TOX

Summary

TOX (thymocyte selection associated high mobility group box, HGNC:18988) is a protein-coding gene on chromosome 8q12.1, encoding Thymocyte selection-associated high mobility group box protein TOX (O94900). Transcriptional regulator with a major role in neural stem cell commitment and corticogenesis as well as in lymphoid cell development and lymphoid tissue organogenesis.

The protein encoded by this gene contains a HMG box DNA binding domain. HMG boxes are found in many eukaryotic proteins involved in chromatin assembly, transcription and replication. This protein may function to regulate T-cell development.

Source: NCBI Gene 9760 — RefSeq curated summary.

At a glance

• GWAS associations: 27 (top 5% of genes corpus-wide)
• Clinical variants (ClinVar): 80 total
• GTEx eGene: eQTL in 14 tissues, sQTL in 0 (q < 0.05)
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.33 (highly constrained)
• MANE Select transcript: NM_014729
• Notable: 80 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18988
Approved symbol	TOX
Name	thymocyte selection associated high mobility group box
Location	8q12.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0808, TOX1
Ensembl gene	ENSG00000198846
Ensembl biotype	protein_coding
OMIM	606863
Entrez	9760

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 6 protein_coding, 1 nonsense_mediated_decay

MANE Select: ENST00000361421

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1

ENST00000361421, ENST00000890858, ENST00000966263, ENST00000966264, ENST00001020049, ENST00001114865, ENST00001138406

RefSeq mRNA: 1 — MANE Select: NM_014729 NM_014729

CCDS: CCDS34897

Canonical transcript exons

ENST00000361421 — 9 exons

Exon	Start	End
ENSE00000980445	58939302	58939544
ENSE00001020338	58851524	58851805
ENSE00001020339	58815338	58815724
ENSE00001020341	58826822	58826902
ENSE00001020343	58808118	58808269
ENSE00001020345	58838081	58838311
ENSE00001136846	58959943	58960008
ENSE00001197897	58805412	58807783
ENSE00002717862	59118886	59119147

Expression profiles

Bgee: expression breadth ubiquitous, 231 present calls, max score 94.51.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.5234 / max 435.3418, expressed in 1062 samples.

Highest expression (Bgee): cortical plate, endothelial cell, ventricular zone, secondary oocyte, thymus.

Genetic regulation across tissues (GTEx eQTL / sQTL)

TOX is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 14 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

14 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Heart Left Ventricle	eqtl	2.8e-31	+0.66	8:59248362:G:A
Artery Tibial	eqtl	3.9e-28	+0.51	8:58799611:T:C
Cells Cultured fibroblasts	eqtl	3.2e-15	-0.20	8:58863753:T:TAA
Artery Aorta	eqtl	6.5e-15	+0.75	8:58801066:T:G
Thyroid	eqtl	3.6e-06	-0.21	8:58913960:C:T
Nerve Tibial	eqtl	9.1e-06	-0.18	8:58991490:C:T
Whole Blood	eqtl	1.4e-04	+0.12	8:60111020:GC:G
Artery Coronary	eqtl	3.9e-04	+0.50	8:58799611:T:C
Esophagus Mucosa	eqtl	2.1e-03	+0.12	8:58823841:T:C
Heart Atrial Appendage	eqtl	2.3e-02	+0.19	8:58939609:A:AAC
Minor Salivary Gland	eqtl	2.5e-02	+0.32	8:58959316:T:C
Breast Mammary Tissue	eqtl	2.6e-02	+0.18	8:58817500:C:G
Adipose Visceral Omentum	eqtl	3.0e-02	+0.27	8:58412812:G:A
Colon Sigmoid	eqtl	4.3e-02	-0.12	8:59060464:A:T

FANTOM5 promoters

8 alternative TSS:

Promoter ID	TPM avg	Samples expressed
93244	4.6842	754
93245	2.0955	682
93246	1.4277	589
93247	0.8666	423
93248	0.4378	249
93249	0.4027	171
93243	0.3585	113
93242	0.2505	93

Top tissues by expression

showing 100 of 290 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	94.51	gold quality
endothelial cell	CL:0000115	92.03	gold quality
ventricular zone	UBERON:0003053	91.32	gold quality
secondary oocyte	CL:0000655	89.20	gold quality
thymus	UBERON:0002370	87.51	gold quality
ganglionic eminence	UBERON:0004023	84.70	gold quality
mucosa of sigmoid colon	UBERON:0004993	84.66	gold quality
oocyte	CL:0000023	84.15	gold quality
orbitofrontal cortex	UBERON:0004167	83.31	gold quality
sigmoid colon	UBERON:0001159	82.70	gold quality
muscle layer of sigmoid colon	UBERON:0035805	82.37	gold quality
islet of Langerhans	UBERON:0000006	81.96	gold quality
colonic mucosa	UBERON:0000317	81.81	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	81.51	gold quality
prefrontal cortex	UBERON:0000451	81.49	gold quality
Brodmann (1909) area 9	UBERON:0013540	81.20	gold quality
jejunal mucosa	UBERON:0000399	80.58	gold quality
lymph node	UBERON:0000029	80.38	gold quality
rectum	UBERON:0001052	80.25	gold quality
large intestine	UBERON:0000059	79.82	gold quality
mucosa of stomach	UBERON:0001199	79.77	gold quality
neocortex	UBERON:0001950	79.69	gold quality
colon	UBERON:0001155	79.67	gold quality
frontal cortex	UBERON:0001870	79.40	gold quality
Brodmann (1909) area 23	UBERON:0013554	79.22	gold quality
cingulate cortex	UBERON:0003027	79.17	gold quality
intestine	UBERON:0000160	79.16	gold quality
Brodmann (1909) area 46	UBERON:0006483	79.05	gold quality
anterior cingulate cortex	UBERON:0009835	78.95	gold quality
superior frontal gyrus	UBERON:0002661	78.93	gold quality
stomach	UBERON:0000945	78.64	gold quality
body of stomach	UBERON:0001161	78.59	gold quality
tibial artery	UBERON:0007610	78.51	gold quality
popliteal artery	UBERON:0002250	78.50	gold quality
right frontal lobe	UBERON:0002810	78.32	gold quality
cerebral cortex	UBERON:0000956	78.29	gold quality
transverse colon	UBERON:0001157	78.03	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	77.66	gold quality
duodenum	UBERON:0002114	77.55	gold quality
lower esophagus muscularis layer	UBERON:0035833	77.39	gold quality
lower esophagus	UBERON:0013473	77.30	gold quality
vermiform appendix	UBERON:0001154	77.28	gold quality
pigmented layer of retina	UBERON:0001782	77.14	gold quality
small intestine	UBERON:0002108	77.13	gold quality
primary visual cortex	UBERON:0002436	77.01	gold quality
tibia	UBERON:0000979	76.97	gold quality
small intestine Peyer’s patch	UBERON:0003454	76.84	gold quality
postcentral gyrus	UBERON:0002581	76.75	gold quality
fundus of stomach	UBERON:0001160	76.74	gold quality
amygdala	UBERON:0001876	76.62	gold quality
granulocyte	CL:0000094	76.36	gold quality
embryo	UBERON:0000922	76.05	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	75.92	gold quality
hypothalamus	UBERON:0001898	75.60	gold quality
amniotic fluid	UBERON:0000173	75.55	gold quality
telencephalon	UBERON:0001893	75.48	gold quality
caecum	UBERON:0001153	75.47	gold quality
adult organism	UBERON:0007023	75.44	gold quality
ileal mucosa	UBERON:0000331	75.41	gold quality
urethra	UBERON:0000057	75.35	gold quality
tibial nerve	UBERON:0001323	74.95	gold quality
temporal lobe	UBERON:0001871	74.83	gold quality
middle temporal gyrus	UBERON:0002771	74.73	gold quality
occipital lobe	UBERON:0002021	74.69	gold quality
gall bladder	UBERON:0002110	74.65	gold quality
CA1 field of hippocampus	UBERON:0003881	74.52	silver quality
parietal lobe	UBERON:0001872	74.41	gold quality
forebrain	UBERON:0001890	74.28	gold quality
colonic epithelium	UBERON:0000397	74.07	gold quality
mucosa of transverse colon	UBERON:0004991	73.79	gold quality
stromal cell of endometrium	CL:0002255	73.69	gold quality
entorhinal cortex	UBERON:0002728	73.27	gold quality
tonsil	UBERON:0002372	72.58	gold quality
sural nerve	UBERON:0015488	72.50	gold quality
spleen	UBERON:0002106	72.32	gold quality
lateral nuclear group of thalamus	UBERON:0002736	72.27	gold quality
caudate nucleus	UBERON:0001873	71.70	gold quality
brain	UBERON:0000955	71.64	gold quality
central nervous system	UBERON:0001017	71.28	gold quality
cartilage tissue	UBERON:0002418	71.13	gold quality
cardia of stomach	UBERON:0001162	70.86	gold quality
left ovary	UBERON:0002119	70.76	gold quality
blood	UBERON:0000178	70.28	gold quality
renal medulla	UBERON:0000362	70.22	gold quality
lower lobe of lung	UBERON:0008949	70.22	gold quality
bone marrow cell	CL:0002092	69.86	silver quality
pylorus	UBERON:0001166	69.76	gold quality
nucleus accumbens	UBERON:0001882	69.69	gold quality
Ammon’s horn	UBERON:0001954	69.58	gold quality
buccal mucosa cell	CL:0002336	69.20	gold quality
Brodmann (1909) area 10	UBERON:0013541	69.15	gold quality
putamen	UBERON:0001874	69.12	gold quality
pancreas	UBERON:0001264	68.91	gold quality
lung	UBERON:0002048	68.79	gold quality
upper lobe of lung	UBERON:0008948	68.73	gold quality
ovary	UBERON:0000992	68.72	gold quality
upper lobe of left lung	UBERON:0008952	68.60	gold quality
type B pancreatic cell	CL:0000169	68.22	gold quality
aorta	UBERON:0000947	68.17	gold quality
jejunum	UBERON:0002115	68.15	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	3123.86
E-GEOD-131882	yes	3093.12
E-HCAD-35	yes	62.73
E-GEOD-109979	yes	44.22
E-ANND-3	yes	10.23
E-CURD-112	yes	3.56
E-GEOD-70580	no	889.97

HPA expression

RNA tissue specificity: Tissue enriched

showing 60 of 79 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Thymus	tissue	48.8
Prefrontal cortex	tissue	41.3
Cerebral cortex	tissue	41.3	low
Retrosplenial cortex	tissue	39.2
Hypothalamus	tissue	36.0
Retrosplenial and cingulate cortex	tissue	34.2
Motor cortex	tissue	32.5
Thalamus	tissue	30.7
Amygdala	tissue	28.8
Postcentral gyrus	tissue	28.7
Periaqueductal gray	tissue	27.8
Pons	tissue	27.7
Insular cortex	tissue	27.2
Hippocampal formation	tissue	26.7
Midbrain	tissue	25.0
Entorhinal cortex	tissue	24.9
Olfactory bulb	tissue	24.0
Superior colliculi	tissue	22.0
Medulla oblongata	tissue	20.6
Temporal cortex	tissue	20.6
Occipital cortex	tissue	19.8
Substantia nigra	tissue	19.6
Somatosensory cortex	tissue	19.0
Septum	tissue	18.8
Tonsil	tissue	17.7	high
Lymph node	tissue	17.0	high
Putamen	tissue	16.4
Basal ganglia	tissue	16.1	not detected
Spinal cord	tissue	15.8
Corpus callosum	tissue	14.7
Ventral forebrain	tissue	13.7
Frontal cortex	tissue	12.2
Locus coeruleus	tissue	10.0
Small intestine	tissue	9.7	low
Duodenum	tissue	8.9	low
Rectum	tissue	8.0	low
Hippocampus	tissue	7.9	low
Nucleus accumbens	tissue	7.4
Colon	tissue	7.2	low
Stomach 1	tissue	7.0	low
Testis	tissue	5.8	high
Retina	tissue	5.5
Cerebellum	tissue	5.4	not detected
Appendix	tissue	5.4	high
Spleen	tissue	5.2	medium
Lung	tissue	4.4	medium
Gallbladder	tissue	4.3	low
Caudate putamen	tissue	4.1
Ovary	tissue	3.9	low
Esophagus	tissue	3.1	low
Bone marrow	tissue	2.8	medium
Kidney	tissue	2.6	high
Parathyroid gland	tissue	2.3	low
Smooth muscle	tissue	2.3	low
Urinary bladder	tissue	1.9	low
Prostate	tissue	1.9	low
Cervix	tissue	1.7	low
Pituitary gland	tissue	1.7
Salivary gland	tissue	1.5	not detected
Choroid plexus	tissue	1.5

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Subiculum (26.7), Orbitofrontal gyrus, anterior (26.2), Nucleus of the diagonal band (25.9), Superior temporal gyrus (24.3), Olfactory tubercle (24.1).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

6 targets:

Target	Regulation
CRP
CYP27A1
NR0B1
OMP
TBXT
TOX

Upstream regulators (CollecTRI, top): GATA3, TOX, ZBTB7B

miRNA regulators (miRDB)

Targeting TOX by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 220 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548P	99.98	72.25	3784
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3688-3P	99.97	72.02	2834

Functional genomics

gnomAD constraint: pLI 1, LOEUF 0.326, missense Z 1.78 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000361421 splits into 3 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
8:58,807,750–58,826,834	239 / 250.7	0.95	no
8:58,826,835–58,838,250	49 / 98.9	0.50	no
8:58,838,251–59,118,987	282 / 315.0	0.90	no

Literature-anchored findings (GeneRIF, showing 35)

• expression of the HMG box protein TOX is sufficient to induce changes in coreceptor gene expression associated with beta-selection, including CD8 gene demethylation (PMID:15078895)
• results suggest that TOX is required for IL-15-mediated natural killer (NK) cell differentiation and affected expression of T-bet that plays critical roles in NK differentiation and maturation (PMID:21126536)
• Compared with TOX4, expression of TOX1, TOX2 and TOX3 in normal lung was 25, 44, and 88%lower, respectively, supporting the premise that reduced promoter activity confers increased susceptibility to methylation during lung carcinogenesis. (PMID:22496870)
• SNP rs2726600 is located in a transcription-factor binding site in the 3’ region of TOX. (PMID:23415668)
• TOX may be a specific marker for tumour cells in some types of cutaneous lymphoma. (PMID:25216799)
• High TOX transcript levels correlate with increased cutaneous T-cell lymphoma. (PMID:25548321)
• The SLC2A9 (rs7660895) and TOX (rs11777927) gene polymorphisms may be associated with formation of intracranial aneurysms, and rs7660895 may be associated with intracranial aneurysms rupture. (PMID:26125895)
• Significant associations between single nucleotide polymorphisms in TOX, CDKN2A/B and type 2 diabetes meillitus. (PMID:26139146)
• TOX expression is insufficient for diagnosis of cutaneous T-cell lymphoma (PMID:26931394)
• data suggest that GATA3 regulates TOX, revealing insight into TOX regulation (PMID:27345620)
• The expression of Sezary signature genes: FCRL3, Tox, and miR-214, was significantly higher in samples from Sezary syndrome patients with CD164 expressing CD4(+) T cells. (PMID:27766406)
• TOX gene SNP rs11777927 was associated with antipsychotic-induced weight gain. (PMID:28327672)
• TOX is an HMG box-containing protein that has important roles in T-ALL initiation and maintenance. TOX inhibits the recruitment of KU70/KU80 to DNA breaks, thereby inhibiting NHEJ repair. Thus, TOX is likely a dominant oncogenic driver in a large fraction of human T-ALL and enhances genomic instability (PMID:28974511)
• Suggest that F nucleatum may suppress antitumor immune responses by decreasing CD4(+) T-cell density and TOX expression in the progression of colorectal cancer. (PMID:29792893)
• hypothesis that TOX-induced exhaustion program serves to prevent the overstimulation of T cells and activation-induced cell death in settings of chronic antigen stimulation such as cancer (PMID:31207604)
• TOX is a critical factor for the normal progression of T cell dysfunction and the maintenance of exhausted T cells during chronic infection, and provide a link between the suppression of effector function intrinsic to CD8 T cells and protection against immunopathology (PMID:31207605)
• Molecular profiling of TOX-deficient neoplastic cells in cutaneous T cell lymphoma. (PMID:31676945)
• The VEGF-A induces the expression of transcription factor TOX in T cells to drive exhaustion-specific transcription program in T cells. (PMID:31704735)
• High TOX expression is associated with pathogenesis of atherosclerosis. (PMID:31949884)
• Single-cell transcriptome analysis reveals TOX as a promoting factor for T cell exhaustion and a predictor for anti-PD-1 responses in human cancer. (PMID:32111241)
• TOX is expressed by exhausted and polyfunctional human effector memory CD8(+) T cells. (PMID:32620560)
• Origin and fine-tuning of effector CD8 T cell subpopulations in chronic infection. (PMID:33137688)
• Increased TOX expression concurrent with PD-1, Tim-3, and CD244 in T cells from patients with non-Hodgkin lymphoma. (PMID:33608984)
• TOX Acts as a Tumor Suppressor by Inhibiting mTOR Signaling in Colorectal Cancer. (PMID:33897695)
• Normal and cancer fibroblasts differentially regulate TWIST1, TOX and cytokine gene expression in cutaneous T-cell lymphoma. (PMID:33941102)
• CD4+ T cells in classical Hodgkin lymphoma express exhaustion associated transcription factors TOX and TOX2: Characterizing CD4+ T cells in Hodgkin lymphoma. (PMID:35111387)
• The transcription factor TOX is involved in the regulation of T-cell exhaustion in neuroblastoma. (PMID:35691410)
• TOX promotes follicular helper T cell differentiation in patients with primary Sjogren’s syndrome. (PMID:35713502)
• Transcriptional Pattern Analysis of Virus-Specific CD8+ T Cells in Hepatitis C Infection: Increased Expression of TOX and Eomesodermin During and After Persistent Antigen Recognition. (PMID:35734162)
• Immune checkpoint receptor VISTA on immune cells is associated with expression of T-cell exhaustion marker TOX and worse prognosis in renal cell carcinoma with venous tumor thrombus. (PMID:36042047)
• High TOX expression on CD8[+] T cells in pure red cell aplasia. (PMID:36933041)
• TOX regulates T lymphocytes differentiation and its function in tumor. (PMID:36969216)
• TOX, TWIST1, STAT4, and SATB1 protein expressions in early-stage mycosis fungoides. (PMID:37932931)
• Evaluation of mRNA Expressions of TOX and NR4As in CD8+ T cells in Acute Leukemia. (PMID:37961948)
• TOX as a new diagnostic marker for T cell large granular lymphocytic leukaemia. (PMID:38087646)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tox	ENSDARG00000032317
mus_musculus	Tox	ENSMUSG00000041272
rattus_norvegicus	Tox	ENSRNOG00000010777
caenorhabditis_elegans	hmg-3	WBGENE00001973
caenorhabditis_elegans		WBGENE00001974

Paralogs (20): HMGB3 (ENSG00000029993), HMG20B (ENSG00000064961), SP100 (ENSG00000067066), SMARCE1 (ENSG00000073584), SP140 (ENSG00000079263), TOX4 (ENSG00000092203), HMGXB4 (ENSG00000100281), TOX3 (ENSG00000103460), TFAM (ENSG00000108064), UBTF (ENSG00000108312), HMGB1P1 (ENSG00000124097), TOX2 (ENSG00000124191), SP110 (ENSG00000135899), HMG20A (ENSG00000140382), SSRP1 (ENSG00000149136), HMGB2 (ENSG00000164104), HMGB4 (ENSG00000176256), SP140L (ENSG00000185404), HMGB1 (ENSG00000189403), UBTFL1 (ENSG00000255009)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:2181659) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 27 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal CD4-positive T cell differentiation	2
decreased bone mineral density	1
abnormal small intestine morphology	1
abnormal spleen morphology	1
abnormal startle reflex	1
increased circulating alkaline phosphatase level	1
decreased liver weight	1
abnormal auditory brainstem response	1
abnormal positive T cell selection	1
increased spleen weight	1
abnormal CD8-positive, alpha beta T cell morphology	1
decreased cytotoxic T cell cytolysis	1
decreased circulating cholesterol level	1
abnormal T cell number	1
decreased NK T cell number	1
decreased NK cell number	1
decreased CD4-positive, alpha-beta T cell number	1
decreased Peyer’s patch number	1
small Peyer’s patches	1
abnormal CD4-positive, CD25-positive, alpha-beta regulatory T cell morphology	1
absent mesenteric lymph nodes	1
decreased prepulse inhibition	1
absent inguinal lymph nodes	1
absent axillary lymph nodes	1
absent popliteal lymph nodes	1

+2 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Papio anubis	A9RA84	100.0%	Diamond
Callithrix jacchus	B0CM99	100.0%	Diamond
Plecturocebus moloch	B1MTB0	100.0%	Diamond
Cricetulus griseus	P07156	100.0%	Diamond
Cryptococcus deneoformans JEC21	P0CO24	100.0%	Diamond
Cryptococcus deneoformans B-3501A	P0CO25	100.0%	Diamond
Bos taurus	P10103	100.0%	Diamond
Equus caballus	Q08IE6	100.0%	Diamond
Macaca fascicularis	Q4R844	100.0%	Diamond
Canis lupus familiaris	Q6YKA4	100.0%	Diamond
Pongo abelii	Q5R6A9	99.8%	Diamond
Gorilla gorilla gorilla	Q9N1Q6	98.0%	Diamond
Sus scrofa	P12682	94.5%	Diamond
Xenopus tropicalis	A4QNP0	94.3%	Diamond
Xenopus laevis	Q6DJL0	94.3%	Diamond
Gallus gallus	Q9YH06	93.9%	Diamond
Saccharomyces cerevisiae S288C	P11632	88.9%	Diamond
Candida albicans SC5314	Q9UVL1	88.0%	Diamond
Kluyveromyces lactis NRRL Y-1140	Q6CVH3	87.6%	Diamond
Eremothecium gossypii ATCC 10895	Q75B82	87.6%	Diamond
Oncorhynchus mykiss	P07746	82.6%	Diamond
Tetrahymena thermophila	P11873	73.7%	Diamond
Yarrowia lipolytica CLIB122	Q6CC79	73.3%	Diamond
Strongylocentrotus purpuratus	P40644	53.6%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
TOX-DT	ncRNA	100505501
NSMAF	protein-coding	8439
SDCBP	protein-coding	6386

Protein

Protein identifiers

Thymocyte selection-associated high mobility group box protein TOX — O94900 (reviewed: O94900)

Alternative names: Thymus high mobility group box protein TOX

All UniProt accessions (1): O94900

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional regulator with a major role in neural stem cell commitment and corticogenesis as well as in lymphoid cell development and lymphoid tissue organogenesis. Binds to GC-rich DNA sequences in the proximity of transcription start sites and may alter chromatin structure, modifying access of transcription factors to DNA. During cortical development, controls the neural stem cell pool by inhibiting the switch from proliferative to differentiating progenitors. Beyond progenitor cells, promotes neurite outgrowth in newborn neurons migrating to reach the cortical plate. May activate or repress critical genes for neural stem cell fate such as SOX2, EOMES and ROBO2. Plays an essential role in the development of lymphoid tissue-inducer (LTi) cells, a subset necessary for the formation of secondary lymphoid organs: peripheral lymph nodes and Peyer’s patches. Acts as a developmental checkpoint and regulates thymocyte positive selection toward T cell lineage commitment. Required for the development of various T cell subsets, including CD4-positive helper T cells, CD8-positive cytotoxic T cells, regulatory T cells and CD1D-dependent natural killer T (NKT) cells. Required for the differentiation of common lymphoid progenitors (CMP) to innate lymphoid cells (ILC). May regulate the NOTCH-mediated gene program, promoting differentiation of the ILC lineage. Required at the progenitor phase of NK cell development in the bone marrow to specify NK cell lineage commitment. Upon chronic antigen stimulation, diverts T cell development by promoting the generation of exhaustive T cells, while suppressing effector and memory T cell programming. May regulate the expression of genes encoding inhibitory receptors such as PDCD1 and induce the exhaustion program, to prevent the overstimulation of T cells and activation-induced cell death.

Subunit / interactions. Interacts with HBO1 complex composed at least of KAT7/HBO1, ING4, MEAF6, and JADE2; this complex is involved in histone acetylation. Interacts with DNMT1, LEO1, PAF1, SAP130 and SIN3A; these interactors regulate chromatin remodeling. Interacts with an array of proteins involved in RNA processing and translation and DNA replication.

Subcellular location. Nucleus.

Tissue specificity. Expressed in NK cells. Highly expressed in tumor-infiltrating CD8-positive T cells (at protein level).

Post-translational modifications. Ubiquitinated by the BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex composed of at least CUL3, KLHL6 and RBX1; leading to proteasomal degradation.

Induction. Up-regulated during differentiation of NK cells from CD34-positive hematopoietic cells in the presence of IL15. Down-regulated in mature NK cells.

Similarity. Belongs to the high motility group (HMG) box superfamily.

RefSeq proteins (1): NP_055544* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009071	HMG_box_dom	Domain
IPR036910	HMG_box_dom_sf	Homologous_superfamily
IPR051365	TOX_protein	Family

Pfam: PF00505

UniProt features (11 total): compositionally biased region 4, region of interest 2, chain 1, DNA-binding region 1, sequence conflict 1, short sequence motif 1, sequence variant 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O94900-F1	54.57	0.13

Human Protein Atlas

Protein class: Predicted intracellular proteins, Transcription factors, Other all-alpha-helical DNA-binding domains

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoli fibrillar center; nucleoplasm

Antibody reliability (HPA): IH enhanced · IF approved

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 0; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

MSigDB gene sets: 360 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, VERHAAK_AML_WITH_NPM1_MUTATED_DN, GOBP_NATURAL_KILLER_CELL_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, MODULE_169, PEREZ_TP63_TARGETS, GOBP_THYMIC_T_CELL_SELECTION, TTTGTAG_MIR520D, GOBP_ALPHA_BETA_T_CELL_DIFFERENTIATION, GOBP_LYMPH_NODE_DEVELOPMENT, GOBP_NEUROGENESIS, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, GOBP_FOREBRAIN_DEVELOPMENT, GOBP_FOREBRAIN_GENERATION_OF_NEURONS, GOBP_NEURAL_PRECURSOR_CELL_PROLIFERATION

GO Biological Process (15): natural killer cell differentiation (GO:0001779), CD4-positive, CD25-positive, alpha-beta regulatory T cell lineage commitment (GO:0002362), NK T cell lineage commitment (GO:0002364), leukocyte differentiation (GO:0002521), chromatin organization (GO:0006325), DNA-templated transcription (GO:0006351), regulation of transcription by RNA polymerase II (GO:0006357), positive regulation of neuron projection development (GO:0010976), cerebral cortex neuron differentiation (GO:0021895), CD4-positive, alpha-beta T cell lineage commitment (GO:0043373), CD8-positive, alpha-beta T cell lineage commitment (GO:0043375), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of positive thymic T cell selection (GO:1902232), positive regulation of neural precursor cell proliferation (GO:2000179), nervous system development (GO:0007399)

GO Molecular Function (3): chromatin DNA binding (GO:0031490), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (1): nucleus (GO:0005634)

GO top-level categories

34 GO namespaces:

Category	Terms
alpha-beta T cell lineage commitment	3
transcription by RNA polymerase II	2
CD4-positive or CD8-positive, alpha-beta T cell lineage commitment	2
lymphocyte differentiation	1
natural killer cell activation	1
CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation	1
CD4-positive, alpha-beta T cell lineage commitment	1
NK T cell differentiation	1
hemopoiesis	1
cell differentiation	1
cellular component organization	1
gene expression	1
RNA biosynthetic process	1
regulation of DNA-templated transcription	1
regulation of neuron projection development	1
neuron projection development	1
positive regulation of cell projection organization	1
forebrain neuron differentiation	1
CD4-positive, alpha-beta T cell differentiation	1
CD8-positive, alpha-beta T cell differentiation	1
regulation of transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
regulation of T cell differentiation in thymus	1
positive thymic T cell selection	1
positive regulation of cell population proliferation	1
neural precursor cell proliferation	1
regulation of neural precursor cell proliferation	1
system development	1
animal gross anatomical part developmental process	1
DNA binding	1
chromatin binding	1
nucleic acid binding	1
binding	1
intracellular membrane-bounded organelle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 1 of 19 annotations. The rest are phylogenetic / computational / electronic (IEA).

1 experimentally-supported GO terms:

GO term	NS	Evidence
natural killer cell differentiation	BP	mutant phenotype

Protein interactions and networks

STRING

showing 15 of 1,164 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TOX	HAVCR2	Q8TDQ0	703
TOX	TCF7	P36402	702
TOX	TIGIT	Q495A1	701
TOX	LAG3	P18627	700
TOX	SDCBP	O00560	696
TOX	PENK	P01210	678
TOX	PDCD1	Q15116	654
TOX	EOMES	O95936	654
TOX	CD8A	P01732	647
TOX	LEF1	Q9UJU2	618
TOX	ZNF461	Q8TAF7	616
TOX	TBX21	Q9UL17	606
TOX	GZMB	P10144	590
TOX	CTLA4	P16410	578
TOX	BATF	Q16520	576

IntAct

Human interaction partners of TOX in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

7 partners by confidence:

Partner	Interaction type	MIscore	Records
BANP	physical association	0.560	3
DMRTB1	physical association	0.560	3
GRAP	physical association	0.560	3
KLK6	physical association	0.560	3
KRTAP12-1	physical association	0.560	3
KRTAP26-1	physical association	0.560	3
ZDHHC17	physical association	0.370	1

BioGRID (21 interactions; top human partners by supporting records): KLHL6 (Proximity Label-MS; 3 records), TOX2 (Affinity Capture-MS; 2 records), BANP (Two-hybrid), DMRTB1 (Two-hybrid), FOXP1 (Affinity Capture-MS), FOXP2 (Affinity Capture-MS), FOXP4 (Affinity Capture-MS), FUS (Affinity Capture-MS), GRAP (Two-hybrid), HIST1H1D (Cross-Linking-MS (XL-MS)), HIST1H1E (Cross-Linking-MS (XL-MS)), KRTAP12-1 (Two-hybrid), KRTAP26-1 (Two-hybrid), NUDT21 (Affinity Capture-RNA), PARP16 (Proximity Label-MS)

Disease & clinical

Genetic variants

Variant evidence for TOX: 80 ClinVar records (0 pathogenic / likely pathogenic); 27 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	62
Likely benign	2
Benign	1

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 23 predictions of 1,820):

Position(s)	Effect	Δscore	Sites
8:58826903–58826904	acceptor_loss	1.0000	4
8:58826910	acceptor_gain	1.0000
8:58826913	acceptor_gain	1.0000
8:58838079–58838080	donor_loss	1.0000	5
8:58838313	acceptor_loss	1.0000
8:58939547	acceptor_gain	1.0000
8:58826820–58826821	donor_loss	0.9900	6
8:58826903–58826904	acceptor_loss	0.9900	2
8:58826907	acceptor_gain	0.9900
8:58838313	acceptor_loss	0.9900

AlphaMissense

1,159 missense substitutions predicted likely pathogenic (of 3,491 scored), across 281 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M298	9	0.984	1.000
F288	8	1.000	1.000
D257	8	0.999	1.000
F272	8	0.999	1.000
D274	8	0.999	1.000
D300	8	0.999	1.000
F271	8	0.998	1.000
N283	8	0.964	0.999
D2	8	0.945	0.989
N259	8	0.930	0.997
D520	8	0.886	0.994
S210	8	0.880	0.996
W299	7	1.000	1.000
E260	7	0.999	1.000
Q276	7	0.997	1.000
E315	7	0.996	0.999
K263	7	0.994	1.000
I279	7	0.994	1.000
I294	7	0.994	1.000
K307	7	0.990	1.000

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA)	favorable	0.000187

Disease associations

OMIM: gene MIM:606863 | disease phenotypes:

GWAS associations

27 associations:

Study	Trait	p-value
GCST010002_278	Refractive error	1e-153
GCST003997_28	Myopia	6e-41
GCST003455_48	Spherical equivalent (joint analysis main effects and education interaction)	8e-18
GCST003455_24	Spherical equivalent (joint analysis main effects and education interaction)	1e-14
GCST007323_8	Risk-taking tendency (4-domain principal component model)	2e-14
GCST011703_86	Smoking initiation	6e-13
GCST001858_6	Refractive error	4e-12
GCST002617_2	Hyperopia	2e-11
GCST007327_184	Smoking status (ever vs never smokers)	4e-11
GCST007603_3	Smoking initiation	1e-9
GCST008810_93	Smoking initiation (ever regular vs never regular)	1e-9
GCST008839_73	Height	2e-9
GCST90014023_17	Type 1 diabetes	2e-9
GCST007576_243	Chronotype	9e-9
GCST002615_2	Myopia	1e-8
GCST009962_7	High myopia	2e-8
GCST006624_55	Systolic blood pressure	3e-8
GCST006701_11	Parental longevity (father’s attained age)	3e-8
GCST010135_25	Oily fish consumption	5e-8
GCST010140_52	Pork consumption	5e-8
GCST002685_4	Refractive astigmatism	3e-7
GCST007947_4	Psychological resilience (outcome-based)	6e-7
GCST001524_5	Visceral adipose tissue/subcutaneous adipose tissue ratio	2e-6
GCST003659_3	Modified Stumvoll Insulin Sensitivity Index (BMI interaction)	4e-6
GCST000477_41	Cognitive performance	6e-6
GCST002927_6	Mercury levels	6e-6
GCST009256_6	Superior temporal sulcus banks volume	9e-6

EFO canonical traits (from GWAS)

13 canonical traits:

EFO ID	Trait name
EFO:0003926	neuropsychological test
EFO:0004767	visceral:subcutaneous adipose tissue ratio
EFO:0004784	self reported educational attainment
EFO:0004340	body mass index
EFO:0004471	insulin sensitivity measurement
EFO:0006335	systolic blood pressure
EFO:0007796	parental longevity
EFO:0008579	risk-taking behaviour
EFO:0004318	smoking behavior
EFO:0008328	chronotype measurement
EFO:0005670	smoking initiation
EFO:0009945	psychological resilience measurement
EFO:0008111	diet measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

6 measured of 6 human assays (6 total across all organisms); most potent 6 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
1-O-[[4-[(2S)-3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl]phenyl]methyl] 4-O-[2-[(8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl]-2-oxoethyl] (2S)-2-aminobutanedioate	IC50	19200 nM	US-11059789: Isoquinoline-steroid conjugates and uses thereof
1-O-[[4-[(2S)-3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl]phenyl]methyl] 4-O-[2-[(1S,2S,4R,8S,9S,11S,12R,13S,19S)-12,19-difluoro-11-hydroxy-6,6,9,13-tetramethyl-16-oxo-5,7-dioxapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-8-yl]-2-oxoethyl] butanedioate	IC50	32900 nM	US-11059789: Isoquinoline-steroid conjugates and uses thereof
1-O-[[4-[(2S)-3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl]phenyl]methyl] 4-O-[2-[(8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl]-2-oxoethyl] butanedioate	IC50	38500 nM	US-11059789: Isoquinoline-steroid conjugates and uses thereof
1-O-[[4-[(2S)-3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl]phenyl]methyl] 4-O-[2-[(1S,2S,4R,8S,9S,11S,12R,13S)-12-fluoro-11-hydroxy-6,6,9,13-tetramethyl-16-oxo-5,7-dioxapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-8-yl]-2-oxoethyl] butanedioate	IC50	40100 nM	US-11059789: Isoquinoline-steroid conjugates and uses thereof
2-O-[[4-[(2S)-3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl]phenyl]methyl] 1-O-[2-[(8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl]-2-oxoethyl] cyclopropane-1,2-dicarboxylate	IC50	46800 nM	US-11059789: Isoquinoline-steroid conjugates and uses thereof
1-O-[[4-[(2S)-3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl]phenyl]methyl] 4-O-[2-[(8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl]-2-oxoethyl] benzene-1,4-dicarboxylate	IC50	50000 nM	US-11059789: Isoquinoline-steroid conjugates and uses thereof

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, decreases expression	6
bisphenol A	affects cotreatment, increases methylation, decreases expression, increases expression	3
trichostatin A	affects cotreatment, increases expression	3
potassium chromate(VI)	affects cotreatment, decreases expression, increases expression	2
nickel sulfate	decreases expression, increases expression	2
mercuric bromide	increases expression, affects cotreatment	2
chromium hexavalent ion	affects expression, decreases expression, increases abundance	2
entinostat	increases expression, affects cotreatment	2
Vorinostat	affects cotreatment, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	increases expression, increases methylation	2
Estradiol	increases expression, affects expression, affects cotreatment	2
Aflatoxin B1	decreases methylation, increases methylation	2
aristolochic acid I	decreases expression	1
triphenyl phosphate	affects expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
arsenite	increases methylation	1
sulforaphane	decreases expression	1
sodium arsenite	affects cotreatment, increases abundance, increases expression	1
cobaltous chloride	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	affects methylation	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Acetaminophen	increases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TT34	HAP1 TOX (-) 1	Cancer cell line	Male
CVCL_TT35	HAP1 TOX (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

1 trials:

NCT	Phase	Status	Title
NCT02905981	Phase 2	TERMINATED	Triferic IRIDA (Iron-Refractory Iron-Deficiency Anemia) Protocol