Tenascin-X, collagen, and Ehlers–Danlos syndrome: Tenascin-X gene defects can protect against adverse cardiovascular events

Abstract

Long thought to be two separate syndromes, Ehlers-Danlos syndrome hypermobility type (EDS-HT) and benign joint hypermobility syndrome (BJHS) appear on close examination to represent the same syndrome, with virtually identical clinical manifestations. While both EDS-HT and BJHS were long thought to lack the genetic loci of other connective tissue disorders, including all other types of EDS, researchers have discovered a genetic locus that accounts for manifestations of both EDS-HT and BJHS in a small population of patients. However, given the modest sample size of these studies and the strong correlation between serum levels of tenascin-X with clinical symptoms of both EDS-HT and BJHS, strong evidence exists for the origins of both types of hypermobility originating in haploinsufficiency or deficiency of the gene TNXB, responsible for tenascin-X. Tenascin-X regulates both the structure and stability of elastic fibers and organizes collagen fibrils in the extra-cellular matrix (ECM), impacting the rigidity or elasticity of virtually every cell in the body. While the impacts of tenascin-X insufficiency or deficiency on the skin and joints have received some attention, its potential cardiovascular impacts remain relatively unexplored. Here we set forth two novel hypotheses. First, TNXB haploinsufficiency or deficiency causes the range of clinical manifestations long identified with both EDS-HT and BJHS. And, second, that haploinsufficiency or deficiency of TNXB may provide some benefits against adverse cardiovascular events, including heart attack and stroke, by lowering levels of arterial stiffness associated with aging, as well as by enhancing accommodation of accrued atherosclerotic plaques. This two-fold hypothesis provides insights into the mechanisms underlying the syndromes previous identified with joint hypermobility, at the same time the hypothesis also sheds light on the role of the composition of the extracellular matrix and its impacts on endothelial sheer stress in adverse cardiovascular events.

Gastrointestinal disorders in joint hypermobility syndrome/Ehlers‐Danlos syndrome hypermobility type: A review for the gastroenterologist

“…To date, no collagen defects and/or associated mutations have been found in JHS/EDS‐HT. Only in 5‐10% of patients a mutation in TNXB, the gene that codes for tenascin‐X, a glycoprotein in the ECM that is responsible for organization and maintenance of the matrix itself, was linked to an autosomal recessive form of JHS/EDS‐HT . Notably, we have previously reported that GI symptoms are encountered frequently in tenascin‐X‐deficient patients .…”

Psychopathological manifestations of joint hypermobility and joint hypermobility syndrome/ Ehlers–Danlos syndrome, hypermobility type: The link between connective tissue and psychological distress revised

“…An inherited alteration of ECM could, therefore, hold a role in an abnormal synaptic functioning and in the development of neuropsychiatric disorders linked to other extra‐neurologic manifestations [Dityatev et al, ]. In this regard, it is noteworthy that TNXB (6p21.33) encoding for tenascin‐XB, an ECM glycoprotein involved in the organization and maintenance of the connective tissue structure [Petersen and Douglas, ], has been linked to both autosomal dominant and autosomal recessive EDS [Burch et al, ; Schalkwijk et al, ; Zweers et al, , ; Voermans et al, ]. Notably, the locus containing TNXB has been also associated with schizophrenia [Wei and Hemmings, ; Tochigi et al, ; Ripke et al, ], while mice lacking the gene for tenascin‐XB show increased anxiety [Kawakami and Matsumoto, ].…”

Multiple Roles of Tenascins in Homeostasis and Pathophysiology of Aorta

“…Petersen and Douglas 123 ) hypothesized that a deficiency in or haploinsufficiency of TNX reduced risk factors for adverse cardiovascular events by the laxity of arterial stiffness. However, this hypothesis does not appear to be supported by existing data.…”