Tenascin X

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.

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)

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). 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. 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. 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 pseudogene is 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*.*

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. 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. It also interacts with Transforming Growth Factor (TGF)-β which is a pro-fibrotic cytokine and Decorin, a small 100 kDa dermatan sulfate proteoglycan that plays a crucial role in collagen fibrillogenesis. In vivo, transmission electron microscopy coupled with immuno-labelling confirms the very close location of TN-X with collagen fibers in dermis, tendons and kidney glomeruli.

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).

Clinical significance

Homozygous mutations, heterozygous compound (bi-allelic) mutations or haploinsufficiency in TN-X cause classical-like Ehlers-Danlos syndrome (EDS), a rare and hereditary connective tissue disorder in mice and humans. 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.

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. 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.

References

References

1. (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.
2. (2015). "Tenascin-X: beyond the architectural function". Cell Adh Migr.
3. (2023). "Tenascin-X as a causal gene for classical-like Ehlers-Danlos syndrome". Front Genet.
4. (2018). "Tenascin-X, Congenital Adrenal Hyperplasia, and the CAH-X Syndrome". Horm Res Paediatr.
5. (June 2000). "The tenascin family of ECM glycoproteins: structure, function, and regulation during embryonic development and tissue remodeling". Developmental Dynamics.
6. (2021). "Genes and Pseudogenes: Complexity of the RCCX Locus and Disease". Front Endocrinol (Lausanne).
7. (October 2012). "Fine-tuned characterization of RCCX copy number variants and their relationship with extended MHC haplotypes". Genes Immun.
8. (2013). "Intraspecific evolution of human RCCX copy number variation traced by haplotypes of the CYP21A2 gene". Genome Biol Evol.
9. (June 2023). "Molecular basis and genetic testing strategies for diagnosing 21-hydroxylase deficiency, including CAH-X syndrome". Ann Pediatr Endocrinol Metab.
10. "TNXA tenascin XA (pseudogene) [ Homo sapiens (human) ]".
11. ["TNXB tenascin XB Homo sapiens (human)".
12. (February 2013). "Tenascin-X haploinsufficiency associated with Ehlers-Danlos syndrome in patients with congenital adrenal hyperplasia". The Journal of Clinical Endocrinology and Metabolism.
13. (2015-01-02). "Tenascin-X: beyond the architectural function". Cell Adhesion & Migration.
14. (November 2006). "A model of tenascin-X integration within the collagenous network". FEBS Letters.
15. (May 2014). "Tenascin-X promotes epithelial-to-mesenchymal transition by activating latent TGF-β". The Journal of Cell Biology.
16. (April 2001). "Binding of tenascin-X to decorin". FEBS Letters.
17. (April 1996). "Flexilin: a new extracellular matrix glycoprotein localized on collagen fibrils". Matrix Biology.
18. (August 1999). "Cell adhesion to tenascin-X mapping of cell adhesion sites and identification of integrin receptors". European Journal of Biochemistry.
19. (October 2009). "Tenascin-X induces cell detachment through p38 mitogen-activated protein kinase activation". Biological & Pharmaceutical Bulletin.
20. (August 2015). "Broadening the Spectrum of Ehlers Danlos Syndrome in Patients With Congenital Adrenal Hyperplasia". The Journal of Clinical Endocrinology and Metabolism.
21. (September 2016). "Ehlers-Danlos Syndrome Caused by Biallelic TNXB Variants in Patients with Congenital Adrenal Hyperplasia". Human Mutation.
22. (March 2017). "The 2017 international classification of the Ehlers-Danlos syndromes". American Journal of Medical Genetics. Part C, Seminars in Medical Genetics.
23. (April 2002). "Tenascin-X deficiency mimics Ehlers-Danlos syndrome in mice through alteration of collagen deposition". Nature Genetics.
24. (October 2001). "A recessive form of the Ehlers-Danlos syndrome caused by tenascin-X deficiency". The New England Journal of Medicine.
25. (March 2017). "Recognizing the tenascin-X deficient type of Ehlers-Danlos syndrome: a cross-sectional study in 17 patients". Clinical Genetics.
26. (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.
27. (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.
28. (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.
29. (2020). "Tenascin-X-Discovery and Early Research". Front Immunol.