Tenascin X (TN-X), also known as flexillin or hexabrachion-like protein, is a 450kDa glycoprotein, a member of the tenascin family, that is expressed in connective tissues. In humans it is encoded by the TNXB gene.[5]
Quick Facts TNXB, Available structures ...
TNXB |
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Aliases | TNXB, EDS3, HXBL, TENX, TN-X, TNX, TNXB1, TNXB2, TNXBS, VUR8, XB, XBS, tenascin XB, EDSCLL, EDSCLL1 |
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External IDs | OMIM: 600985; MGI: 1932137; HomoloGene: 49589; GeneCards: TNXB; OMA:TNXB - orthologs |
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The TN-X protein is expressed in many parts of the human body, including the skin, muscles, kidneys, blood vessels, and digestive tract.[6][7]
Deficiencies in the TN-X protein due to mutations or not enough of it being produced (haploinsufficiency) can lead to a rare condition called classical-like Ehlers-Danlos syndrome (EDS). People with EDS may have loose joints and weak tissues because their bodies don't make enough collagen properly.[8]
TN-X possesses a modular structure composed, from the N- to the C-terminal part by a Tenascin assembly domain (TAD), a series of 18.5 repeats of epidermal growth factor (EGF)-like motif, a high number of Fibronectin type III (FNIII) module, and a fibrinogen (FBG)-like globular domain.[9]
TNXB (functional gene)
The TNXB gene localizes to the major histocompatibility complex (MHC class III) region on chromosome 6. The structure of this gene is unusual in that it overlaps the CREBL1 and CYP21A2 genes at its 5' and 3' ends, respectively.[10]
TNXA (pseudogene)
The TNXB gene has an associated pseudogene, TNXA.
Both TNXA and TNXB genes are located within the RCCX cluster, which consists of a series of modules with genes close to each other: serine/threonine kinase 19 (STK19), complement 4 (C4), steroid 21-hydroxylase (CYP21), and tenascin-X (TNX).[11] In a monomodular structure of the RCCX cluster, all of the genes are functional, i.e. protein-coding, but if there are two or more modules within the cluster, there is only one copy of each functional gene rest being non-coding pseudogenes with the exception of the C4 gene which always has active copies.[12][13] For example, in a bimodular configuration most common among Europeans, the cluster consists of the following genes: STK19-C4A-CYP21A1P-TNXA-STK19B-C4B-CYP21A2-TNXB.[11][14] As such, TNXA is a duplicated copy of TNXB, but is incomplete, therefore, TNXA a pseudogene that is transcribed but does not encode a protein.[15][10]
The presence of the pseudogeneis a consequence of MHC class III locus duplication during evolution. Strong 3' homology between TNXB and TNXA can provoke genetic recombination between the two loci, thus leading to the apparition of TNXA/TNXB chimera[16].
TN-X is constitutively expressed in adult tissues such as skin, ligaments, tendons, lungs, kidneys, optic nerves, mammary and adrenal glands, blood vessels, testis, and ovaries. It is also found in different compartments of the digestive tract, including pancreas, stomach, jejunum, ileum, and colon. In this wide variety of organs, TN-X is mainly located within the connective tissue such as peritendineum (external structural component of tendons), epimysium and perimysium (muscle components), renal glomeruli, blood vessels and skin dermis.[17] TN-X has been proposed to have an important structural and architectural function, especially within the skin. In fact, in vitro experiments demonstrate that TN-X physically interacts with fibrillar collagens type I, III and V, as well as FACIT (Fibrillar Associated Collagen with Interruption of the Triple helix) including type XII and XIV collagens.[18] It also interacts with Transforming Growth Factor (TGF)-β[19] which is a pro-fibrotic cytokine and Decorin, a small 100 kDa dermatan sulfate proteoglycan that plays a crucial role in collagen fibrillogenesis.[20] In vivo, transmission electron microscopy coupled with immuno-labelling confirms the very close location of TN-X with collagen fibbers in dermis, tendons and kidney glomeruli.[21]
In addition to this architectural function, TN-X also demonstrated counter-adhesive properties, at least for human osteosarcoma cells (MG-63), murine embryonic fibroblasts (MRC-5) as well as human endothelial cells (ECV-304).[22][23]
Homozygous mutations,[24] heterozygous compound (bi-allelic) mutations[25] or haploinsufficiency[16] in TN-X cause classical-like Ehlers-Danlos syndrome (EDS),[26] a rare and hereditary connective tissue disorder in mice[27] and human.[28][29] This pathology is characterized by skin hyperlaxity, joint hypermobility and global tissue weakness as a consequence of elastin fragmentation and reduced collagen density, especially in skin.[30][31]
Tenascin-X (TNX) protein was discovered during studies of human steroidogenesis and its disorders, particularly in patients with 21-hydroxylase deficiency, rather than during studies of connective tissue disorders.[32] Researchers sequenced a 2.7 kb cDNA clone that showed similarities to tenascin, leading to the identification of the XB gene.[33] This gene was initially called "Gene X" because its nature and function were unknown at the time. Further research revealed that this gene encodes the Tenascin-X protein, which belongs to the family of tenascins.[32]
ENSG00000236221, ENSG00000229353, ENSG00000229341, ENSG00000233323, ENSG00000231608, ENSG00000206258, ENSG00000168477 GRCh38: Ensembl release 89: ENSG00000236236, ENSG00000236221, ENSG00000229353, ENSG00000229341, ENSG00000233323, ENSG00000231608, ENSG00000206258, ENSG00000168477 – Ensembl, May 2017
Tee MK, Thomson AA, Bristow J, Miller WL (July 1995). "Sequences promoting the transcription of the human XA gene overlapping P450c21A correctly predict the presence of a novel, adrenal-specific, truncated form of tenascin-X". Genomics. 28 (2): 171–178. doi:10.1006/geno.1995.1128. PMID 8530023.
Lethias C, Descollonges Y, Boutillon MM, Garrone R (April 1996). "Flexilin: a new extracellular matrix glycoprotein localized on collagen fibrils". Matrix Biology. 15 (1): 11–19. doi:10.1016/S0945-053X(96)90122-5. PMID 8783183.
Mao JR, Taylor G, Dean WB, Wagner DR, Afzal V, Lotz JC, et al. (April 2002). "Tenascin-X deficiency mimics Ehlers-Danlos syndrome in mice through alteration of collagen deposition". Nature Genetics. 30 (4): 421–425. doi:10.1038/ng850. PMID 11925569. S2CID 21274161.
Demirdas S, Dulfer E, Robert L, Kempers M, van Beek D, Micha D, et al. (March 2017). "Recognizing the tenascin-X deficient type of Ehlers-Danlos syndrome: a cross-sectional study in 17 patients". Clinical Genetics. 91 (3): 411–425. doi:10.1111/cge.12853. PMID 27582382. S2CID 205001452.
Voermans NC, Jenniskens GJ, Hamel BC, Schalkwijk J, Guicheney P, van Engelen BG (September 2007). "Ehlers-Danlos syndrome due to tenascin-X deficiency: muscle weakness and contractures support overlap with collagen VI myopathies". American Journal of Medical Genetics. Part A. 143A (18): 2215–2219. doi:10.1002/ajmg.a.31899. PMID 17702048. S2CID 6760626.
- Goepel C (2008). "Differential elastin and tenascin immunolabeling in the uterosacral ligaments in postmenopausal women with and without pelvic organ prolapse". Acta Histochemica. 110 (3): 204–209. doi:10.1016/j.acthis.2007.10.014. PMID 18155129.
- Yuan Y, Nymoen DA, Stavnes HT, Rosnes AK, Bjørang O, Wu C, et al. (November 2009). "Tenascin-X is a novel diagnostic marker of malignant mesothelioma". The American Journal of Surgical Pathology. 33 (11): 1673–1682. doi:10.1097/PAS.0b013e3181b6bde3. PMC 2783994. PMID 19738457.
- Egging D, van Vlijmen-Willems I, van Tongeren T, Schalkwijk J, Peeters A (2007). "Wound healing in tenascin-X deficient mice suggests that tenascin-X is involved in matrix maturation rather than matrix deposition". Connective Tissue Research. 48 (2): 93–98. doi:10.1080/03008200601166160. PMID 17453911. S2CID 34586536.
- Egging DF, van Vlijmen-Willems I, Choi J, Peeters AC, van Rens D, Veit G, et al. (June 2008). "Analysis of obstetric complications and uterine connective tissue in tenascin-X-deficient humans and mice". Cell and Tissue Research. 332 (3): 523–532. doi:10.1007/s00441-008-0591-y. PMC 2386751. PMID 18335242.
- Kato A, Endo T, Abiko S, Ariga H, Matsumoto K (August 2008). "Induction of truncated form of tenascin-X (XB-S) through dissociation of HDAC1 from SP-1/HDAC1 complex in response to hypoxic conditions". Experimental Cell Research. 314 (14): 2661–2673. doi:10.1016/j.yexcr.2008.05.019. PMID 18588874.
- Bristow J, Carey W, Egging D, Schalkwijk J (November 2005). "Tenascin-X, collagen, elastin, and the Ehlers-Danlos syndrome". American Journal of Medical Genetics. Part C, Seminars in Medical Genetics. 139C (1): 24–30. doi:10.1002/ajmg.c.30071. PMID 16278880. S2CID 23825221. Archived from the original on 2022-06-10. Retrieved 2019-07-11.
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This article incorporates text from the United States National Library of Medicine, which is in the public domain.