Tenascin X Explained

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.[1]

The TN-X protein is expressed in many parts of the human body, including the skin, muscles, kidneys, blood vessels, and digestive tract.[2] [3]

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.[4]

Structure

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.[5]

Gene

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.

TNXA (pseudogene)

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).[6] 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.[7] [8] 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.[6] [9] 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.

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[10] .

Function

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.[11] 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.[12] It also interacts with Transforming Growth Factor (TGF)-β[13] which is a pro-fibrotic cytokine and Decorin, a small 100 kDa dermatan sulfate proteoglycan that plays a crucial role in collagen fibrillogenesis.[14] 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.[15]

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).[16] [17]

Clinical significance

Homozygous mutations,[18] heterozygous compound (bi-allelic) mutations[19] or haploinsufficiency in TN-X cause classical-like Ehlers-Danlos syndrome (EDS),[20] a rare and hereditary connective tissue disorder in mice[21] and human.[22] [23] 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.[24] [25]

History

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. Researchers sequenced a 2.7 kb cDNA clone that showed similarities to tenascin, leading to the identification of the XB gene.[26] 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.[27]

Further reading

External links

Notes and References

  1. Tee MK, Thomson AA, Bristow J, Miller WL . 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 . July 1995 . 8530023 . 10.1006/geno.1995.1128 .
  2. Valcourt U, Alcaraz LB, Exposito JY, Lethias C, Bartholin L . Tenascin-X: beyond the architectural function . Cell Adh Migr . 9 . 1–2 . 154–65 . 2015 . 25793578 . 4422802 . 10.4161/19336918.2014.994893 .
  3. Okuda-Ashitaka E, Matsumoto KI . Tenascin-X as a causal gene for classical-like Ehlers-Danlos syndrome . Front Genet . 14 . 1107787 . 2023 . 37007968 . 10050494 . 10.3389/fgene.2023.1107787 . free .
  4. Miller WL, Merke DP . Tenascin-X, Congenital Adrenal Hyperplasia, and the CAH-X Syndrome . Horm Res Paediatr . 89 . 5 . 352–361 . 2018 . 29734195 . 6057477 . 10.1159/000481911 .
  5. Jones FS, Jones PL . The tenascin family of ECM glycoproteins: structure, function, and regulation during embryonic development and tissue remodeling . Developmental Dynamics . 218 . 2 . 235–259 . June 2000 . 10842355 . 10.1002/(SICI)1097-0177(200006)218:2<235::AID-DVDY2>3.0.CO;2-G . 16267174 . free .
  6. Carrozza C, Foca L, De Paolis E, Concolino P . Genes and Pseudogenes: Complexity of the RCCX Locus and Disease . Front Endocrinol (Lausanne) . 12 . 709758 . 2021 . 34394006 . 8362596 . 10.3389/fendo.2021.709758 . free .
  7. Bánlaki Z, Doleschall M, Rajczy K, Fust G, Szilágyi A . Fine-tuned characterization of RCCX copy number variants and their relationship with extended MHC haplotypes . Genes Immun . 13 . 7 . 530–535 . October 2012 . 22785613 . 10.1038/gene.2012.29 . 36582994 . free .
  8. Bánlaki Z, Szabó JA, Szilágyi Á, Patócs A, Prohászka Z, Füst G, Doleschall M . Intraspecific evolution of human RCCX copy number variation traced by haplotypes of the CYP21A2 gene . Genome Biol Evol . 5 . 1 . 98–112 . 2013 . 23241443 . 3595039 . 10.1093/gbe/evs121.
  9. Kim JH, Kim GH, Yoo HW, Choi JH . Molecular basis and genetic testing strategies for diagnosing 21-hydroxylase deficiency, including CAH-X syndrome . Ann Pediatr Endocrinol Metab . 28 . 2 . 77–86 . June 2023 . 37401054 . 10329939 . 10.6065/apem.2346108.054.
  10. Merke DP, Chen W, Morissette R, Xu Z, Van Ryzin C, Sachdev V, Hannoush H, Shanbhag SM, Acevedo AT, Nishitani M, Arai AE, McDonnell NB . 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 . February 2013 . 23284009 . 3565116 . 10.1210/jc.2012-3148 .
  11. Valcourt U, Alcaraz LB, Exposito JY, Lethias C, Bartholin L . Tenascin-X: beyond the architectural function . Cell Adhesion & Migration . 9 . 1–2 . 154–165 . 2015-01-02 . 25793578 . 4422802 . 10.4161/19336918.2014.994893 .
  12. Lethias C, Carisey A, Comte J, Cluzel C, Exposito JY . A model of tenascin-X integration within the collagenous network . FEBS Letters . 580 . 26 . 6281–6285 . November 2006 . 17078949 . 10.1016/j.febslet.2006.10.037 . 29297624 . free . 2006FEBSL.580.6281L .
  13. Alcaraz LB, Exposito JY, Chuvin N, Pommier RM, Cluzel C, Martel S, Sentis S, Bartholin L, Lethias C, Valcourt U . Tenascin-X promotes epithelial-to-mesenchymal transition by activating latent TGF-β . The Journal of Cell Biology . 205 . 3 . 409–428 . May 2014 . 24821840 . 10.1083/jcb.201308031 . 4018787 .
  14. Elefteriou F, Exposito JY, Garrone R, Lethias C . Binding of tenascin-X to decorin . FEBS Letters . 495 . 1–2 . 44–47 . April 2001 . 11322944 . 10.1016/S0014-5793(01)02361-4 . 13988411 . free . 2001FEBSL.495...44E .
  15. Lethias C, Descollonges Y, Boutillon MM, Garrone R . Flexilin: a new extracellular matrix glycoprotein localized on collagen fibrils . Matrix Biology . 15 . 1 . 11–19 . April 1996 . 8783183 . 10.1016/S0945-053X(96)90122-5 .
  16. Elefteriou F, Exposito JY, Garrone R, Lethias C . Cell adhesion to tenascin-X mapping of cell adhesion sites and identification of integrin receptors . European Journal of Biochemistry . 263 . 3 . 840–848 . August 1999 . 10469149 . 10.1046/j.1432-1327.1999.00563.x . free .
  17. Fujie S, Maita H, Ariga H, Matsumoto K . Tenascin-X induces cell detachment through p38 mitogen-activated protein kinase activation . Biological & Pharmaceutical Bulletin . 32 . 10 . 1795–1799 . October 2009 . 19801846 . 10.1248/bpb.32.1795 . free . 2115/53700 . free .
  18. Morissette R, Chen W, Perritt AF, Dreiling JL, Arai AE, Sachdev V, Hannoush H, Mallappa A, Xu Z, McDonnell NB, Quezado M, Merke DP . Broadening the Spectrum of Ehlers Danlos Syndrome in Patients With Congenital Adrenal Hyperplasia . The Journal of Clinical Endocrinology and Metabolism . 100 . 8 . E1143–E1152 . August 2015 . 26075496 . 4525000 . 10.1210/jc.2015-2232 .
  19. Chen W, Perritt AF, Morissette R, Dreiling JL, Bohn MF, Mallappa A, Xu Z, Quezado M, Merke DP . Ehlers-Danlos Syndrome Caused by Biallelic TNXB Variants in Patients with Congenital Adrenal Hyperplasia . Human Mutation . 37 . 9 . 893–897 . September 2016 . 27297501 . 4983206 . 10.1002/humu.23028 .
  20. Malfait F, Francomano C, Byers P, Belmont J, Berglund B, Black J, Bloom L, Bowen JM, Brady AF, Burrows NP, Castori M, Cohen H, Colombi M, Demirdas S, De Backer J, De Paepe A, Fournel-Gigleux S, Frank M, Ghali N, Giunta C, Grahame R, Hakim A, Jeunemaitre X, Johnson D, Juul-Kristensen B, Kapferer-Seebacher I, Kazkaz H, Kosho T, Lavallee ME, Levy H, Mendoza-Londono R, Pepin M, Pope FM, Reinstein E, Robert L, Rohrbach M, Sanders L, Sobey GJ, Van Damme T, Vandersteen A, van Mourik C, Voermans N, Wheeldon N, Zschocke J, Tinkle B . The 2017 international classification of the Ehlers-Danlos syndromes . American Journal of Medical Genetics. Part C, Seminars in Medical Genetics . 175 . 1 . 8–26 . March 2017 . 28306229 . 10.1002/ajmg.c.31552 . 4440499 . free .
  21. Mao JR, Taylor G, Dean WB, Wagner DR, Afzal V, Lotz JC, Rubin EM, Bristow J . Tenascin-X deficiency mimics Ehlers-Danlos syndrome in mice through alteration of collagen deposition . Nature Genetics . 30 . 4 . 421–425 . April 2002 . 11925569 . 10.1038/ng850 . 21274161 .
  22. Schalkwijk J, Zweers MC, Steijlen PM, Dean WB, Taylor G, van Vlijmen IM, van Haren B, Miller WL, Bristow J . A recessive form of the Ehlers-Danlos syndrome caused by tenascin-X deficiency . The New England Journal of Medicine . 345 . 16 . 1167–1175 . October 2001 . 11642233 . 10.1056/NEJMoa002939 . 2066/185552 . 42748708 . free .
  23. Demirdas S, Dulfer E, Robert L, Kempers M, van Beek D, Micha D, van Engelen BG, Hamel B, Schalkwijk J, Loeys B, Maugeri A, Voermans NC . Recognizing the tenascin-X deficient type of Ehlers-Danlos syndrome: a cross-sectional study in 17 patients . Clinical Genetics . 91 . 3 . 411–425 . March 2017 . 27582382 . 10.1111/cge.12853 . 205001452 .
  24. Zweers MC, Schalkwijk J, van Kuppevelt TH, van Vlijmen-Willems IM, Bergers M, Lethias C, Lamme EN . 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 . February 2005 . 15558324 . 10.1007/s00441-004-1011-6 . 5889106 .
  25. Voermans NC, Jenniskens GJ, Hamel BC, Schalkwijk J, Guicheney P, van Engelen BG . 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 . September 2007 . 17702048 . 10.1002/ajmg.a.31899 . 6760626 .
  26. Morel Y, Bristow J, Gitelman SE, Miller WL . 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 . September 1989 . 2475872 . 297888 . 10.1073/pnas.86.17.6582 . free . 1989PNAS...86.6582M .
  27. Miller WL . Tenascin-X-Discovery and Early Research . Front Immunol . 11 . 612497 . 2020 . 33505400 . 7829301 . 10.3389/fimmu.2020.612497 . free .

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