPO2	TBX2	psi-mi:“MI:0915”(physical association)	0.000
ATXN1L	TBX2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (31): SOX2 (Affinity Capture-Western), TBX2 (Affinity Capture-Western), TBX2 (Affinity Capture-Luminescence), PML (Affinity Capture-Western), TBX2 (Affinity Capture-MS), TBX2 (Affinity Capture-MS), TBX2 (Affinity Capture-Western), TBX2 (Two-hybrid), TBX2 (Two-hybrid), TBX2 (Two-hybrid), MEIS2 (Two-hybrid), LMO2 (Two-hybrid), CIDEB (Two-hybrid), CYSRT1 (Two-hybrid), KRTAP6-3 (Two-hybrid)

ESM2 similar proteins: A2A9A2, A6QQ94, A6YP92, A7MB54, B5RHS5, E9PZZ1, M0R6D8, O02786, O08934, O09029, O35085, P13297, P28360, P46153, P50548, P78413, P78414, P78415, P81067, P81068, P84550, P97830, Q12952, Q13207, Q14549, Q14774, Q2VL76, Q2VL77, Q2VL78, Q2VL79, Q2VL80, Q2VL82, Q2VL83, Q2VL84, Q2VL85, Q2VL86, Q2VL87, Q2VL88, Q2VWA4, Q5SQQ9

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

7 interactions.

A	Effect	B	Mechanism
TBX2	“down-regulates quantity by repression”	CDKN1A	“transcriptional regulation”
TBX2	“down-regulates quantity by repression”	CDKN2A	“transcriptional regulation”
PAX3	“up-regulates quantity by expression”	TBX2	“transcriptional regulation”
TBX2	“down-regulates activity”	MYOD1	binding
TBX2	“down-regulates activity”	MYOG	binding
TBX2	up-regulates	Proliferation
TBX2	down-regulates	Skeletal_muscle_differentiation

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	3
Uncertain significance	116
Likely benign	29
Benign	13

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
2443992	NM_005994.4(TBX2):c.499T>C (p.Phe167Leu)	Likely pathogenic
2631595	NM_005994.4(TBX2):c.1090C>T (p.Pro364Ser)	Likely pathogenic
978728	NM_005994.4(TBX2):c.110T>G (p.Phe37Cys)	Likely pathogenic

SpliceAI

1238 predictions. Top by Δscore:

Variant	Effect	Δscore
17:61400537:C:G	donor_gain	1.0000
17:61400569:G:GT	donor_gain	1.0000
17:61400569:G:T	donor_gain	1.0000
17:61400569:GAGG:G	donor_loss	1.0000
17:61400570:AGGT:A	donor_loss	1.0000
17:61400573:T:A	donor_loss	1.0000
17:61401681:CAG:C	acceptor_loss	1.0000
17:61401682:A:AG	acceptor_gain	1.0000
17:61401683:G:GG	acceptor_gain	1.0000
17:61401683:GGC:G	acceptor_gain	1.0000
17:61401947:GCTTC:G	donor_gain	1.0000
17:61401949:TTC:T	donor_gain	1.0000
17:61401950:TC:T	donor_gain	1.0000
17:61401952:G:GG	donor_gain	1.0000
17:61403060:GACC:G	acceptor_gain	1.0000
17:61403204:CAAGG:C	donor_loss	1.0000
17:61404409:T:TA	acceptor_gain	1.0000
17:61404416:CGCA:C	acceptor_loss	1.0000
17:61404417:GCA:G	acceptor_loss	1.0000
17:61404418:CA:C	acceptor_loss	1.0000
17:61404419:A:AG	acceptor_gain	1.0000
17:61404419:A:C	acceptor_loss	1.0000
17:61404420:G:GC	acceptor_gain	1.0000
17:61404420:GATC:G	acceptor_gain	1.0000
17:61404493:AAAAG:A	donor_loss	1.0000
17:61404495:AAGGT:A	donor_loss	1.0000
17:61404496:AGGT:A	donor_loss	1.0000
17:61404498:G:A	donor_loss	1.0000
17:61404499:T:A	donor_loss	1.0000
17:61404601:CCCA:C	acceptor_loss	1.0000

AlphaMissense

4586 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:61400483:G:C	D103H	1.000
17:61400490:C:A	P105H	1.000
17:61400490:C:G	P105R	1.000
17:61400496:T:A	V107E	1.000
17:61400502:T:A	L109Q	1.000
17:61400502:T:C	L109P	1.000
17:61400517:T:C	L114P	1.000
17:61400519:T:A	W115R	1.000
17:61400519:T:C	W115R	1.000
17:61400519:T:G	W115G	1.000
17:61400520:G:C	W115S	1.000
17:61400520:G:T	W115L	1.000
17:61400521:G:C	W115C	1.000
17:61400521:G:T	W115C	1.000
17:61400528:T:A	F118I	1.000
17:61400528:T:C	F118L	1.000
17:61400528:T:G	F118V	1.000
17:61400529:T:C	F118S	1.000
17:61400529:T:G	F118C	1.000
17:61400530:C:A	F118L	1.000
17:61400530:C:G	F118L	1.000
17:61400540:G:C	G122R	1.000
17:61400541:G:A	G122D	1.000
17:61400541:G:T	G122V	1.000
17:61400546:G:A	E124K	1.000
17:61400547:A:C	E124A	1.000
17:61400547:A:G	E124G	1.000
17:61400547:A:T	E124V	1.000
17:61400548:G:C	E124D	1.000
17:61400548:G:T	E124D	1.000

dbSNP variants (sampled 300 via entrez): RS1000002796 (17:61408867 C>G,T), RS1000197126 (17:61398231 G>C), RS1000379778 (17:61402884 G>A,C), RS1000423 (17:61398281 C>A,T), RS1000660871 (17:61398454 C>G,T), RS1001112190 (17:61402015 G>A), RS1001455062 (17:61407937 T>C), RS1001892083 (17:61400879 G>A,T), RS1002111591 (17:61400652 G>C,T), RS1002219890 (17:61400930 G>A), RS1002387220 (17:61400646 A>G), RS1002406974 (17:61406911 T>C), RS1002640655 (17:61404132 T>A,C,G), RS1002954004 (17:61399970 C>G,T), RS1003257041 (17:61403321 C>A,G,T)

Disease associations

OMIM: gene MIM:600747 | disease phenotypes: MIM:618223

GenCC curated gene-disease

Disease	Classification	Inheritance
vertebral anomalies and variable endocrine and T-cell dysfunction	Strong	Autosomal dominant

Mondo (2): vertebral anomalies and variable endocrine and T-cell dysfunction (MONDO:0032607), microcephaly (MONDO:0001149)

Orphanet (0):

HPO phenotypes

40 total (30 of 40 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000175	Cleft palate
HP:0000189	Narrow palate
HP:0000248	Brachycephaly
HP:0000286	Epicanthus
HP:0000294	Low anterior hairline
HP:0000316	Hypertelorism
HP:0000325	Triangular face
HP:0000369	Low-set ears
HP:0000378	Cupped ear
HP:0000396	Overfolded helix
HP:0000437	Depressed nasal tip
HP:0000455	Broad nasal tip
HP:0000465	Webbed neck
HP:0000470	Short neck
HP:0000729	Autistic behavior
HP:0000824	Decreased response to growth hormone stimulation test
HP:0000829	Hypoparathyroidism
HP:0000872	Hashimoto thyroiditis
HP:0000912	Sprengel anomaly
HP:0001076	Glabellar hemangioma
HP:0001631	Atrial septal defect
HP:0001642	Pulmonic stenosis
HP:0001643	Patent ductus arteriosus
HP:0001719	Double outlet right ventricle
HP:0002650	Scoliosis
HP:0002808	Kyphosis
HP:0002846	Abnormal B cell morphology
HP:0002937	Hemivertebrae
HP:0003577	Congenital onset

GWAS associations

39 associations (top):

Study	Trait	p-value
GCST000175_44	Height	6.000000e-08
GCST000522_6	Height	3.000000e-06
GCST000649_4	Chronic kidney disease	1.000000e-15
GCST000651_4	Creatinine levels	3.000000e-10
GCST000817_194	Height	2.000000e-24
GCST002843_5	Sitting height ratio	8.000000e-14
GCST003275_2	Mean arterial pressure	2.000000e-16
GCST004776_69	Systolic blood pressure	4.000000e-06
GCST005196_222	Coronary artery disease	9.000000e-06
GCST006020_28	Diastolic blood pressure	3.000000e-18
GCST006021_15	Systolic blood pressure	2.000000e-17
GCST006022_12	Pulse pressure	3.000000e-07
GCST006023_9	Hypertension	3.000000e-12
GCST006030_16	Chloride levels	3.000000e-22
GCST006031_13	Potassium levels	6.000000e-14
GCST006227_14	Diastolic blood pressure	3.000000e-18
GCST006228_13	Systolic blood pressure	4.000000e-17
GCST006231_3	Mean arterial pressure	2.000000e-08
GCST006491_5	Circulating fibroblast growth factor 23 levels	6.000000e-07
GCST007094_32	Diastolic blood pressure	2.000000e-07
GCST007096_99	Pulse pressure	2.000000e-06
GCST007099_85	Systolic blood pressure	1.000000e-10
GCST007485_9	Anthropometric traits	1.000000e-78
GCST007490_28	Anthropometric traits (multi-trait analysis)	5.000000e-43
GCST007703_111	Systolic blood pressure	9.000000e-07
GCST007704_120	Diastolic blood pressure	9.000000e-06
GCST007704_47	Diastolic blood pressure	4.000000e-07
GCST007706_145	Mean arterial pressure	3.000000e-06
GCST007706_65	Mean arterial pressure	8.000000e-08
GCST007707_42	Hypertension	6.000000e-07

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0007118	sitting height ratio
EFO:0006340	mean arterial pressure
EFO:0006335	systolic blood pressure
EFO:0006336	diastolic blood pressure
EFO:0005763	pulse pressure measurement
EFO:0009283	potassium measurement
EFO:0004324	body weights and measures
EFO:0006917	spontaneous preterm birth
EFO:0010067	corneal resistance factor
EFO:0010066	corneal hysteresis
EFO:0007789	BMI-adjusted waist circumference

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs8068318	Efficacy	3	atenolol	Hypertension

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs8068318	TBX2	3	3.00	1	atenolol

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, increases expression	3
Valproic Acid	affects cotreatment, increases expression, increases methylation	3
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	2
Arsenic	affects methylation, affects cotreatment, increases abundance, increases expression	2
Tretinoin	increases expression	2
Cyclosporine	decreases expression, decreases methylation	2
aristolochic acid I	increases expression	1
bisphenol A	affects cotreatment, increases methylation	1
ascorbate-2-phosphate	affects cotreatment, increases expression, affects binding	1
beta-lapachone	decreases expression	1
tobacco tar	decreases reaction, increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
diallyl disulfide	decreases reaction, increases expression	1
4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid	affects cotreatment, increases expression	1
diallyl trisulfide	increases expression	1
tebuconazole	decreases expression	1
Chir 99021	increases expression, affects binding, affects cotreatment	1
clothianidin	increases expression	1
ICG 001	decreases expression	1
abrine	increases expression	1
pyrachlostrobin	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	decreases expression	1
XAV939	affects binding, affects cotreatment, increases expression	1
LDN 193189	affects cotreatment, increases expression	1
MK-8776	decreases expression	1
3-(4-pyridyl)-1H-indole	affects cotreatment, increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Sunitinib	decreases expression	1

Cellosaurus cell lines

4 cell lines: 3 embryonic stem cell, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A7A5	SEES3-1V human TBX2, clone1	Embryonic stem cell	Male
CVCL_A7A6	SEES3-1V human TBX2, clone2	Embryonic stem cell	Male
CVCL_A7A7	SEES3-1V human TBX2, clone3	Embryonic stem cell	Male
CVCL_D1UK	Abcam U-87MG TBX2 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic
NCT03330600	Not specified	COMPLETED	Efficacy of Aquatic Physiotherapy in Children With Microcephaly by Zika Virus Congenital Syndrome
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT03651687	Not specified	COMPLETED	Guangzhou Surveillance and Clinical Study in Microcephaly (GSCSM)
NCT03922594	Not specified	TERMINATED	Surveillance of Zika-related Microcephaly in Sub-Saharan Africa and Asia
NCT04816175	Not specified	COMPLETED	Intensive Therapy for Children With Microcephaly, Hyperkinetic Movements, or Global Developmental Delay
NCT05322980	Not specified	COMPLETED	Summary of Infants Weighing 500 Grams or Less
NCT06019182	Not specified	RECRUITING	MEHMO Natural History and Biomarkers
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.