TNXB

Summary

TNXB (tenascin XB, HGNC:11976) is a protein-coding gene on chromosome 6p21.33-p21.32, encoding Tenascin-X (P22105). Appears to mediate interactions between cells and the extracellular matrix.

This gene encodes a member of the tenascin family of extracellular matrix glycoproteins. The tenascins have anti-adhesive effects, as opposed to fibronectin which is adhesive. This protein is thought to function in matrix maturation during wound healing, and its deficiency has been associated with the connective tissue disorder Ehlers-Danlos syndrome. This gene localizes to the major histocompatibility complex (MHC) class III region on chromosome 6. It is one of four genes in this cluster which have been duplicated. The duplicated copy of this gene is incomplete and is a pseudogene which is transcribed but does not encode a protein. The structure of this gene is unusual in that it overlaps the CREBL1 and CYP21A2 genes at its 5’ and 3’ ends, respectively. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 7148 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Ehlers-Danlos syndrome due to tenascin-X deficiency (Definitive, GenCC) — +3 more curated relationships
• GWAS associations: 83
• Clinical variants (ClinVar): 3,455 total — 52 pathogenic, 69 likely-pathogenic
• Phenotypes (HPO): 38
• MANE Select transcript: NM_001365276

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11976
Approved symbol	TNXB
Name	tenascin XB
Location	6p21.33-p21.32
Locus type	gene with protein product
Status	Approved
Aliases	TNXBS, XBS, XB, HXBL, TN-X, TNX
Ensembl gene	ENSG00000168477
Ensembl biotype	protein_coding
OMIM	600985
Entrez	7148

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 6 protein_coding, 3 retained_intron

ENST00000375244, ENST00000442721, ENST00000451343, ENST00000479795, ENST00000486148, ENST00000490077, ENST00000498094, ENST00000644971, ENST00000647633

RefSeq mRNA: 4 — MANE Select: NM_001365276 NM_001365276, NM_001428335, NM_019105, NM_032470

CCDS: CCDS4736, CCDS93886

Canonical transcript exons

ENST00000412618 — 0 exons

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 98.76.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.3761 / max 41.5373, expressed in 1751 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
72881	12.5975	511
72886	6.3761	1751
72880	5.0764	378
72883	0.3864	201
72879	0.0962	47

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	98.76	gold quality
right adrenal gland cortex	UBERON:0035827	98.47	gold quality
right adrenal gland	UBERON:0001233	98.39	gold quality
left adrenal gland	UBERON:0001234	98.36	gold quality
left adrenal gland cortex	UBERON:0035825	98.12	gold quality
adrenal gland	UBERON:0002369	98.02	gold quality
mucosa of stomach	UBERON:0001199	97.93	gold quality
right atrium auricular region	UBERON:0006631	97.74	gold quality
left ovary	UBERON:0002119	97.46	gold quality
body of uterus	UBERON:0009853	97.46	gold quality
myometrium	UBERON:0001296	97.45	gold quality
tibial nerve	UBERON:0001323	97.43	gold quality
right coronary artery	UBERON:0001625	97.41	gold quality
subcutaneous adipose tissue	UBERON:0002190	97.36	gold quality
left uterine tube	UBERON:0001303	97.32	gold quality
right ovary	UBERON:0002118	97.30	gold quality
endocervix	UBERON:0000458	97.28	gold quality
adipose tissue	UBERON:0001013	97.11	gold quality
omental fat pad	UBERON:0010414	96.84	gold quality
ovary	UBERON:0000992	96.83	gold quality
lower esophagus muscularis layer	UBERON:0035833	96.65	gold quality
lower esophagus	UBERON:0013473	96.59	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	96.55	gold quality
thoracic mammary gland	UBERON:0005200	96.35	gold quality
upper lobe of left lung	UBERON:0008952	95.94	gold quality
sural nerve	UBERON:0015488	95.56	gold quality
left coronary artery	UBERON:0001626	95.33	gold quality
heart	UBERON:0000948	95.15	gold quality
descending thoracic aorta	UBERON:0002345	95.13	gold quality
heart left ventricle	UBERON:0002084	95.01	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-8410	yes	56.26
E-ANND-3	yes	24.42
E-CURD-46	yes	20.30
E-MTAB-9543	yes	18.16
E-MTAB-10287	yes	16.30
E-CURD-119	yes	9.24

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXC1, SP1

miRNA regulators (miRDB)

9 targeting TNXB, 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-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-6887-3P	99.66	67.83	1778
HSA-MIR-942-5P	99.41	68.40	1977
HSA-MIR-4664-5P	98.17	65.07	1020
HSA-MIR-4483	98.09	64.12	1642

Literature-anchored findings (GeneRIF, showing 40)

• molecular studies on RCCX haplotypes revealing a unique recombination giving rise to a TNXB/TNXA hybrid gene, CYP21A deletion and CYP21B duplication on one chromosome (PMID:12121677)
• localization and analysis of the principal promoter for human tenascin-X (PMID:12376099)
• chromosomal mapping of a de novo unequal crossover causing a deletion of the steroid 21-hydroxylase gene and a non-functional hybrid tenascin-X gene (PMID:12746407)
• The transmission disequilibrium test did not show allelic association between these two TNXB single nucleotide polymorphisms and schizophrenia, and the rs1009382-rs204887 haplotypes were not associated with the illness either. (PMID:14729256)
• Both elastic fiber abnormalities and reduced collagen content contribute to the observed phenotype in TNX-deficient patients. (PMID:15102077)
• 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)
• elastic fiber abnormalities in hypermobility type Ehlers-Danlos syndrome are specific for TNX-haploinsufficient individuals and confirm an important role for TNX in regulating elastic fiber integrity (PMID:15733269)
• Tenascin-X expression is markedly decreased in AAA tissue, and AAA is associated with high serum concentrations of tenascin-X. (PMID:16567571)
• TNX contributes to matrix stability and is possibly involved in collagen fibril formation. (PMID:17033827)
• Association of the TNXB locus or its adjacent region of the NOTCH4 locus with schizophrenia. (PMID:17192952)
• TNXB and TNC may be involved in the malignant transformation of plexiform neurofibromas (PMID:17202312)
• Multiple species of TNX in blood were identified and characterized. (PMID:17263730)
• TNX is unlikely to be involved in matrix deposition in the early phase of wound healing, but it is required in the later phase when remodeling and maturation of the matrix establishes and improves its biomechanical properties. (PMID:17453911)
• TNXB(tenascin XB protein) gene is a candidate gene susceptible to Systemic lupus erythematosus in the Japanese population. (PMID:18058064)
• This study showed different patterns of expression of tenascin and fibronectin along the process of tumorigenesis and tumor progression in pleomorphic adenoma, a fact that might play a role in invasion properties of these tumors. (PMID:18091320)
• Data indicate a complex architecture of the extracellular matrix in the uterosacral ligaments, with marked differences in tenascin and elastin expression between postmenopausal women with or without pelvic organ prolapse. (PMID:18155129)
• TNX-deficient women are at risk of obstetric complications. (PMID:18335242)
• These results indicate that the hypoxia-induced activation of the XB-S promoter is regulated through dissociation of HDAC1 from an Sp1-binding hypoxia-responsive element site. (PMID:18588874)
• These results suggest possible involvement of XB-S in the function of Eg5. (PMID:18679583)
• Tenascin-X may be a new diagnostic marker of malignant mesothelioma in the differential diagnosis of cancers involving the serosal cavities. (PMID:19738457)
• Three point mutations in TNX gene were found to be associated with hypermobility type Ehlers-Danlos syndrome (EDS) . The phenotypic effects of V1195M mutation on 7th fibronectin Type III domain (TNXfn7) with regards to EDS were investigated. (PMID:20853426)
• rs204887 itself or a nearby variant is unlikely to play a major role in the development of schizophrenia although a cumulative contribution of rare variants in the TNXB gene cannot be ruled out. (PMID:21317684)
• Combined analysis of tenascin-C expression and the nodule size improved the prediction of malignancy in this patient cohort. (PMID:22588153)
• Genome-wide association study of age-related macular degeneration identifies TNXB, FKBPL and NOTCH4 as candidate susceptibility genes. (PMID:22694956)
• Noticeable decreased expression of tenascin-X in calcific aortic valves. (PMID:22827484)
• no difference in genotype frequency was detected between patients who experienced a re-dislocation after the initial surgery and patients who did not sustain a re-dislocation. (PMID:22991340)
• Tenascin-X haploinsufficiency was associated with Ehlers-Danlos syndrome in patients with congenital adrenal hyperplasia (PMID:23284009)
• these results suggest that mutations in TNXB can cause hereditary primary vesicoureteral reflux . (PMID:23620400)
• It plays regulatory roles in collagen functions such as fibril organization and fibrillogenesis in calcific aortic valves. (PMID:25926574)
• We then quantified the tenascin-X level in serum of patients and identified tenascin-X as potent marker for ovarian cancer, showing that secretomic analysis is suitable for the identification of protein biomarkers when combined with protein immunoassay. (PMID:26090390)
• the identification of a rare missense variant in TNXB in combination with a positive family history of VUR and joint hypermobility may represent a non-invasive method to diagnose PVUR and warrants further evaluation in other cohorts (PMID:26408188)
• Study describes a biallelic TNXB variants in patients with congenital adrenal hyperplasia due to CYP21A2 deletions resulting in a classical Ehlers-Danlos syndrome phenotype with skin hyperextensibility, widened atrophic scars and joint hypermobility. (PMID:27297501)
• Hypermethylated sites at TNXB are associagted with response to starvation in anorexia nervosa. (PMID:27367046)
• patients with the TNX-deficient type EDS typically have generalized joint hypermobility, skin hyperextensibility and easy bruising. In contrast to the classical type, the inheritance pattern is autosomal recessive and atrophic scarring is absent. Molecular analysis of TNXB in a diagnostic setting is challenging. (PMID:27582382)
• mRNA for tenascin-X gene values was higher in ventricular septal defects. (PMID:29470764)
• Loss of TNXB expression is associated with Gastrointestinal diseases. (PMID:29917237)
• These results suggest that fetal membranes may be a source of amniotic fluid TNX whereby protein and mRNA expression seem to be significantly impacted by inflammation independent of fetal membrane status. (PMID:30277495)
• TNX-deficient patients with Ehlers-Danlos syndrome have upper gastric dysfunction. (PMID:30605228)
• Data demonstrates gene expression changes in differentially methylated TNXB gene in patients with age-related macular degeneration. (PMID:30642396)
• TNXB is a novel diagnostic biomarker for Malignant Mesothelioma (PMID:30711938)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tnxba	ENSDARG00000001760
mus_musculus	Tnxb	ENSMUSG00000033327
rattus_norvegicus	AABR07044388.2	ENSRNOG00000033581

Paralogs (25): TNC (ENSG00000041982), 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), FGG (ENSG00000171557), FGA (ENSG00000171560), FGB (ENSG00000171564), ANGPTL7 (ENSG00000171819), ANGPTL5 (ENSG00000187151)

Protein

Protein identifiers

Tenascin-X — P22105 (reviewed: P22105)

Alternative names: Hexabrachion-like protein

All UniProt accessions (4): P22105, A0A1B0GX77, A0A3B3ISX9, C9J7W4

UniProt curated annotations — full annotation on UniProt →

Function. Appears to mediate interactions between cells and the extracellular matrix. Substrate-adhesion molecule that appears to inhibit cell migration. Accelerates collagen fibril formation. May play a role in supporting the growth of epithelial tumors.

Subunit / interactions. Homotrimer. Interacts with type I, III and V collagens and tropoelastin via its 29th fibronectin type-III domain.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Tissue specificity. Highly expressed in fetal adrenal, in fetal testis, fetal smooth, striated and cardiac muscle. Isoform XB-short is only expressed in the adrenal gland.

Disease relevance. Ehlers-Danlos syndrome, classic-like, 1 (EDSCLL1) [MIM:606408] A form of Ehlers-Danlos syndrome, a group of connective tissue disorders characterized by skin hyperextensibility, articular hypermobility, and tissue fragility. EDSCLL1 patients lack atrophic scars, a major diagnostic criteria for classic Ehlers-Danlos syndrome. Delayed wound healing is only present in a subset of patients. EDSCLL1 inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry. Vesicoureteral reflux 8 (VUR8) [MIM:615963] A disease belonging to the group of congenital anomalies of the kidney and urinary tract. It is characterized by the reflux of urine from the bladder into the ureters and sometimes into the kidneys, and is a risk factor for urinary tract infections. Primary disease results from a developmental defect of the ureterovesical junction. In combination with intrarenal reflux, the resulting inflammatory reaction may result in renal injury or scarring, also called reflux nephropathy. Extensive renal scarring impairs renal function and may predispose patients to hypertension, proteinuria, renal insufficiency and end-stage renal disease. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. May be due to competing acceptor splice site in exon 24. May be due to competing donor splice site in exon 1.

Similarity. Belongs to the tenascin family.

Isoforms (4)

UniProt ID	Names	Canonical?
P22105-3	4	yes
P22105-1	3
P22105-2	XB-short, 2
P22105-4	5

RefSeq proteins (4): NP_001352205, NP_001415264, NP_061978, NP_115859 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000742	EGF	Domain
IPR002181	Fibrinogen_a/b/g_C_dom	Domain
IPR003961	FN3_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR014716	Fibrinogen_a/b/g_C_1	Homologous_superfamily
IPR020837	Fibrinogen_CS	Conserved_site
IPR036056	Fibrinogen-like_C	Homologous_superfamily
IPR036116	FN3_sf	Homologous_superfamily
IPR041161	EGF_Tenascin	Domain
IPR050991	ECM_Regulatory_Proteins	Family

Pfam: PF00041, PF00147, PF18720, PF23106, PF25024

UniProt features (186 total): disulfide bond 56, domain 52, strand 24, sequence variant 18, region of interest 12, sequence conflict 7, compositionally biased region 5, glycosylation site 5, splice variant 3, signal peptide 1, chain 1, turn 1, short sequence motif 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
2CUH	SOLUTION NMR
2CUI	SOLUTION NMR
2CUM	SOLUTION NMR

Predicted structure (AlphaFold)

No AlphaFold model available for P22105 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

Functional residue map

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

Disulfide bonds (56): 421–430, 435–445, 439–450, 452–461, 466–476, 470–481, 483–492, 497–507, 501–512, 514–523, 528–538, 532–543, 545–554, 559–569, 563–574, 576–585, 590–600, 594–605, 607–616, 621–631 …

Glycosylation sites (5): 31, 3855, 3908, 3920, 4095

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-3000178	ECM proteoglycans
R-HSA-1474244	Extracellular matrix organization

MSigDB gene sets: 316 (showing top): AP1_01, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, CHIARADONNA_NEOPLASTIC_TRANSFORMATION_KRAS_DN, GOBP_VASCULAR_ENDOTHELIAL_GROWTH_FACTOR_SIGNALING_PATHWAY, PAX4_01, GOBP_COLLAGEN_FIBRIL_ORGANIZATION, GOBP_POSITIVE_REGULATION_OF_EPITHELIAL_TO_MESENCHYMAL_TRANSITION, YAO_HOXA10_TARGETS_VIA_PROGESTERONE_UP, MODULE_45, GOBP_NEUROGENESIS, GOBP_EXTRACELLULAR_MATRIX_ASSEMBLY, TGACCTY_ERR1_Q2, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_1, MODULE_16, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS

GO Biological Process (21): fatty acid metabolic process (GO:0006631), triglyceride metabolic process (GO:0006641), cell adhesion (GO:0007155), cell-matrix adhesion (GO:0007160), positive regulation of cell population proliferation (GO:0008284), positive regulation of epithelial to mesenchymal transition (GO:0010718), actin cytoskeleton organization (GO:0030036), regulation of cell adhesion (GO:0030155), collagen fibril organization (GO:0030199), regulation of cell migration (GO:0030334), neuron projection development (GO:0031175), collagen metabolic process (GO:0032963), regulation of cell differentiation (GO:0045595), regulation of JNK cascade (GO:0046328), elastic fiber assembly (GO:0048251), cell-cell adhesion (GO:0098609), positive regulation of vascular endothelial growth factor signaling pathway (GO:1900748), positive regulation of collagen fibril organization (GO:1904028), positive regulation of cell fate determination (GO:1905935), lipid metabolic process (GO:0006629), extracellular matrix organization (GO:0030198)

GO Molecular Function (6): integrin binding (GO:0005178), extracellular matrix structural constituent (GO:0005201), collagen binding (GO:0005518), heparin binding (GO:0008201), collagen fibril binding (GO:0098633), protein binding (GO:0005515)

GO Cellular Component (5): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), extracellular matrix (GO:0031012), extracellular exosome (GO:0070062), tenascin complex (GO:0090733)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Extracellular matrix organization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
positive regulation of cellular process	2
cell adhesion	2
regulation of cellular process	2
protein-containing complex binding	2
lipid metabolic process	1
monocarboxylic acid metabolic process	1
acylglycerol metabolic process	1
cellular process	1
cell-substrate adhesion	1
cell population proliferation	1
regulation of cell population proliferation	1
epithelial to mesenchymal transition	1
regulation of epithelial to mesenchymal transition	1
positive regulation of cell differentiation	1
positive regulation of multicellular organismal process	1
cytoskeleton organization	1
actin filament-based process	1
extracellular matrix organization	1
cell migration	1
regulation of cell motility	1
neuron development	1
plasma membrane bounded cell projection organization	1
metabolic process	1
cell differentiation	1
regulation of developmental process	1
JNK cascade	1
regulation of MAPK cascade	1
extracellular matrix assembly	1
supramolecular fiber organization	1
positive regulation of signal transduction	1
vascular endothelial growth factor signaling pathway	1
regulation of vascular endothelial growth factor signaling pathway	1
collagen fibril organization	1
positive regulation of extracellular matrix organization	1
regulation of collagen fibril organization	1
cell fate determination	1
positive regulation of developmental process	1
regulation of cell fate determination	1
primary metabolic process	1
signaling receptor binding	1

Protein interactions and networks

STRING

1302 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TNXB	CYP21A2	P04033	948
TNXB	WHR1	P49842	879
TNXB	C4A	P01028	842
TNXB	COL5A1	P20908	774
TNXB	COL5A2	P05997	746
TNXB	COL3A1	P02461	735
TNXB	ATF6B	Q99941	706
TNXB	COL6A1	P12109	703
TNXB	POLR3D	P05423	667
TNXB	COL6A2	P12110	623
TNXB	ELN	P15502	614
TNXB	C4A	P01028	573
TNXB	NOMO2	Q5JPE7	572
TNXB	NOMO3	P69849	571
TNXB	FKBP14	Q9NWM8	570

IntAct

17 interactions, top by confidence:

A	B	Type	Score
TGFBR2	TGFB1	psi-mi:“MI:0915”(physical association)	0.890
BANP	TNXB	psi-mi:“MI:0915”(physical association)	0.670
TNXB	TGFB1	psi-mi:“MI:0407”(direct interaction)	0.540
TGFB1	TNXB	psi-mi:“MI:0915”(physical association)	0.540
TNXB	PCOLCE	psi-mi:“MI:0407”(direct interaction)	0.440
P4HB	TNXB	psi-mi:“MI:0915”(physical association)	0.400
TNXB	TFAP2A	psi-mi:“MI:0915”(physical association)	0.370
TFAP2C	TNXB	psi-mi:“MI:0915”(physical association)	0.370
TNXB	HELZ	psi-mi:“MI:0914”(association)	0.350
E2F3	MYO1C	psi-mi:“MI:0914”(association)	0.350
purA	TNXB	psi-mi:“MI:0915”(physical association)	0.000
TNXB		psi-mi:“MI:0915”(physical association)	0.000

BioGRID (16): BANP (Two-hybrid), TNXB (Two-hybrid), FIGNL1 (Affinity Capture-MS), TNXB (Two-hybrid), TNXB (Two-hybrid), TNXB (Two-hybrid), BANP (Two-hybrid), TNXB (Proximity Label-MS), TNXB (Affinity Capture-RNA), PAK6 (Affinity Capture-MS), FIGNL1 (Affinity Capture-MS), HELZ (Affinity Capture-MS), TNXB (Affinity Capture-MS), TNXB (Affinity Capture-MS), RPL23A (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0A1D5NSM8, A2AVA0, D3ZHH1, O18016, O76840, P02751, P07589, P07996, P0C6B8, P10039, P10184, P11722, P14585, P22105, P24821, P28175, P35440, P35441, P35442, P35443, P35448, P49747, P97677, P98160, Q00546, Q03350, Q05546, Q06561, Q09165, Q20911, Q26422, Q28178, Q28275, Q28377, Q29116, Q3SWW8, Q4LDE5, Q5ZQU0, Q6DI48, Q70E20

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

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

3455 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	52
Likely pathogenic	69
Uncertain significance	1793
Likely benign	1112
Benign	57

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1323701	NM_001365276.2(TNXB):c.8411del (p.Leu2804fs)	Pathogenic
1342141	NM_001365276.2(TNXB):c.7943G>A (p.Trp2648Ter)	Pathogenic
144112	NM_001365276.2(TNXB):c.12220C>T (p.Arg4074Cys)	Pathogenic
144114	NM_001365276.2(TNXB):c.3991G>A (p.Gly1331Arg)	Pathogenic
1701499	NM_001365276.2(TNXB):c.7440delinsAC (p.Tyr2480Ter)	Pathogenic
1743006	NM_001365276.2(TNXB):c.4778_4779del (p.Val1593fs)	Pathogenic
1763690	NM_001365276.2(TNXB):c.8516_8517del (p.Pro2839fs)	Pathogenic
1797774	NM_001365276.2(TNXB):c.2929del (p.Leu977fs)	Pathogenic
2391120	NM_001365276.2(TNXB):c.4573C>T (p.Arg1525Ter)	Pathogenic
2656444	NM_001365276.2(TNXB):c.8278C>T (p.Gln2760Ter)	Pathogenic
2691676	NM_001365276.2(TNXB):c.3908del (p.Gln1303fs)	Pathogenic
3227247	NM_001365276.2(TNXB):c.1894G>T (p.Glu632Ter)	Pathogenic
3234290	NM_001365276.2(TNXB):c.9937C>T (p.Arg3313Ter)	Pathogenic
3255080	NM_001365276.2(TNXB):c.9589del (p.Thr3197fs)	Pathogenic
3327917	NM_001365276.2(TNXB):c.5810_5811del (p.Ser1937fs)	Pathogenic
3338902	NM_001365276.2(TNXB):c.510dup (p.Thr171fs)	Pathogenic
3356235	NM_001365276.2(TNXB):c.4213C>T (p.Gln1405Ter)	Pathogenic
3358300	NM_001365276.2(TNXB):c.6605_6608del (p.Val2202fs)	Pathogenic
3374955	NM_001365276.2(TNXB):c.10442dup (p.Gln3482fs)	Pathogenic
3376963	NM_001365276.2(TNXB):c.1136del (p.Gly379fs)	Pathogenic
3459796	NM_001365276.2(TNXB):c.4461dup (p.Asn1488fs)	Pathogenic
3593471	NM_001365276.2(TNXB):c.4411del (p.Ser1471fs)	Pathogenic
3768456	NM_001365276.2(TNXB):c.7056_7063del (p.His2352fs)	Pathogenic
3768974	NM_001365276.2(TNXB):c.2086dup (p.Glu696fs)	Pathogenic
3769358	NM_001365276.2(TNXB):c.3372dup (p.Lys1125fs)	Pathogenic
3772628	NM_001365276.2(TNXB):c.10215_10216delinsT (p.Gln3405fs)	Pathogenic
3899274	NM_001365276.2(TNXB):c.6454_6460dup (p.Glu2154fs)	Pathogenic
3902286	NM_001365276.2(TNXB):c.2539C>T (p.Arg847Ter)	Pathogenic
3910745	NM_001365276.2(TNXB):c.8356G>T (p.Glu2786Ter)	Pathogenic
4081807	NM_001365276.2(TNXB):c.4296dup (p.Gly1433fs)	Pathogenic

SpliceAI

8081 predictions. Top by Δscore:

Variant	Effect	Δscore
6:32041766:CTCA:C	donor_loss	1.0000
6:32041767:TCAC:T	donor_loss	1.0000
6:32041769:A:C	donor_loss	1.0000
6:32041770:C:A	donor_loss	1.0000
6:32041789:C:CA	donor_gain	1.0000
6:32041890:C:CT	acceptor_gain	1.0000
6:32041930:GTCCC:G	acceptor_gain	1.0000
6:32041931:TCCC:T	acceptor_gain	1.0000
6:32041932:CCC:C	acceptor_gain	1.0000
6:32041932:CCCC:C	acceptor_gain	1.0000
6:32041933:CC:C	acceptor_gain	1.0000
6:32041933:CCC:C	acceptor_gain	1.0000
6:32041933:CCCTG:C	acceptor_loss	1.0000
6:32041934:CC:C	acceptor_gain	1.0000
6:32041934:CCTGG:C	acceptor_loss	1.0000
6:32041935:C:CC	acceptor_gain	1.0000
6:32041935:C:T	acceptor_gain	1.0000
6:32041940:C:CT	acceptor_gain	1.0000
6:32042007:CTTA:C	donor_loss	1.0000
6:32042008:TTA:T	donor_loss	1.0000
6:32042010:A:AC	donor_gain	1.0000
6:32042010:AC:A	donor_gain	1.0000
6:32042011:C:CA	donor_gain	1.0000
6:32042011:CC:C	donor_gain	1.0000
6:32042011:CCT:C	donor_gain	1.0000
6:32042011:CCTG:C	donor_gain	1.0000
6:32042169:ATTGC:A	acceptor_gain	1.0000
6:32042170:TTGC:T	acceptor_gain	1.0000
6:32042171:TGC:T	acceptor_gain	1.0000
6:32042172:GC:G	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000096853 (6:32066094 A>T), RS1000117595 (6:32104130 A>C,T), RS1000176342 (6:32060171 A>G), RS1000222892 (6:32054816 C>A), RS1000256396 (6:32079795 C>G), RS1000279441 (6:32073091 C>A), RS1000398677 (6:32064276 G>A,T), RS1000414399 (6:32080224 T>G), RS1000427938 (6:32106908 G>A), RS1000499909 (6:32092794 T>C), RS1000605910 (6:32100352 G>A), RS1000663982 (6:32087626 G>A), RS1000718360 (6:32078985 G>A), RS1000780741 (6:32107097 T>A), RS1000857100 (6:32078394 G>A)

Disease associations

OMIM: gene MIM:600985 | disease phenotypes: MIM:606408, MIM:615963, MIM:130000, MIM:130020, MIM:613990

GenCC curated gene-disease

Disease	Classification	Inheritance
Ehlers-Danlos syndrome due to tenascin-X deficiency	Definitive	Autosomal recessive
Ehlers-Danlos syndrome	Definitive	Autosomal recessive
familial vesicoureteral reflux	Supportive	Autosomal dominant
vesicoureteral reflux 8	Limited	Autosomal dominant

Mondo (7): Ehlers-Danlos syndrome due to tenascin-X deficiency (MONDO:0011670), vesicoureteral reflux 8 (MONDO:0014422), Ehlers-Danlos syndrome (MONDO:0020066), vesicoureteral reflux (MONDO:0006007), Ehlers-Danlos syndrome, hypermobility type (MONDO:0007523), dyskeratosis congenita, autosomal dominant 3 (MONDO:0013522), familial vesicoureteral reflux (MONDO:0017329)

Orphanet (4): Classical-like Ehlers-Danlos syndrome type 1 (Orphanet:230839), Familial vesicoureteral reflux (Orphanet:289365), Ehlers-Danlos syndrome (Orphanet:98249), Hypermobile Ehlers-Danlos syndrome (Orphanet:285)

HPO phenotypes

38 total (30 of 38 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000061	Ambiguous genitalia, female
HP:0000076	Vesicoureteral reflux
HP:0000081	Duplicated collecting system
HP:0000122	Unilateral renal agenesis
HP:0000763	Sensory neuropathy
HP:0000813	Bicornuate uterus
HP:0000835	Adrenal hypoplasia
HP:0000963	Thin skin
HP:0000974	Hyperextensible skin
HP:0000977	Soft skin
HP:0000978	Bruising susceptibility
HP:0001058	Poor wound healing
HP:0001065	Striae distensae
HP:0001075	Atrophic scars
HP:0001252	Hypotonia
HP:0001297	Stroke
HP:0001324	Muscle weakness
HP:0001382	Joint hypermobility
HP:0001634	Mitral valve prolapse
HP:0002036	Hiatus hernia
HP:0002239	Gastrointestinal hemorrhage
HP:0002829	Arthralgia
HP:0003202	Skeletal muscle atrophy
HP:0003298	Spina bifida occulta
HP:0003326	Myalgia
HP:0003555	Muscle fiber splitting
HP:0003701	Proximal muscle weakness

GWAS associations

83 associations (top):

Study	Trait	p-value
GCST000549_6	HIV-1 control	3.000000e-06
GCST000996_1	Systemic lupus erythematosus	6.000000e-29
GCST001179_15	Plasma omega-3 polyunsaturated fatty acid levels (docosapentaenoic acid)	5.000000e-07
GCST001571_3	Age-related macular degeneration	1.000000e-09
GCST001942_21	Prostate cancer	5.000000e-09
GCST002100_3	Atopic dermatitis	3.000000e-14
GCST002876_5	Type 1 diabetes and autoimmune thyroid diseases	5.000000e-25
GCST003103_5	Systemic lupus erythematosus	6.000000e-09
GCST003156_23	Systemic lupus erythematosus	6.000000e-107
GCST004131_25	Inflammatory bowel disease	2.000000e-31
GCST004133_79	Ulcerative colitis	5.000000e-65
GCST004521_114	Autism spectrum disorder or schizophrenia	3.000000e-17
GCST004521_117	Autism spectrum disorder or schizophrenia	3.000000e-15
GCST004521_118	Autism spectrum disorder or schizophrenia	3.000000e-15
GCST004521_126	Autism spectrum disorder or schizophrenia	2.000000e-10
GCST004521_154	Autism spectrum disorder or schizophrenia	3.000000e-08
GCST004521_17	Autism spectrum disorder or schizophrenia	2.000000e-12
GCST004521_170	Autism spectrum disorder or schizophrenia	4.000000e-14
GCST004521_173	Autism spectrum disorder or schizophrenia	4.000000e-14
GCST004521_209	Autism spectrum disorder or schizophrenia	5.000000e-16
GCST004521_211	Autism spectrum disorder or schizophrenia	5.000000e-15
GCST004521_213	Autism spectrum disorder or schizophrenia	5.000000e-13
GCST004521_226	Autism spectrum disorder or schizophrenia	4.000000e-12
GCST004521_227	Autism spectrum disorder or schizophrenia	4.000000e-12
GCST004521_296	Autism spectrum disorder or schizophrenia	6.000000e-18
GCST004521_45	Autism spectrum disorder or schizophrenia	2.000000e-16
GCST004521_81	Autism spectrum disorder or schizophrenia	1.000000e-14
GCST004602_52	Mean corpuscular volume	3.000000e-13
GCST004606_137	Eosinophil count	8.000000e-50
GCST004610_16	White blood cell count	3.000000e-95

EFO canonical traits (18, from GWAS)

EFO ID	Trait name
EFO:0000180	HIV-1 infection
EFO:0006809	docosapentaenoic acid measurement
EFO:0004842	eosinophil count
EFO:0005090	basophil count
EFO:0006335	systolic blood pressure
EFO:0008401	susceptibility to shingles measurement
EFO:0004695	intraocular pressure measurement
EFO:0006336	diastolic blood pressure
EFO:0006527	smoking status measurement
EFO:0008579	risk-taking behaviour
EFO:0010443	triacylglycerol 58:9 measurement
EFO:0004509	hemoglobin measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0007789	BMI-adjusted waist circumference
EFO:0004531	urate measurement
EFO:0004833	neutrophil count
EFO:0007984	platelet component distribution width

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D004535	Ehlers-Danlos Syndrome	C14.907.454.240; C15.378.463.515.240; C16.131.831.428; C16.320.850.260; C17.300.200.310; C17.800.804.428; C17.800.827.260
D014718	Vesico-Ureteral Reflux	C12.050.351.968.829.920; C12.200.777.829.920; C12.950.829.920
C536193	Ehlers-Danlos syndrome caused by tenascin-X deficiency (supp.)
C536196	Ehlers-Danlos syndrome type 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol F	affects cotreatment, increases methylation, decreases expression	2
bisphenol A	decreases expression, decreases methylation, affects cotreatment, increases methylation	2
sodium arsenite	decreases expression, increases methylation	2
bisphenol S	affects cotreatment, decreases methylation, decreases expression	2
Glyphosate	decreases expression	2
Air Pollutants	affects methylation, increases abundance, increases expression	2
Doxorubicin	decreases expression, increases expression	2
Particulate Matter	affects methylation, increases abundance, increases expression	2
aristolochic acid I	increases expression	1
afuresertib	increases expression	1
sotorasib	affects cotreatment, decreases expression	1
2,4,6-tribromophenol	increases expression	1
triphenyl phosphate	affects expression	1
decabromobiphenyl ether	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
tetrabromobisphenol A	increases expression	1
paricalcitol	affects cotreatment, increases expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
clothianidin	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
pentabrominated diphenyl ether 100	increases expression	1
hexabrominated diphenyl ether 153	increases expression	1
NSC 689534	increases expression, affects binding	1
trametinib	affects cotreatment, decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
excavatolide B	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Fulvestrant	affects cotreatment, increases methylation, decreases methylation	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E0RS	Ubigene HeLa TNXB KO	Cancer cell line	Female
CVCL_E0X1	Ubigene KYSE-30 TNXB KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04890431	PHASE4	UNKNOWN	Impact of Oxygen Therapy on Fatigue in Patients With Hypermobile-type Ehlers-Danlos Syndrome
NCT05603741	PHASE4	ACTIVE_NOT_RECRUITING	Local Anesthetic Response in Ehlers-Danlos Syndrome (EDS) and Healthy Volunteers
NCT05279937	PHASE3	NOT_YET_RECRUITING	The Ultrasound-Guided Dextrose Prolotherapy in Ehlers-Danlos Syndrome Patients
NCT00004487	PHASE3	UNKNOWN	Phase III Study of Chondrocyte Alginate Gel Suspension in Pediatric Patients With Vesicoureteral Reflux
NCT00405704	PHASE3	COMPLETED	Randomized Intervention for Children With Vesicoureteral Reflux (RIVUR)
NCT02021006	PHASE3	UNKNOWN	Antibiotic Prophylaxis and Renal Damage In Congenital Abnormalities of the Kidney and Urinary Tract
NCT00001966	PHASE2	COMPLETED	Mind-Body Therapy for Pain in Ehlers-Danlos Syndrome
NCT02786810	PHASE2	COMPLETED	Contrast Enhanced Ultrasound for Evaluation of Reflux Nephropathy
NCT03686748	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Two Point Discrimination
NCT00001641	Not specified	COMPLETED	Study of Heritable Connective Tissue Disorders
NCT00270686	Not specified	COMPLETED	Studies of Heritable Disorders of Connective Tissue
NCT01322165	Not specified	COMPLETED	National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions
NCT01356134	Not specified	COMPLETED	Vascular Fundus Changes in Patients With High Probability of Chronic Cerebrospinal Venous Insufficiency (CCSVI)
NCT01367977	Not specified	COMPLETED	Head Circumference Growth in Children With Ehlers-Danlos Syndrome Who Develop Dysautonomia Later in Life
NCT02050113	Not specified	RECRUITING	Complex Aortic Aneurysm Repair Using Physician Modified Endografts and Custom Made Devices
NCT02435745	Not specified	COMPLETED	Obstructive Sleep Apnoea in Ehlers-Danlos Syndrome
NCT02721797	Not specified	UNKNOWN	Origins and Impact of EDS in Connective Tissues and Skin
NCT02985710	Not specified	COMPLETED	Assessment of Small Fiber Neuropathy in Rare Diseases Using Sudoscan
NCT03093493	Not specified	COMPLETED	Genetics of Ehlers-Danlos Syndrome
NCT03330977	Not specified	UNKNOWN	Efficiency Clinical Study of NOVATEX MEDICAL Compression Garments in Patients With Ehlers-Danlos Syndrome
NCT03575182	Not specified	UNKNOWN	Gait Retraining in Patients With Joint Hypermobility Syndrome/Hypermobile Ehlers Danlos Syndrome
NCT03596437	Not specified	UNKNOWN	Study of Arterial Properties by Ultra-high Frequency Ultrasound in Fibromuscular Dysplasia and Vascular Ehlers-Danlos Syndrome
NCT03602482	Not specified	COMPLETED	Standing Cognition and Co-morbidities of POTS Evaluation
NCT03681080	Not specified	COMPLETED	Concentration and Attentional Deficits in POTS and Other Autonomic Neuropathies
NCT03986229	Not specified	COMPLETED	Evaluation of the Effect of Custom Compression Garments on Standing Static Balance in Ehlers Danlos Syndrome
NCT04036305	Not specified	ACTIVE_NOT_RECRUITING	Local Anesthetic Response in Ehlers-Danlos Syndrome (EDS) and Healthy Volunteers
NCT04133272	Not specified	RECRUITING	Registry of Ehlers-Danlos Syndrome
NCT04437589	Not specified	COMPLETED	Opioid-Free Anesthesia for Patients With Joint Hypermobility Syndrome Undergoing Craneo-Cervical Fixation: A Case-series
NCT04680793	Not specified	COMPLETED	Effects of a Multidisciplinary Outpatient Rehabilitation Program in Patients With Ehlers-Danlos Syndrome.
NCT04734041	Not specified	COMPLETED	Integrative Medicine for Hypermobility Spectrum Disorder and Ehlers-Danlos Syndromes (IMforHSDandEDS)
NCT04742803	Not specified	COMPLETED	Straberi Epistamp Needling Treatment For Skin Rejuvenation
NCT04806620	Not specified	RECRUITING	Unhide® Project: A Digital Health Platform to Collect Lifestyle Data for Brain Inflammation Research
NCT05137379	Not specified	COMPLETED	Evaluation of a Cohort of Patients With Ehlers-Danlos Syndrome Treated With Orthopedic Surgery (SED-eval)
NCT05366114	Not specified	UNKNOWN	Vision-based Assessment of Joint Extensibility in Ehlers Danlos Syndrome
NCT05389865	Not specified	ACTIVE_NOT_RECRUITING	Proximal Aortopathy in Scotland - Epidemiology and Surgical Outcomes
NCT05429996	Not specified	UNKNOWN	Ultrastructural Collagen Markers in Ehlers Danlos Syndromes
NCT05434728	Not specified	UNKNOWN	Characterization of Bleeding Disorders in EDS
NCT05516043	Not specified	COMPLETED	Safety and Performance of POLYTHESE® Vascular Prosthesis
NCT05561270	Not specified	RECRUITING	Light Exposure on Pain in Hypermobile Ehlers-Danlos Syndrome
NCT05720923	Not specified	ACTIVE_NOT_RECRUITING	Analysis of Muscular Properties in Patients With MFS and EDS