Tenascin-X, Collagen, and Ehlers-Danlos Syndrome

Tenascin-X, collagen, and Ehlers-Danlos syndrome: Tenascin-X gene defects can protect against adverse cardiovascular events | free full text PMC | Med Hypotheses. 2013

Long thought to be two separate syndromes, Ehlers-Danlos syndrome hypermobility type (EDS-HT) and benign joint hypermobility syndrome (BJHS) appear to represent the same syndrome, with virtually identical clinical manifestations

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

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

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

Introduction

Ehlers-Danlos syndrome (EDS) is the most common form of hereditary connective tissue diseases (HCTD).

EDS now falls into six types, with three types receiving the most attention in both research and clinical practice: classical type (formerly types I and II), hypermobility type (formerly type III) and vascular (formerly type IV)

While the classical and vascular types are relatively rare, have dramatic and distinctive clinical manifestations, and specific genetic loci, the hypermobility type is distinct from all other types in its frequency range of clinical manifestations, and, to date, a lack of a genetic locus

However, researchers over the past decade have discovered a genetic locus for what some believe to be a recessive form of EDS-HT, in contrast to the usual autosomal dominant pattern of inheritance for EDS-HT.

In this subtype of EDS-HT, individuals may have either haploinsufficiency or a complete deficiency of TNXB, the gene responsible for tenascin-X. Tenascin-X regulates the structure and stability of elastic fibers within the ECM (7), and the TNXB genetic locus may account for both the range of symptom severity notable in EDS-HT and also in BJHS

the role of tenascin-X in the composition of the extracellular matrix (ECM) suggests the reason for the range of clinical manifestations of EDS-HT, from sinus and gastric dysmotility to cardiac arrhythmias and orthostatic hypotension

Hypothesis

Our hypothesis, therefore, is two-fold, as well as both novel and unexpected.

First, TNXB haploinsufficiency or deficiency causes EDS-HT and BJHS.

Second, rather than placing patients at greater risk of adverse cardiovascular events, joint hypermobility syndrome and deficient or even insufficient levels of TNX may protect patients against heart attack and stroke.

EDS-HT and BJHS may be the same phenomenon

In terms of its clinical manifestations, researchers and medical practitioners generally consider EDS-HT to be the least severe type of EDS.

However, significant complications can include subluxations and dislocations, which occur spontaneously or with only minimal trauma.

Other complications include gastroparesis, hiatal hernia, and pan-GI dysmotility, as well as orthostatic hypotension, positional orthostatic tachycardia, and orthostatic intolerance

Notably, all these clinical manifestations of EDS-HT have in common laxity or hypotonic tissues, consistent with some of the earliest studies of epidermis tissue samples from EDS-HT patients that found the epidermis to be both thicker and more extensible in EDS-HT patients, which pioneering researchers attributed to an abnormal disposition of collagen fibrils

The similarities between clinical manifestations of BJHS and EDS-HT led early researchers to class BJHS as a form of EDS-HT

Providing a genetic locus and basis for the spectrum ofseverity of clinical manifestations of EDS-HT

Two other major puzzles have challenged researchers examining EDS-HT: the spectrum of severity of its clinical manifestations and its lack of a genetic locus, both of which differentiated this type of EDS from the other types

Moreover, clinical manifestations for all other types of EDS were both consistent and observable in all patients exhibiting defects to the specific genes for each type of EDS, leading researchers to conclude that all forms of EDS resulted from a disorder of fibrillar collagen metabolism

One of the earliest studies of TNX deficiency linked this deficiency with the skin and joint hyperextensibility and connective tissue findings typical of EDS-HT

Tenascin-X and the ECM

While not as well studied as the genes responsible for the production and organization of collagens, the TNXB gene provides instructions for the creation of the protein tenascin-X.

Found in the ECM, tenascin-X appears to play a central role in organizing and maintaining the structure of tissue supporting muscles, joints, organs, and skin, specifically by determining the formation of collagen fibrils in the ECM. Tenascin-X may also regulate the structure and stability of elastic fibers within the ECM

haploinsufficiency of the TNXB gene prevent one copy of the gene from creating functional protein, thus reducing the total levels of tenascin-X in the body. These reduced levels disrupt both the organization of collagen and of elastic fibers throughout the body

researchers hypothesized that TNX-deficiency is responsible for the clinical manifestations of EDS-HT—not by interfering with collagen synthesis itself but by poorly regulating the organization of fibriis in the ECM via dermal fibroblasts. As dermal fibroblasts regulate the deposition of collagen, the impact of TNX haploinsufficiency or deficiency can have profound effects on the ECM

The impact of the organization of collagen fibrils is far-reaching. In normal skin, fibrils align in tissue-specific patterns.

In skin, for example, bundles of fibrils orient in different directions to resist forces from multiple axes. In contrast, in TNX-deficient patients and in TNX-null mice, fibrils are less densely organized and not as well aligned to neighboring fibrils (6). This lowered density and disorganization of fibrils could account for some of the most common clinical manifestations of hypermobility in both EDS-HT and BJHS populations: easy bruising, skin fragility, and joint laxity

Moreover, tenascin-X deficient humans also display dramatic differences to elastic fibers, a component of the ECM that provides resilience and elasticity to all connective tissues, complementing the collagen fibrils that provide cells with tensile strength

ultrastructural examination of the dermis also showed abnormalities in both microfibrillar and the elastin component of TNX-deficient patients diagnosed with EDS-HT

TNXB haploinsufficiency resulted in mild-to-moderate neuromuscular effects from EDS-HT, while a complete absence of TNX resulted in more severe neuromuscular symptoms, including muscle rupture, musculoskeletal pain, and, significanty, muscle hypotonia

Cardiovascular effects of joint hypermobility syndromes

Patients with joint hypermobility frequently display orthostatic hypotension, orthostatic intolerance, and postural orthostatic tachycardia

These clinical manifestations are consistent with the same laxity seen in tissue of the skin and joints. And, when coupled with the gastrointestinal dysmotility associated with joint hypermobility, this pooling of blood in the lower limbs suggests a straightforward cause

Blood pools in the lower limbs, providing poor vascular return, because the vessels themselves display the same laxity or hypotonic state as other tissues affected by joint hypermobility

Cardiovascular impacts of tenascin-X deficiency

Hypotonic blood vessels may protect against high blood pressure, prevent against abnormal pressure wave propagation, and accommodate accrued atherosclerotic plaques.

The elastic central arteries, such as the aorta, are required to be distensible and compliant to accommodate the recurrent pulsatile flow generated by the left ventricle

Patients with low levels of tenascin-X may not develop abnormal arterial stiffness that is common with aging and therefore may be protected from the impact of abnormally quick round-trip travel time of the pressure wave

In fact, blood pressure and pulse pressure have been shown to be lower with increased joint mobility and skin extensibility

Another advantage of low tenascin-X levels may relate to the ability of hypotonic blood vessels to accommodate accrued atherosclerosis.

In addition to preventing coronary luminal obstruction, tenascin-X deficiency may improve the rate of progression and stability of coronary atherosclerotic plaques by augmenting endothelial shear stress.

Conclusions

Clearly, tenascin-X haploinsufficiency and deficiency play a significant role in the broad range of clinical manifestations in patients with both EDS-HT and BJHS

Moreover, the roles played by tenascin-X haploinsufficiency or deficiency in reducing risk factors for adverse cardiovascular events merits more intensive investigation.

See Also:

• Titin-based stiffening of muscle fibers in EDS
• Dermal Ultrastructure in Low Beighton Score EDSH & BJHS
• Tx targeting cause of EDS being developed