Tenascin X

Last updated
TNXB
PDB 2cum EBI.jpg
Available structures
PDB Human UniProt search: PDBe RCSB
Identifiers
Aliases TNXB , EDS3, HXBL, TENX, TN-X, TNX, TNXB1, TNXB2, TNXBS, VUR8, XB, XBS, tenascin XB, EDSCLL, EDSCLL1
External IDs OMIM: 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 Mb Chr 17: 34.88 – 34.94 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/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]

Contents

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

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

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] .

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. [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

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

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]


Related Research Articles

<span class="mw-page-title-main">Ehlers–Danlos syndrome</span> Group of genetic connective tissues disorders

Ehlers–Danlos syndromes (EDS) are a group of 13 genetic connective-tissue disorders. Symptoms often include loose joints, joint pain, stretchy velvety skin, and abnormal scar formation. These may be noticed at birth or in early childhood. Complications may include aortic dissection, joint dislocations, scoliosis, chronic pain, or early osteoarthritis. The current classification was last updated in 2017, when a number of rarer forms of EDS were added.

<span class="mw-page-title-main">Occipital horn syndrome</span> Medical condition

Occipital horn syndrome (OHS), formerly considered a variant of Ehlers–Danlos syndrome, is an X-linked recessive mitochondrial and connective tissue disorder. It is caused by a deficiency in the transport of the essential mineral copper, associated with mutations in the ATP7A gene.

<span class="mw-page-title-main">ADAMTS2</span> Protein-coding gene in the species Homo sapiens

A disintegrin and metalloproteinase with thrombospondin motifs 2 (ADAM-TS2) also known as procollagen I N-proteinase is an enzyme that in humans is encoded by the ADAMTS2 gene.

<span class="mw-page-title-main">Collagen, type I, alpha 1</span> Mammalian protein found in humans

Collagen, type I, alpha 1, also known as alpha-1 type I collagen, is a protein that in humans is encoded by the COL1A1 gene. COL1A1 encodes the major component of type I collagen, the fibrillar collagen found in most connective tissues, including cartilage.

<span class="mw-page-title-main">Hypermobility (joints)</span> Joints that stretch further than normal

Hypermobility, also known as double-jointedness, describes joints that stretch farther than normal. For example, some hypermobile people can bend their thumbs backwards to their wrists and bend their knee joints backwards, put their leg behind the head or perform other contortionist "tricks". It can affect one or more joints throughout the body.

Fibrillogenesis is the development of fine fibrils normally present in collagen fibers of connective tissue. It is derived from the New Latin fibrilla and Greek genesis.

<span class="mw-page-title-main">Collagen, type III, alpha 1</span>

Type III Collagen is a homotrimer, or a protein composed of three identical peptide chains (monomers), each called an alpha 1 chain of type III collagen. Formally, the monomers are called collagen type III, alpha-1 chain and in humans are encoded by the COL3A1 gene. Type III collagen is one of the fibrillar collagens whose proteins have a long, inflexible, triple-helical domain.

<span class="mw-page-title-main">Tenascin</span> Extracellular matrix glycoprotein family

Tenascins are extracellular matrix glycoproteins. They are abundant in the extracellular matrix of developing vertebrate embryos and they reappear around healing wounds and in the stroma of some tumors.

Type I collagen is the most abundant collagen of the human body, consisting of around 90% of the body's total collagen in vertebrates. Due to this, it is also the most abundant protein type found in all vertebrates. Type I forms large, eosinophilic fibers known as collagen fibers, which make up most of the rope-like dense connective tissue in the body.

Type V collagen is a form of fibrillar collagen associated with classical Ehlers-Danlos syndrome. It is found within the dermal/epidermal junction, placental tissues, as well as in association with tissues containing type I collagen.

<span class="mw-page-title-main">Collagen, type V, alpha 1</span> Protein found in humans

Collagen alpha-1(V) chain is a protein that in humans is encoded by the COL5A1 gene.

<span class="mw-page-title-main">Collagen, type V, alpha 2</span> Protein found in humans

Collagen alpha-2(V) chain is a protein that in humans is encoded by the COL5A2 gene.

<span class="mw-page-title-main">Tenascin C</span> Human protein-coding gene

Tenascin C (TN-C) is a glycoprotein that in humans is encoded by the TNC gene. It is expressed in the extracellular matrix of various tissues during development, disease or injury, and in restricted neurogenic areas of the central nervous system. Tenascin-C is the founding member of the tenascin protein family. In the embryo it is made by migrating cells like the neural crest; it is also abundant in developing tendons, bone and cartilage.

<span class="mw-page-title-main">Collagen, type XII, alpha 1</span> Protein found in humans

Collagen alpha-1(XII) chain is a protein that in humans is encoded by the COL12A1 gene.

<span class="mw-page-title-main">B4GALT7</span> Protein-coding gene in the species Homo sapiens

Beta-1,4-galactosyltransferase 7 also known as galactosyltransferase I is an enzyme that in humans is encoded by the B4GALT7 gene. Galactosyltransferase I catalyzes the synthesis of the glycosaminoglycan-protein linkage in proteoglycans. Proteoglycans in turn are structural components of the extracellular matrix that is found between cells in connective tissues.

<span class="mw-page-title-main">CHST14</span> Protein-coding gene in the species Homo sapiens

Carbohydrate sulfotransferase 14 is an enzyme that in humans is encoded by the CHST14 gene.

<span class="mw-page-title-main">Tenascin-R</span> Protein-coding gene in the species Homo sapiens

Tenascin-R is a protein that in humans is encoded by the TNR gene.

Walter L. Miller is an American endocrinologist and professor emeritus of pediatrics at the University of California, San Francisco (UCSF). Miller is expert in the field of human steroid biosynthesis and disorders of steroid metabolism. Over the past 40 years Miller's group at UCSF has described molecular basis of several metabolic disorders including, congenital adrenal hyperplasia, pseudo vitamin D dependent rickets, severe, recessive form of Ehlers-Danlos syndrome, 17,20 lyase deficiency caused by CYP17A1 defects, P450scc deficiency caused by CYP11A1 defects, P450 oxidoreductase deficiency.

FKBP14 is a gene which codes for a structural protein named FKBP prolyl isomerase 14. This protein is believed to aid in the process of procollagen folding and is located in the endoplasmic reticulum that functions to process and transport proteins. Procollagens are collagen precursors located in the extracellular matrix that give tissues elasticity, strength, and support. This gene is involved in patterning the collagen structure. FKBP prolyl isomerase 14 may also be involved in altering other factors in the extracellular matrix. Mutations of this gene are associated with the kyphoscoliotic type of Ehlers-Danlos syndrome. This condition is characterized by a high range of joint movement, muscle atrophy, curved spine, and delicate cardiovascular vessels. These symptoms are brought about by a loss of the protein which results in a disruption of endoplasmic reticulum activities and extracellular matrix organization. FKBP14 mRNA levels are found higher in ovarian cancer tissues than healthy ovarian tissue and knocked down expression of FKBP14 by lentiviral shRNA leads to an impaired proliferative ability of ovarian cancer cells.

RCCX is a complex, multiallelic, and tandem copy number variation (CNV) human DNA locus on chromosome 6p21.3, a cluster located in the major histocompatibility complex (MHC) class III region. CNVs are segments of DNA that vary in copy number compared to a reference genome and play a significant role in human phenotypic variation and disease development. The RCCX cluster consists of one or more modules each having a series of genes close to each other: serine/threonine kinase 19 (STK19), complement 4 (C4), steroid 21-hydroxylase (CYP21), and tenascin-X (TNX).

References

  1. 1 2 3 ENSG00000236221, ENSG00000229353, ENSG00000229341, ENSG00000233323, ENSG00000231608, ENSG00000206258, ENSG00000168477 GRCh38: Ensembl release 89: ENSG00000236236, ENSG00000236221, ENSG00000229353, ENSG00000229341, ENSG00000233323, ENSG00000231608, ENSG00000206258, ENSG00000168477 – Ensembl, May 2017
  2. 1 2 3 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. 1 2 PD-icon.svg This article incorporates public domain material from "TNXB tenascin XB [ Homo sapiens (human)". Reference Sequence collection . National Center for Biotechnology Information.
  11. 1 2 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. ↑ PD-icon.svg This article incorporates public domain material from "TNXA tenascin XA (pseudogene) [ Homo sapiens (human) ]". Reference Sequence collection . National Center for Biotechnology Information.
  16. 1 2 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. 1 2 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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