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Tenascin X

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TNXB
Available structures
PDBHuman UniProt search: PDBe RCSB
Identifiers
AliasesTNXB, EDS3, HXBL, TENX, TN-X, TNX, TNXB1, TNXB2, TNXBS, VUR8, XB, XBS, tenascin XB, EDSCLL, EDSCLL1
External IDsOMIM: 600985; MGI: 1932137; HomoloGene: 49589; GeneCards: TNXB; OMA:TNXB - orthologs
Orthologs
SpeciesHumanMouse
Entrez

7148

81877

Ensembl

ENSMUSG00000033327

UniProt

P22105

n/a

RefSeq (mRNA)

NM_032470
NM_019105
NM_001365276

NM_031176

RefSeq (protein)

NP_061978
NP_115859
NP_001352205

n/a

Location (UCSC)Chr 6: 32.04 – 32.12 MbChr 17: 34.88 – 34.94 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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]

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]

Structure

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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]

Gene

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TNXB (functional gene)

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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)

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See also: RCCX

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].

Function

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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]

Clinical significance

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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]

History

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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]


References

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  1. ^ a b c ENSG00000236221, ENSG00000229353, ENSG00000229341, ENSG00000233323, ENSG00000231608, ENSG00000206258, ENSG00000168477 GRCh38: Ensembl release 89: ENSG00000236236, ENSG00000236221, ENSG00000229353, ENSG00000229341, ENSG00000233323, ENSG00000231608, ENSG00000206258, ENSG00000168477 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000033327 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ 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.
  6. ^ Valcourt U, Alcaraz LB, Exposito JY, Lethias C, Bartholin L (2015). "Tenascin-X: beyond the architectural function". Cell Adh Migr. 9 (1–2): 154–65. doi:10.4161/19336918.2014.994893. PMC 4422802. PMID 25793578.
  7. ^ Okuda-Ashitaka E, Matsumoto KI (2023). "Tenascin-X as a causal gene for classical-like Ehlers-Danlos syndrome". Front Genet. 14: 1107787. doi:10.3389/fgene.2023.1107787. PMC 10050494. PMID 37007968.
  8. ^ Miller WL, Merke DP (2018). "Tenascin-X, Congenital Adrenal Hyperplasia, and the CAH-X Syndrome". Horm Res Paediatr. 89 (5): 352–361. doi:10.1159/000481911. PMC 6057477. PMID 29734195.
  9. ^ Jones FS, Jones PL (June 2000). "The tenascin family of ECM glycoproteins: structure, function, and regulation during embryonic development and tissue remodeling". Developmental Dynamics. 218 (2): 235–259. doi:10.1002/(SICI)1097-0177(200006)218:2<235::AID-DVDY2>3.0.CO;2-G. PMID 10842355. S2CID 16267174.
  10. ^ a b Public Domain This article incorporates public domain material from "TNXB tenascin XB [ Homo sapiens (human)". Reference Sequence collection. National Center for Biotechnology Information.
  11. ^ a b Carrozza C, Foca L, De Paolis E, Concolino P (2021). "Genes and Pseudogenes: Complexity of the RCCX Locus and Disease". Front Endocrinol (Lausanne). 12. 709758. doi:10.3389/fendo.2021.709758. PMC 8362596. PMID 34394006.
  12. ^ Bánlaki Z, Doleschall M, Rajczy K, Fust G, Szilágyi A (October 2012). "Fine-tuned characterization of RCCX copy number variants and their relationship with extended MHC haplotypes". Genes Immun. 13 (7): 530–535. doi:10.1038/gene.2012.29. PMID 22785613. S2CID 36582994.
  13. ^ Bánlaki Z, Szabó JA, Szilágyi Á, Patócs A, Prohászka Z, Füst G, et al. (2013). "Intraspecific evolution of human RCCX copy number variation traced by haplotypes of the CYP21A2 gene". Genome Biol Evol. 5 (1): 98–112. doi:10.1093/gbe/evs121. PMC 3595039. PMID 23241443.
  14. ^ Kim JH, Kim GH, Yoo HW, Choi JH (June 2023). "Molecular basis and genetic testing strategies for diagnosing 21-hydroxylase deficiency, including CAH-X syndrome". Ann Pediatr Endocrinol Metab. 28 (2): 77–86. doi:10.6065/apem.2346108.054. PMC 10329939. PMID 37401054.
  15. ^ Public Domain This article incorporates public domain material from "TNXA tenascin XA (pseudogene) [ Homo sapiens (human) ]". Reference Sequence collection. National Center for Biotechnology Information.
  16. ^ a b Merke DP, Chen W, Morissette R, Xu Z, Van Ryzin C, Sachdev V, et al. (February 2013). "Tenascin-X haploinsufficiency associated with Ehlers-Danlos syndrome in patients with congenital adrenal hyperplasia". The Journal of Clinical Endocrinology and Metabolism. 98 (2): E379 – E387. doi:10.1210/jc.2012-3148. PMC 3565116. PMID 23284009.
  17. ^ Valcourt U, Alcaraz LB, Exposito JY, Lethias C, Bartholin L (2015-01-02). "Tenascin-X: beyond the architectural function". Cell Adhesion & Migration. 9 (1–2): 154–165. doi:10.4161/19336918.2014.994893. PMC 4422802. PMID 25793578.
  18. ^ Lethias C, Carisey A, Comte J, Cluzel C, Exposito JY (November 2006). "A model of tenascin-X integration within the collagenous network". FEBS Letters. 580 (26): 6281–6285. Bibcode:2006FEBSL.580.6281L. doi:10.1016/j.febslet.2006.10.037. PMID 17078949. S2CID 29297624.
  19. ^ Alcaraz LB, Exposito JY, Chuvin N, Pommier RM, Cluzel C, Martel S, et al. (May 2014). "Tenascin-X promotes epithelial-to-mesenchymal transition by activating latent TGF-β". The Journal of Cell Biology. 205 (3): 409–428. doi:10.1083/jcb.201308031. PMC 4018787. PMID 24821840.
  20. ^ Elefteriou F, Exposito JY, Garrone R, Lethias C (April 2001). "Binding of tenascin-X to decorin". FEBS Letters. 495 (1–2): 44–47. Bibcode:2001FEBSL.495...44E. doi:10.1016/S0014-5793(01)02361-4. PMID 11322944. S2CID 13988411.
  21. ^ 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.
  22. ^ Elefteriou F, Exposito JY, Garrone R, Lethias C (August 1999). "Cell adhesion to tenascin-X mapping of cell adhesion sites and identification of integrin receptors". European Journal of Biochemistry. 263 (3): 840–848. doi:10.1046/j.1432-1327.1999.00563.x. PMID 10469149.
  23. ^ Fujie S, Maita H, Ariga H, Matsumoto K (October 2009). "Tenascin-X induces cell detachment through p38 mitogen-activated protein kinase activation". Biological & Pharmaceutical Bulletin. 32 (10): 1795–1799. doi:10.1248/bpb.32.1795. hdl:2115/53700. PMID 19801846.
  24. ^ Morissette R, Chen W, Perritt AF, Dreiling JL, Arai AE, Sachdev V, et al. (August 2015). "Broadening the Spectrum of Ehlers Danlos Syndrome in Patients With Congenital Adrenal Hyperplasia". The Journal of Clinical Endocrinology and Metabolism. 100 (8): E1143 – E1152. doi:10.1210/jc.2015-2232. PMC 4525000. PMID 26075496.
  25. ^ Chen W, Perritt AF, Morissette R, Dreiling JL, Bohn MF, Mallappa A, et al. (September 2016). "Ehlers-Danlos Syndrome Caused by Biallelic TNXB Variants in Patients with Congenital Adrenal Hyperplasia". Human Mutation. 37 (9): 893–897. doi:10.1002/humu.23028. PMC 4983206. PMID 27297501.
  26. ^ Malfait F, Francomano C, Byers P, Belmont J, Berglund B, Black J, et al. (March 2017). "The 2017 international classification of the Ehlers-Danlos syndromes". American Journal of Medical Genetics. Part C, Seminars in Medical Genetics. 175 (1): 8–26. doi:10.1002/ajmg.c.31552. PMID 28306229. S2CID 4440499.
  27. ^ 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.
  28. ^ Schalkwijk J, Zweers MC, Steijlen PM, Dean WB, Taylor G, van Vlijmen IM, et al. (October 2001). "A recessive form of the Ehlers-Danlos syndrome caused by tenascin-X deficiency". The New England Journal of Medicine. 345 (16): 1167–1175. doi:10.1056/NEJMoa002939. hdl:2066/185552. PMID 11642233. S2CID 42748708.
  29. ^ 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.
  30. ^ Zweers MC, Schalkwijk J, van Kuppevelt TH, van Vlijmen-Willems IM, Bergers M, Lethias C, et al. (February 2005). "Transplantation of reconstructed human skin on nude mice: a model system to study expression of human tenascin-X and elastic fiber components". Cell and Tissue Research. 319 (2): 279–287. doi:10.1007/s00441-004-1011-6. PMID 15558324. S2CID 5889106.
  31. ^ 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.
  32. ^ a b Miller WL (2020). "Tenascin-X-Discovery and Early Research". Front Immunol. 11: 612497. doi:10.3389/fimmu.2020.612497. PMC 7829301. PMID 33505400.
  33. ^ Morel Y, Bristow J, Gitelman SE, Miller WL (September 1989). "Transcript encoded on the opposite strand of the human steroid 21-hydroxylase/complement component C4 gene locus". Proc Natl Acad Sci U S A. 86 (17): 6582–6. Bibcode:1989PNAS...86.6582M. doi:10.1073/pnas.86.17.6582. PMC 297888. PMID 2475872.

Further reading

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This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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