TNC

Summary

TNC (tenascin C, HGNC:5318) is a protein-coding gene on chromosome 9q33.1, encoding Tenascin (P24821). Extracellular matrix protein implicated in guidance of migrating neurons as well as axons during development, synaptic plasticity as well as neuronal regeneration.

This gene encodes an extracellular matrix protein with a spatially and temporally restricted tissue distribution. This protein is homohexameric with disulfide-linked subunits, and contains multiple EGF-like and fibronectin type-III domains. It is implicated in guidance of migrating neurons as well as axons during development, synaptic plasticity, and neuronal regeneration.

Source: NCBI Gene 3371 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal dominant nonsyndromic hearing loss 56 (Moderate, GenCC) — +2 more curated relationships
• GWAS associations: 9
• Clinical variants (ClinVar): 613 total — 2 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 5
• Druggable target: yes
• Cancer driver (intOGen): activating (oncogene-like) across 7 cancer types
• MANE Select transcript: NM_002160

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5318
Approved symbol	TNC
Name	tenascin C
Location	9q33.1
Locus type	gene with protein product
Status	Approved
Aliases	TN, MGC167029
Ensembl gene	ENSG00000041982
Ensembl biotype	protein_coding
OMIM	187380
Entrez	3371

Gene structure

Transcript identifiers

Ensembl transcripts: 31 — 30 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000341037, ENST00000350763, ENST00000423613, ENST00000460345, ENST00000473855, ENST00000476680, ENST00000481475, ENST00000534839, ENST00000537320, ENST00000542877, ENST00000544972, ENST00000635336, ENST00000705190, ENST00000705191, ENST00000705192, ENST00000901443, ENST00000901444, ENST00000901445, ENST00000901446, ENST00000901447, ENST00000901448, ENST00000901449, ENST00000901450, ENST00000901451, ENST00000901452, ENST00000932048, ENST00000932049, ENST00000968432, ENST00000968433, ENST00000968434, ENST00000968435

RefSeq mRNA: 2 — MANE Select: NM_002160 NM_001410991, NM_002160

CCDS: CCDS6811, CCDS94467

Canonical transcript exons

ENST00000350763 — 28 exons

Exon	Start	End
ENSE00000722592	115057153	115057425
ENSE00000722641	115059730	115060002
ENSE00000722656	115062917	115063189
ENSE00000722678	115063796	115064068
ENSE00000722704	115064647	115064919
ENSE00000722751	115073603	115073866
ENSE00000722787	115076032	115076121
ENSE00000926913	115023973	115024136
ENSE00000926914	115026534	115026695
ENSE00000926915	115029360	115029456
ENSE00000926916	115030254	115030405
ENSE00000926919	115036098	115036241
ENSE00000926923	115046410	115046682
ENSE00000926925	115076390	115076575
ENSE00000926926	115077943	115078212
ENSE00000926927	115081772	115081928
ENSE00000926928	115082692	115082807
ENSE00000926929	115084209	115084472
ENSE00000926930	115085864	115087273
ENSE00001376978	115090562	115091154
ENSE00001948855	115019575	115021267
ENSE00003475722	115048260	115048532
ENSE00003515325	115042219	115042341
ENSE00003533323	115031553	115031685
ENSE00003569363	115040941	115041084
ENSE00003602158	115038261	115038380
ENSE00003686028	115035204	115035334
ENSE00003842429	115117982	115118157

Expression profiles

Bgee: expression breadth ubiquitous, 272 present calls, max score 99.52.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 66.7694 / max 2026.3317, expressed in 1277 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
102219	62.0414	1246
102220	3.4376	844
102223	0.9079	263
102222	0.1587	83
102217	0.1409	73
102221	0.0830	33

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
saphenous vein	UBERON:0007318	99.52	gold quality
tibial artery	UBERON:0007610	98.80	gold quality
popliteal artery	UBERON:0002250	98.79	gold quality
cartilage tissue	UBERON:0002418	98.59	gold quality
periodontal ligament	UBERON:0008266	98.34	gold quality
tibia	UBERON:0000979	98.27	gold quality
tendon of biceps brachii	UBERON:0008188	98.21	gold quality
mucosa of paranasal sinus	UBERON:0005030	98.15	gold quality
ventricular zone	UBERON:0003053	97.85	gold quality
pericardium	UBERON:0002407	97.48	gold quality
superficial temporal artery	UBERON:0001614	97.47	gold quality
muscle layer of sigmoid colon	UBERON:0035805	97.26	gold quality
stromal cell of endometrium	CL:0002255	97.22	gold quality
colonic epithelium	UBERON:0000397	96.79	gold quality
vermiform appendix	UBERON:0001154	96.63	gold quality
vena cava	UBERON:0004087	96.17	gold quality
aorta	UBERON:0000947	95.92	gold quality
synovial joint	UBERON:0002217	95.85	gold quality
smooth muscle tissue	UBERON:0001135	95.60	gold quality
trabecular bone tissue	UBERON:0002483	95.45	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	95.17	gold quality
metanephros cortex	UBERON:0010533	95.13	gold quality
ganglionic eminence	UBERON:0004023	95.12	gold quality
blood vessel layer	UBERON:0004797	95.10	gold quality
caecum	UBERON:0001153	94.84	gold quality
hair follicle	UBERON:0002073	94.80	gold quality
decidua	UBERON:0002450	94.68	gold quality
layer of synovial tissue	UBERON:0007616	94.41	gold quality
myometrium	UBERON:0001296	94.35	gold quality
lower esophagus muscularis layer	UBERON:0035833	93.86	gold quality

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 12.

Experiment	Marker?	Max mean expression
E-GEOD-124472	yes	820.78
E-GEOD-93593	yes	798.58
E-CURD-114	yes	413.30
E-MTAB-11121	yes	387.25
E-MTAB-9388	yes	312.74
E-HCAD-30	yes	90.14
E-HCAD-10	yes	64.36
E-GEOD-84465	yes	29.61
E-CURD-112	yes	16.15
E-CURD-46	yes	12.19
E-HCAD-25	yes	5.68
E-GEOD-124858	no	954.58
E-MTAB-6386	no	8.18
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, ATF4, EGR1, ESR2, ETS1, ETS2, EVX1, EWSR1, FLCN, FLI1, FOSB, GABPA, GATA6, GLI2, HOXA5, HOXB5, JUN, NFKB1, NFKB, OTX2, PAX6, PRRX1, PRRX2, RBPJ, RELA, SMAD3, SMAD4, SOX4, SP1, SRF

miRNA regulators (miRDB)

116 targeting TNC, 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-9-5P	100.00	72.28	2361
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4713-3P	100.00	65.92	505
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-106B-5P	99.88	74.72	2795

Literature-anchored findings (GeneRIF, showing 40)

• The alternatively spliced fibronectin type III domains of tenascin-C (TnFnIII A-D) inhibit both early and late lymphocyte activation events including activation-induced TCR/CD8 down-modulation, cytokine production, and DNA synthesis. (PMID:11714809)
• tenascin-C is highly expressed in the walls of alveoli and bronchioli in respiratory distress syndrome and bronchopulmonary dysplasia (PMID:11850444)
• tenacin-c isoforms in gliomas support tumor cell proliferation and tumor cell migration (PMID:11920587)
• Results suggest that tenascin-C degradation is a reliable marker for recurrence potential of stage-1 NSCLC. (PMID:11948127)
• The atypical and malignant meningiomas showed higher levels of tenascin expression than the typical meningiomas. The more sensitive messenger ribonucleic acid-based methods confirmed the finding. Tenascin expression was correlated with peritumoral edema (PMID:12182416)
• tenascin C in cervical neoplasms (PMID:12209613)
• differences in protein levels found in the vitreous body of patients with diabetic retinopathy (PMID:12351514)
• Data show that tenascin-C regulates cell responses to a fibrin-FN matrix through modulation of focal adhesion kinase (FAK) and RhoA activation. (PMID:12388760)
• TNC expression is involved in invasive and malignant phenotype of several Ewing family tumors. (PMID:12557222)
• Findings provide strong evidence that the FNIII alternatively spliced region of tenascin-C has important roles in tumor progression of breast cancer. (PMID:12759243)
• These results clearly indicated that the expressions of both TN-C and VEGF depend on the surrounding mesenchyme, and that the function of mesenchyme is regulated by its own mesenchymal TN-C. (PMID:14618612)
• Tenascin is detectable in inflammatory vulvar disease, preinvasive and invasive vulvar lesions, but not in normal vulvar tissue and might therefore be a tumor marker. (PMID:14981900)
• a novel, functional binding element in the proximal region of the TN-C promoter mediating responsiveness to TGF-beta involving Smad3/4, Sp1, Ets1, and CBP/p300 (PMID:15001984)
• TNC has a role in tissue remodeling after myocardial injury (review) (PMID:15024713)
• two convergent proinvasive agents secreted by myofibroblasts, namely hepatocyte growth factor and the TGF-beta-upregulated extracellular matrix glycoprotein tenascin-C, are each necessary though not sufficient for neoplasm invasion (PMID:15059978)
• versican and tenascin have roles in preventing relapse of node-negative breast cancer (PMID:15073129)
• Tn-C upregulates matrix metalloprotease expression that cleaves Tn-C into fragments containing the EGF-like domain. This domain has proapoptotic activity for smooth muscle cells. (PMID:15178565)
• tenascin-C expression may be a potential prognostic marker in colorectal carcinoma (PMID:15239346)
• different distributions of tenascin-C and -X were found around the epithelium and the endomysium of the mental symphyseal region, and affect the specific formation of the mandible during ossification in the fetus (PMID:15455729)
• In primary melanoma of the skin, absence of Tn-C in the stroma of invasion fronts and within tumour cells seems to be related to a more benign disease behaviour with a lower risk of developing metastases. (PMID:15469480)
• kinetics and thermodynamics drive the correct pairing of cysteines in epidermal growth factor-like repeats of human tenascin (PMID:15511229)
• modulation of cell shape, focal adhesion formation, and actin stress fiber organization by TNC, thereby modulating chondrocyte differentiation (PMID:15530854)
• TNC expression can be studied on reconstructed skin on nude mice. (PMID:15558324)
• Tn-C may play an important role in angiogenesis of patients with non-small cell lung cancer (PMID:15816617)
• The expression of Tenascin-C mRNA is markedly enhanced in keloids. (PMID:15844597)
• Astrocytes grown on TN-C revert to a quiescent, nonactivated state that is partially reversible. This raises the possibility that therapeutic strategies aimed at manipulating TN-C levels during CNS injury may help reduce astrocytic scarring. (PMID:15892123)
• Persons who have variants of the tenascin-C gene with 12 and 14 guanine-thymine repeats appear to have a 6-fold risk of developing Achilles tendon injuries. (PMID:15983124)
• Tenascin-C is a beta-catenin target gene in human colorectal tumors. (PMID:16091738)
• Tenascin C, a gene induced by TGF-beta, is markedly increased in mouse lung during acute lung injury (PMID:16100012)
• Leu1677Ile is valuable marker for evaluating the risk for developing asthma and plays a role in its pathogenesis. (PMID:16115819)
• Up-regulated expression of TNC in nasal polyp tissues is related to eosinophil-derived TGF-beta1. (PMID:16144346)
• TnC-mediated adhesion can promote cell survival through Akt in human chondrosarcoma cells (PMID:16157221)
• These results suggest that the upregulation of TN-C expression by PDGF involves Ets family transcription factors, co-operating with Sp1. (PMID:16245312)
• Tn-C re-expression has been observed in papillary and medullary thyroid carcinomas with different staining patterns accompanied by the prevalence of different mRNA splice variants in cell cultures. (PMID:16259977)
• Tenascin-C and TGF-beta1 were expressed in the majority of high-grade gliomas. Induction of Tenascin-C by TGF-beta1 may be a possibe mechanism for invasion of high-grade gliomas. (PMID:16292494)
• results indicate that TN-C plays a role in angiogenesis and tumor cell proliferation in glioblastoma (PMID:16388320)
• The role of tenascin-C as a microenvironmental regulator of cardiac endothelial/EPC activity is reported. (PMID:16461331)
• although the exact interaction between tenascin-C and PG-M/versican remains not entirely clear, these two molecules appear to play significant roles in the pathological mechanisms of idiopathic carpal tunnel syndrome (PMID:16493581)
• Link between BMPR2 mutations and induction of Prx 1-dependent tenascin-c gene transcription in familial pulmonary hypertension smooth muscle cells. (PMID:16782755)
• endogenous expression of tenascin-C down-regulates cell contractility and exerts its effects via a Rho GTPase signaling pathway (PMID:16926030)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Tnc	ENSMUSG00000028364
rattus_norvegicus	Tnc	ENSRNOG00000058645

Paralogs (25): FCN1 (ENSG00000085265), ANGPT2 (ENSG00000091879), ANGPT4 (ENSG00000101280), FGL1 (ENSG00000104760), FN1 (ENSG00000115414), TNR (ENSG00000116147), ANGPTL1 (ENSG00000116194), TNN (ENSG00000120332), FGL2 (ENSG00000127951), FIBCD1 (ENSG00000130720), ANGPTL6 (ENSG00000130812), ANGPTL3 (ENSG00000132855), ANGPTL2 (ENSG00000136859), FCN3 (ENSG00000142748), FNDC7 (ENSG00000143107), ANGPT1 (ENSG00000154188), FCN2 (ENSG00000160339), MFAP4 (ENSG00000166482), ANGPTL4 (ENSG00000167772), TNXB (ENSG00000168477), FGG (ENSG00000171557), FGA (ENSG00000171560), FGB (ENSG00000171564), ANGPTL7 (ENSG00000171819), ANGPTL5 (ENSG00000187151)

Protein

Protein identifiers

Tenascin — P24821 (reviewed: P24821)

Alternative names: Cytotactin, GMEM, GP 150-225, Glioma-associated-extracellular matrix antigen, Hexabrachion, JI, Myotendinous antigen, Neuronectin, Tenascin-C

All UniProt accessions (13): A0A0U1RR80, A0A994J4S6, A0A994J510, A0A994J5G0, A0A994J7C1, A0A994J7R0, A0A994J7R4, E9PC84, P24821, F5H5D6, F5H7V9, H0YGZ3, J3QSU6

UniProt curated annotations — full annotation on UniProt →

Function. Extracellular matrix protein implicated in guidance of migrating neurons as well as axons during development, synaptic plasticity as well as neuronal regeneration. Promotes neurite outgrowth from cortical neurons grown on a monolayer of astrocytes. Ligand for integrins alpha-8/beta-1, alpha-9/beta-1, alpha-V/beta-3 and alpha-V/beta-6. In tumors, stimulates angiogenesis by elongation, migration and sprouting of endothelial cells.

Subunit / interactions. Homohexamer; disulfide-linked. A homotrimer may be formed in the triple coiled-coil region and may be stabilized by disulfide rings at both ends. Two of such half-hexabrachions may be disulfide linked within the central globule. Interacts with CSPG4. Interacts (via the 3rd fibronectin type-III domain) with integrin ITGA9:ITGB1.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Tissue specificity. Detected in fibroblasts (at protein level).

Disease relevance. Deafness, autosomal dominant, 56 (DFNA56) [MIM:615629] A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. DFNA56 is characterized by progressive hearing impairment with postlingual onset. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the tenascin family.

Isoforms (6)

UniProt ID	Names	Canonical?
P24821-1	1	yes
P24821-2	2, HT-5
P24821-3	3
P24821-4	4, HT-33
P24821-5	5
P24821-6	6, P31

RefSeq proteins (2): NP_001397920, NP_002151* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000742	EGF	Domain
IPR002181	Fibrinogen_a/b/g_C_dom	Domain
IPR003961	FN3_dom	Domain
IPR013111	EGF_extracell	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR014716	Fibrinogen_a/b/g_C_1	Homologous_superfamily
IPR036056	Fibrinogen-like_C	Homologous_superfamily
IPR036116	FN3_sf	Homologous_superfamily
IPR041161	EGF_Tenascin	Domain
IPR050991	ECM_Regulatory_Proteins	Family

Pfam: PF00041, PF00147, PF07974, PF18720, PF23106, PF25024

UniProt features (159 total): disulfide bond 42, domain 31, glycosylation site 24, strand 21, helix 12, sequence variant 10, sequence conflict 7, splice variant 4, modified residue 4, signal peptide 1, chain 1, turn 1, coiled-coil region 1

Structure

Experimental structures (PDB)

21 structures.

PDB	Method	Resolution (Å)
5R61	X-RAY DIFFRACTION	1.38
9R5Y	X-RAY DIFFRACTION	1.4
5R62	X-RAY DIFFRACTION	1.4
6QNV	X-RAY DIFFRACTION	1.4
2RB8	X-RAY DIFFRACTION	1.45
5R5U	X-RAY DIFFRACTION	1.52
5R5T	X-RAY DIFFRACTION	1.55
5R5X	X-RAY DIFFRACTION	1.56
5R5Y	X-RAY DIFFRACTION	1.57
5R63	X-RAY DIFFRACTION	1.59
5R5W	X-RAY DIFFRACTION	1.6
5R5Z	X-RAY DIFFRACTION	1.67
5R5V	X-RAY DIFFRACTION	1.7
5R60	X-RAY DIFFRACTION	1.79
1TEN	X-RAY DIFFRACTION	1.8
8FNB	X-RAY DIFFRACTION	1.8
8FN8	X-RAY DIFFRACTION	1.89
2RBL	X-RAY DIFFRACTION	2.1
9NIH	X-RAY DIFFRACTION	2.4
6BRB	X-RAY DIFFRACTION	2.82
9NIG	X-RAY DIFFRACTION	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P24821-F1	75.48	0.10

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 (4): 65, 70, 72, 905

Disulfide bonds (42): 580–589, 594–604, 598–609, 611–620, 190–200, 194–205, 207–216, 221–231, 225–236, 238–247, 252–263, 256–268, 270–279, 284–294, 288–299, 301–310, 315–325, 319–330, 332–341, 346–356 …

Glycosylation sites (24): 38, 72, 166, 184, 327, 788, 1018, 1034, 1079, 1093, 1119, 1184, 1210, 1261, 1275, 1301, 1366, 1392, 1445, 1455 …

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-216083	Integrin cell surface interactions
R-HSA-3000170	Syndecan interactions
R-HSA-3000178	ECM proteoglycans
R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
R-HSA-8957275	Post-translational protein phosphorylation
R-HSA-1474244	Extracellular matrix organization
R-HSA-3000171	Non-integrin membrane-ECM interactions
R-HSA-392499	Metabolism of proteins
R-HSA-597592	Post-translational protein modification

MSigDB gene sets: 356 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, GOBP_NEUROMUSCULAR_JUNCTION_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, MODULE_52, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_EPITHELIUM_DEVELOPMENT, MULLIGHAN_NPM1_SIGNATURE_3_UP, GOBP_GLAND_MORPHOGENESIS, GOBP_PROSTATE_GLAND_MORPHOGENESIS, GOBP_INFLAMMATORY_RESPONSE, MODULE_64, GOBP_GROWTH, GOBP_OSTEOBLAST_DIFFERENTIATION, MCBRYAN_PUBERTAL_TGFB1_TARGETS_UP

GO Biological Process (25): regulation of cell growth (GO:0001558), osteoblast differentiation (GO:0001649), morphogenesis of an epithelium (GO:0002009), cell adhesion (GO:0007155), negative regulation of cell adhesion (GO:0007162), neuromuscular junction development (GO:0007528), positive regulation of cell population proliferation (GO:0008284), response to wounding (GO:0009611), response to mechanical stimulus (GO:0009612), positive regulation of gene expression (GO:0010628), peripheral nervous system axon regeneration (GO:0014012), regulation of cell adhesion (GO:0030155), regulation of cell migration (GO:0030334), odontogenesis of dentin-containing tooth (GO:0042475), response to ethanol (GO:0045471), regulation of inflammatory response (GO:0050727), bud outgrowth involved in lung branching (GO:0060447), mesenchymal-epithelial cell signaling involved in prostate gland development (GO:0060739), prostate gland epithelium morphogenesis (GO:0060740), cellular response to retinoic acid (GO:0071300), cellular response to vitamin D (GO:0071305), response to fibroblast growth factor (GO:0071774), cellular response to prostaglandin D stimulus (GO:0071799), prostate gland development (GO:0030850), neuron projection development (GO:0031175)

GO Molecular Function (4): integrin binding (GO:0005178), extracellular matrix structural constituent (GO:0005201), syndecan binding (GO:0045545), protein binding (GO:0005515)

GO Cellular Component (12): extracellular region (GO:0005576), basement membrane (GO:0005604), interstitial matrix (GO:0005614), obsolete extracellular space (GO:0005615), endoplasmic reticulum lumen (GO:0005788), focal adhesion (GO:0005925), membrane (GO:0016020), extracellular matrix (GO:0031012), tenascin complex (GO:0090733), extracellular matrix of synaptic cleft (GO:0098965), perisynaptic extracellular matrix (GO:0098966), glutamatergic synapse (GO:0098978)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Extracellular matrix organization	3
Metabolism of proteins	2
Non-integrin membrane-ECM interactions	1
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
extracellular matrix	3
cell adhesion	2
cellular anatomical structure	2
synapse-associated extracellular matrix	2
cell growth	1
regulation of growth	1
regulation of cellular component organization	1
ossification	1
cell differentiation	1
tissue morphogenesis	1
epithelium development	1
cellular process	1
regulation of cell adhesion	1
negative regulation of cellular process	1
synapse organization	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
response to stress	1
response to external stimulus	1
response to abiotic stimulus	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
axon regeneration	1
regulation of cellular process	1
cell migration	1
regulation of cell motility	1
odontogenesis	1
response to alcohol	1
inflammatory response	1
regulation of defense response	1
regulation of response to external stimulus	1
epithelial tube branching involved in lung morphogenesis	1
branch elongation of an epithelium	1
prostate gland development	1
mesenchymal-epithelial cell signaling	1
morphogenesis of an epithelium	1
developmental process involved in reproduction	1
prostate gland morphogenesis	1

Protein interactions and networks

STRING

1294 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TNC	ACAN	P16112	572
TNC	EGF	P01133	558
TNC	FN1	P02751	552
TNC	GFM1	Q96RP9	548
TNC	CYP21A2	P04033	541
TNC	SDC4	P31431	536
TNC	POSTN	Q15063	530
TNC	ITGA9	Q13797	513
TNC	NPSR1	Q6W5P4	513
TNC	SCIN	Q9Y6U3	509
TNC	GSN	P06396	481
TNC	NCAM1	P13591	467
TNC	TGFB1	P01137	466
TNC	SEMA3F	Q13275	451
TNC	SPP1	P10451	448

IntAct

25 interactions, top by confidence:

A	B	Type	Score
TNC	TNC	psi-mi:“MI:0915”(physical association)	0.670
TNC	TLR4	psi-mi:“MI:0407”(direct interaction)	0.540
TNC	TLR4	psi-mi:“MI:0915”(physical association)	0.540
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
LGALS1	PODXL	psi-mi:“MI:0914”(association)	0.530
COL5A1	TNC	psi-mi:“MI:0915”(physical association)	0.510
TNC	COL5A1	psi-mi:“MI:0915”(physical association)	0.510
	TNC	psi-mi:“MI:0915”(physical association)	0.480
TNC	MBD1	psi-mi:“MI:0915”(physical association)	0.370
MAPT	LANCL1	psi-mi:“MI:0914”(association)	0.350
PRNP	CARNS1	psi-mi:“MI:0914”(association)	0.350
PRNP	WDR91	psi-mi:“MI:0914”(association)	0.350
	PLXNB2	psi-mi:“MI:0914”(association)	0.350
FBXO6	TMEM131L	psi-mi:“MI:0914”(association)	0.350
LGALS3	SDCBP	psi-mi:“MI:0914”(association)	0.350
OLFML2B	PDIA4	psi-mi:“MI:0914”(association)	0.350
TACC3	TNC	psi-mi:“MI:0914”(association)	0.350
SLC9A8	AP1G1	psi-mi:“MI:0914”(association)	0.350
SULF2	HNRNPCL1	psi-mi:“MI:0914”(association)	0.350
ATF2	PLOD2	psi-mi:“MI:0914”(association)	0.350
ATF3	ILVBL	psi-mi:“MI:0914”(association)	0.350
GATA2	ILVBL	psi-mi:“MI:0914”(association)	0.350

BioGRID (36): TNC (Affinity Capture-MS), TNC (Affinity Capture-RNA), TNC (Affinity Capture-MS), Itgb1 (Reconstituted Complex), Itga7 (Reconstituted Complex), TNC (Reconstituted Complex), TNC (Affinity Capture-Western), NCAN (Far Western), TNC (Affinity Capture-MS), ANXA2 (Reconstituted Complex), TNC (Affinity Capture-Western), SMOC1 (Affinity Capture-Western), SMOC1 (Reconstituted Complex), SMOC2 (Reconstituted Complex), SPARC (Reconstituted Complex)

ESM2 similar proteins: A0A096LNW5, A2RUV0, A8XMW6, B8JI71, G3I6Z6, O35516, O57409, O77469, P07207, P07996, P0DPK3, P10039, P10040, P10079, P21783, P24821, P34576, P35440, P35441, P35442, P35448, P46530, P46531, P49013, P78504, Q00174, Q01705, Q03350, Q04721, Q07008, Q21281, Q21313, Q28178, Q29116, Q5ZQU0, Q61982, Q63722, Q6DI48, Q70E20, Q7Z3S9

Diamond homologs: A0A8J8, A2AV25, D8VNS7, D8VNS8, D8VNS9, D8VNT0, E2IYB3, E9PV24, O00602, O08538, O15123, O18920, O35460, O35462, O35608, O43827, O70165, O70497, O75636, O77802, O93526, O95841, P02671, P02675, P02676, P02678, P02679, P02680, P04115, P06399, P10039, P12799, P12804, P14448, P14480, P17634, P19477, P21520, P22105, P24821

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
TNC	“up-regulates activity”	“A8/b1 integrin”	binding
TNC	“up-regulates activity”	“A9/b1 integrin”	binding
ETS1	“up-regulates quantity by expression”	TNC	“transcriptional regulation”
SP1	“up-regulates quantity by expression”	TNC	“transcriptional regulation”
TNC	“up-regulates activity”	“Av/b1 integrin”	binding
TNC	“up-regulates activity”	“Av/b3 integrin”	binding

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 7 cancer types — ACC, AML, BLADDER, LUSC, MLYM, NBL, OVT.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	3
Uncertain significance	312
Likely benign	102
Benign	117

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
2775398	NM_002160.4(TNC):c.5247A>T (p.Gly1749=)	Pathogenic
97009	NM_002160.4(TNC):c.5386A>T (p.Thr1796Ser)	Pathogenic
3250407	NM_002160.4(TNC):c.323G>A (p.Arg108His)	Likely pathogenic
3336965	NM_002160.4(TNC):c.3191C>T (p.Pro1064Leu)	Likely pathogenic
374544	NM_002160.4(TNC):c.4172A>G (p.Gln1391Arg)	Likely pathogenic

SpliceAI

4067 predictions. Top by Δscore:

Variant	Effect	Δscore
9:115023972:CCTGA:C	donor_gain	1.0000
9:115026529:TGTA:T	donor_loss	1.0000
9:115026530:GTACC:G	donor_loss	1.0000
9:115026531:TAC:T	donor_loss	1.0000
9:115026533:C:CA	donor_loss	1.0000
9:115026694:CC:C	acceptor_gain	1.0000
9:115026695:CC:C	acceptor_gain	1.0000
9:115026695:CCTG:C	acceptor_loss	1.0000
9:115026696:C:CC	acceptor_gain	1.0000
9:115026697:T:C	acceptor_loss	1.0000
9:115030252:A:AC	donor_gain	1.0000
9:115030252:ACAAT:A	donor_gain	1.0000
9:115030253:C:CC	donor_gain	1.0000
9:115030253:CAAT:C	donor_gain	1.0000
9:115030253:CAATC:C	donor_gain	1.0000
9:115030294:T:TA	donor_gain	1.0000
9:115030401:TCCAA:T	acceptor_gain	1.0000
9:115030402:CCAA:C	acceptor_gain	1.0000
9:115030402:CCAAC:C	acceptor_gain	1.0000
9:115030403:CAA:C	acceptor_gain	1.0000
9:115030403:CAAC:C	acceptor_gain	1.0000
9:115030406:C:CC	acceptor_gain	1.0000
9:115031551:A:AC	donor_gain	1.0000
9:115031552:C:CC	donor_gain	1.0000
9:115036242:C:CC	acceptor_gain	1.0000
9:115038257:TTA:T	donor_loss	1.0000
9:115038258:TAC:T	donor_loss	1.0000
9:115038259:A:AC	donor_gain	1.0000
9:115038259:A:AT	donor_loss	1.0000
9:115038260:C:CA	donor_loss	1.0000

AlphaMissense

14450 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:115082745:A:G	W732R	1.000
9:115082745:A:T	W732R	1.000
9:115021247:C:A	W2172C	0.999
9:115021247:C:G	W2172C	0.999
9:115021256:C:A	W2169C	0.999
9:115021256:C:G	W2169C	0.999
9:115021258:A:G	W2169R	0.999
9:115021258:A:T	W2169R	0.999
9:115024021:A:C	C2149W	0.999
9:115024022:C:G	C2149S	0.999
9:115024022:C:T	C2149Y	0.999
9:115024023:A:G	C2149R	0.999
9:115024023:A:T	C2149S	0.999
9:115024033:C:A	W2145C	0.999
9:115024033:C:G	W2145C	0.999
9:115024035:A:G	W2145R	0.999
9:115024035:A:T	W2145R	0.999
9:115024036:G:C	F2144L	0.999
9:115024036:G:T	F2144L	0.999
9:115024038:A:G	F2144L	0.999
9:115024060:A:C	C2136W	0.999
9:115024061:C:G	C2136S	0.999
9:115024061:C:T	C2136Y	0.999
9:115024062:A:G	C2136R	0.999
9:115024062:A:T	C2136S	0.999
9:115026638:A:G	L2076P	0.999
9:115026650:A:G	L2072P	0.999
9:115029409:C:A	W2040C	0.999
9:115029409:C:G	W2040C	0.999
9:115046617:A:G	W1640R	0.999

dbSNP variants (sampled 300 via entrez): RS1000037085 (9:115116928 T>A), RS1000062090 (9:115023377 C>T), RS1000064148 (9:115081010 T>C), RS1000076351 (9:115039478 A>G), RS1000087667 (9:115079967 G>A), RS1000117997 (9:115026617 G>A,T), RS1000153650 (9:115100353 C>T), RS1000157367 (9:115104611 C>T), RS1000163598 (9:115075053 C>T), RS1000218578 (9:115033449 C>T), RS1000225582 (9:115071941 C>G,T), RS1000337685 (9:115062654 T>C), RS1000340197 (9:115092130 G>A), RS1000363561 (9:115110417 G>A), RS1000374008 (9:115069380 G>A)

Disease associations

OMIM: gene MIM:187380 | disease phenotypes: MIM:615629, MIM:156000, MIM:160700

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal dominant nonsyndromic hearing loss 56	Moderate	Autosomal dominant
autosomal dominant nonsyndromic hearing loss	Supportive	Autosomal dominant
nonsyndromic genetic hearing loss	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Limited	AD

Mondo (7): autosomal dominant nonsyndromic hearing loss 56 (MONDO:0014283), hearing loss disorder (MONDO:0005365), Meniere disease (MONDO:0007972), nonsyndromic genetic hearing loss (MONDO:0019497), myopia (MONDO:0001384), hereditary breast ovarian cancer syndrome (MONDO:0003582), autosomal dominant nonsyndromic hearing loss (MONDO:0019587)

Orphanet (4): Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635), Rare non-syndromic genetic deafness (Orphanet:87884), Hereditary breast and/or ovarian cancer syndrome (Orphanet:145), NON RARE IN EUROPE: Menière disease (Orphanet:45360)

HPO phenotypes

5 total (6 of 5 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000407	Sensorineural hearing impairment
HP:0001751	Abnormal vestibular function
HP:0003621	Juvenile onset
HP:0011462	Young adult onset
HP:0000545	Myopia

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST001725_101	Inflammatory bowel disease	3.000000e-32
GCST003398_1	Developmental language disorder (syntactic complexity)	4.000000e-06
GCST003398_2	Developmental language disorder (syntactic complexity)	3.000000e-06
GCST003806_3	Response to bupropion and depression	1.000000e-06
GCST004863_3	Mosquito bite size	2.000000e-07
GCST006926_2	Osteoarthritis (hip)	7.000000e-12
GCST009391_1636	Metabolite levels	2.000000e-06
GCST010988_404	Adult body size	4.000000e-08
GCST90000025_421	Appendicular lean mass	6.000000e-12

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007799	syntactic complexity measurement
EFO:0008378	mosquito bite reaction size measurement
EFO:0007787	plasma betaine measurement
EFO:0004980	appendicular lean mass

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D061325	Hereditary Breast and Ovarian Cancer Syndrome	C04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431
D008575	Meniere Disease	C09.218.568.217.500
D009216	Myopia	C11.744.636
C580334	Nonsyndromic Deafness (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3712856 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression	6
Progesterone	affects cotreatment, decreases expression, increases expression	5
Valproic Acid	decreases expression, increases expression	5
Benzo(a)pyrene	affects expression, decreases expression, increases expression, increases methylation	4
Estradiol	affects cotreatment, decreases expression, increases expression	4
Particulate Matter	increases abundance, increases expression, affects cotreatment, decreases expression	4
methylmercuric chloride	increases expression, affects cotreatment	3
bisphenol A	decreases expression, increases expression	3
trichostatin A	affects cotreatment, increases expression	3
(+)-JQ1 compound	decreases reaction, increases expression, decreases expression	3
Cisplatin	affects expression, affects cotreatment, decreases expression	3
Doxorubicin	affects expression, decreases expression, increases expression	3
Rotenone	increases expression	3
Tretinoin	increases expression, decreases expression, decreases reaction	3
Cyclosporine	decreases expression, increases expression	3
Raloxifene Hydrochloride	decreases expression, affects expression, affects cotreatment, increases expression	3
entinostat	affects cotreatment, decreases expression, increases expression	2
belinostat	affects cotreatment, decreases expression	2
Temozolomide	decreases expression, affects response to substance	2
Acetaminophen	decreases expression, increases expression	2
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, increases expression	2
Arsenic	affects methylation, decreases expression, increases abundance	2
Formaldehyde	decreases expression, increases expression	2
Ozone	increases oxidation, increases abundance, increases expression, affects cotreatment	2
Tetrachlorodibenzodioxin	affects expression, affects cotreatment, decreases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
8-Bromo Cyclic Adenosine Monophosphate	decreases expression, increases expression, affects cotreatment	2
Cadmium Chloride	increases expression	2
aristolochic acid I	increases expression	1
GSK-J4	increases expression	1

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B0Z4	Abcam U2OS TNC KO	Cancer cell line	Female
CVCL_B2IZ	Abcam HeLa TNC KO	Cancer cell line	Female
CVCL_D1UN	Abcam U-87MG TNC KO	Cancer cell line	Male
CVCL_E0RK	Ubigene HeLa TNC KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT00013455	PHASE2	COMPLETED	Quantifying Auditory Perceptual Learning Following Hearing Aid Fitting
NCT00323427	PHASE2	COMPLETED	Clinical Trial of the Living Well With Hearing Loss Workshop
NCT00552786	PHASE2	COMPLETED	Antioxidation Medication for Noise-induced Hearing Loss
NCT00802425	PHASE2	COMPLETED	Efficacy of AM-111 in Patients With Acute Sensorineural Hearing Loss
NCT01139281	PHASE2	COMPLETED	The Protective Effect of Ginkgo Biloba Extract on Cisplatin-induced Ototoxicity in Humans
NCT01451853	PHASE2	UNKNOWN	SPI-1005 for Prevention and Treatment of Chemotherapy Induced Hearing Loss
NCT01588925	PHASE2	COMPLETED	Hearing Preservation Using Dexamethasone and Hyaluronic Acid for Cochlear Implantation
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT02832128	PHASE2	COMPLETED	Evaluating Possible Improvement in Speech and Hearing Tests After 28 Days of Dosing of the Study Drug AUT00063 Compared to Placebo (QuicKfire)
NCT04915183	PHASE2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer
NCT05258773	PHASE2	COMPLETED	Evaluation of the Presence of SENS-401 in the Perilymph
NCT06340633	PHASE2	RECRUITING	SPI-1005 in Adults Receiving Cochlear Implant
NCT00582946	PHASE1	COMPLETED	Wide-Bandwidth Open Canal Hearing Aid For Better Multitalker Speech Understanding
NCT00584155	PHASE1	WITHDRAWN	Protection From Cisplatin Ototoxicity by Lactated Ringers
NCT01206829	PHASE1	UNKNOWN	Hearing Impairment, Cognitive Therapy and Coping
NCT01256229	PHASE1	COMPLETED	Outcomes In Children With Developmental Delay And Deafness
NCT01343394	PHASE1	WITHDRAWN	Safety of Autologous Human Umbilical Cord Blood Mononuclear Fraction to Treat Acquired Hearing Loss in Children
NCT01452607	PHASE1	COMPLETED	Study to Evaluate the Safety and Pharmacokinetics of SPI-1005
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT04041440	PHASE1	COMPLETED	Speech Recognition Training in Children With Hearing Loss
NCT07218913	PHASE1	RECRUITING	Testing the Addition of Pedmark to Cisplatin Chemotherapy for Reducing Drug-Induced Ear Damage in Men With Stage II-III Metastatic Testicular Germ Cell Tumors
NCT01802190	Not specified	TERMINATED	Prevalence of POU4F3 and SLC17A8 Mutations
NCT00486577	PHASE2/PHASE3	COMPLETED	Chronic Electrical Stimulation of the Auditory Cortex for Intractable Tinnitus
NCT00789061	PHASE2/PHASE3	UNKNOWN	Applying Proton Pump Inhibitor to Prevent and Treat Acute Fluctuating Hearing Loss in Patients With SLC26A4 Mutation
NCT01423409	PHASE2/PHASE3	COMPLETED	Multicenter Trial Assessing an Innovative VAS of Pain Among Deaf People
NCT05786378	PHASE2/PHASE3	UNKNOWN	Assessment of The Efficacy of Intratympanic Platelet Rich Plasma for Treatment of Sensorineural Hearing Loss.
NCT01108601	PHASE1/PHASE2	UNKNOWN	Transtympanic Ringer’s Lactate for the Prevention of Cisplatin Ototoxicity
NCT01621256	PHASE1/PHASE2	COMPLETED	Efficacy, Safety, and Tolerability of Ancrod in Patients With Sudden Hearing Loss
NCT06370351	PHASE1/PHASE2	RECRUITING	A Phase I/II Clinical Trial with SENS-501 in Children Suffering from Severe to Profound Hearing Loss Due to Otoferlin (OTOF) Mutations
NCT06545175	PHASE1/PHASE2	RECRUITING	Intracochlear Application of VSF1.01 for the Reduction of Cochlear Implant Surgery Related Trauma
NCT07304024	PHASE1/PHASE2	RECRUITING	A Treatment for a Form of Age-Related Central Auditory Processing Disorder Consisting of Clemastine Fumarate Plus Engineered Sound