Tenascin-X as a causal gene for classical-like Ehlers-Danlos syndrome

Abstract

Tenascin-X (TNX) is an extracellular matrix glycoprotein for which a deficiency results in a recessive form of classical-like Ehlers-Danlos syndrome (clEDS), a heritable connective tissue disorder with hyperextensible skin without atrophic scarring, joint hypermobility, and easy bruising. Notably, patients with clEDS also suffer from not only chronic joint pain and chronic myalgia but also neurological abnormalities such as peripheral paresthesia and axonal polyneuropathy with high frequency. By using TNX-deficient (Tnxb−/−) mice, well-known as a model animal of clEDS, we recently showed that Tnxb−/− mice exhibit hypersensitivity to chemical stimuli and the development of mechanical allodynia due to the hypersensitization of myelinated A-fibers and activation of the spinal dorsal horn. Pain also occurs in other types of EDS. First, we review the underlying molecular mechanisms of pain in EDS, especially that in clEDS. In addition, the roles of TNX as a tumor suppressor protein in cancer progression have been reported. Recent in silico large-scale database analyses have shown that TNX is downregulated in various tumor tissues and that high expression of TNX in tumor cells has a good prognosis. We describe what is so far known about TNX as a tumor suppressor protein. Furthermore, some patients with clEDS show delayed wound healing. Tnxb−/− mice also exhibit impairment of epithelial wound healing in corneas. TNX is also involved in liver fibrosis. We address the molecular mechanism for the induction of COL1A1 by the expression of both a peptide derived from the fibrinogen-related domain of TNX and integrin α11.

The coordinated activities of collagen VI and XII in maintenance of tissue structure, function and repair: evidence for a physical interaction

“…Expression of tenascin X and collagen VI also appears to be coordinately regulated ( Minamitani et al, 2004b ) and they collaborate in driving the formation of heterotypic fibrils containing collagen I ( Minamitani et al, 2004a ). Tenascin X deficiency also causes a spectrum of mEDS-like disorders that mimic the phenotype of collagen VI related myopathies ( Burch et al, 1997 ; Brisset et al, 2020 ; Marino et al, 2022 ; Okuda-Ashitaka and Matsumoto, 2023 ).…”

Hypersensitivity of myelinated A-fibers via toll-like receptor 5 promotes mechanical allodynia in tenascin-X-deficient mice associated with Ehlers–Danlos syndrome

“…In addition, pain is a sever clinical manifestation of EDS patients, and approximately 90% of EDS patients complain of chronic pain 6 – 8 . EDS patients suffer from chronic neuropathic pain, generalized body pain, gastrointestinal pain, headache, dysmenorrhea, and fatigue, in addition to connective tissues-related pain such as joint pain, soft-tissue pain, and dislocations 6 , 7 . TNX-deficient EDS patients complain of chronic pain such as chronic joint pain, myalgia, abdominal pain, fatigue, paresthesia, and axonal polyneuropathy 3 , 5 .…”