Tenascin X (TN-X), also known as flexillinorhexabrachion-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 TNXBgene.[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]
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]
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]
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].
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]orhaploinsufficiency[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]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^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. PMID8530023.
^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. PMID8783183.
^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. PMID11925569. S2CID21274161.
^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. PMID11642233. S2CID42748708.
^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. PMID27582382. S2CID205001452.
^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. PMID15558324. S2CID5889106.
^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. PMID17702048. S2CID6760626.
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. PMID18155129.
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. PMID17453911. S2CID34586536.
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. PMID18588874.
Yu CY (1998). "Molecular genetics of the human MHC complement gene cluster". Experimental and Clinical Immunogenetics. 15 (4): 213–230. doi:10.1159/000019075. PMID10072631. S2CID25061446.
Endo T, Ariga H, Matsumoto K (January 2009). "Truncated form of tenascin-X, XB-S, interacts with mitotic motor kinesin Eg5". Molecular and Cellular Biochemistry. 320 (1–2): 53–66. doi:10.1007/s11010-008-9898-y. PMID18679583. S2CID23394214.
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This article incorporates public domain material from "TNXB tenascin XB [ Homo sapiens (human)". Reference Sequence collection. National Center for Biotechnology Information.
