TNXB Gene In Medicine

INTRODUCTION

The TNXB gene is cytogenically located at the histocompatibility complex III on chromosome 6 in the human genome (6p21.33- p21.32). The gene has a unique structure as it overlaps with other genes by embedding its 5’ and 3’ end in CREBL1 and CYP21 genes respectively. It is the gene that encodes for Tenascin X which can also be called Texabrachian - like protein. This protein is a member of the tenascin family which are extracellular matrix glycoproteins.

FUNCTION OF TENASCIN-X PROTEIN

In normal conditions, Tenascin-X is a major component of collagen; whose primary function is to give structure and strength to bones, joints, muscles, connective tissues, skin, and organs throughout the body. Mutation of the TNXB gene impair the production of Tenascin -X which negatively affects the quality of collagen produced by the cells (collagen in ligaments and tendons becomes more flexible). This gives rise to a rare medical condition called Hypermobile Ehlers Danlos Syndrome (hEDS).

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TYPES OF EHLERS DANLOS SYNDROME (EDS)

Several studies have been done concerning the disease and it was discovered that there are about thirteen different types of Ehler Danlos Syndrome (EDS) Diseases which are caused by mutation to other genes. However, hEDS happens to be the most common of them all. According to the Ehler-Danlos Society, the other types of EDS include, Classical EDS, Vascular EDS, Kyphoscoliosis, Arthrochalasia, Dermatosparaxis, Tenascin – X deficient type, Cardiac – Valvular EDS, Brittle Cornea Syndrome, Spondylodysplastic EDS, Musculocontractural EDS, Myopathic EDS, and lastly Periodontal EDS. EDS can have different level of severity in patients. For some, it can be relatively mild, while for others their symptoms can be disabling and very life threatening.

SYMPTOMS OF HYPERMOBILE EHLER DANLOS SYNDROME

A major symptom of the disease is an unusual large range of motion of joints, hyperextensibility of the skin and tissue fragility (easy bruising, atrophic scars and superficial injury) Bristow and Mao 2001. Some other symptoms include; loose, unstable joints that dislocate easily, joint pain and clicking joints, extreme tiredness (fatigue), digestive problems (heart burn and constipation), Dizziness and an increase heart rate after standing up, problems with internal organs (mitral valve prolapse/organ prolapse), and problems with bladder control (stress incontinence). Etc. In infants and children, weak muscle tone (hypotonia) is often noticed which can delay motor skills development (Crawling, sitting, walking and standing)

Figure 1. outcome of histopathological examination of Patients Skin with Tenascin-X Deficiency. Panels I and J show the skin hyperextensibility and joint hypermobility typical of patients with the hEDS. Panels A - D show normal skin, and Panels E - J show the skin and joints of a patient with hypermobile Ehlers–Danlos syndrome. Hematoxylin and eosin staining showed a less dense eosinophilic staining in tenascin-X–deficient skin (Panel E) than in normal skin (Panel A) of the papillary dermis. Immunostaining with antiserum against recombinant tenascin-X showed substantial staining of the papillary dermis and moderate staining of the deeper dermal layers in normal skin (Panel B), but no staining for tenascin-X was seen in the extracellular matrix of tenascin-X–deficient skin (Panel F). Staining for tenascin-C (Panels C and G) and type V collagen (Panels F and H) was alike in control and tenascin-X–deficient skin. Schalkwijk et al 2001

STUDIES LINKING THE CAUSE OF hEDS TO TNXB GENE (TENASCIN-X protein)

STUDY ONE

Several studies have been done to link the hEDS to Tenascin-X. An example of such studies is that of Bristow et al 2005, where members of patients’ (with hEDS) families were examined, and twenty heterozygous affected members were found to have TNX levels of around 50% of normal individuals. Nine (9) of the twenty (20) had isolated joint hypermobility and were all women. The males were not affected even though they were also heterozygous for the disease.

STUDY TWO

A second study was done and TNX level was evaluated by ELISA in 80 unrelated women with hEDS. It was discovered that 6 of the patients had TNX levels with more than 2.5 standard deviation below the mean which was unusual. These 6 women were also known to have frequent joint subluxations and chronic arthralgias. Using allele – specific PCR and sequencing of coding regions, it was observed that two inactivating mutation occurred in the 6 individuals which explained the unusual low level of TNX. To conclude the study, it was stated by Bristow et al 2005, that “50% reduction in the TNX was likely responsible for the hEDS.” However, the question of why only women with TNX heterozygote genes were consistently affected remained unanswered.

INHERITANCE OF hEDS

The inheritance pattern of EDS varies by subtype. In the case of the hypermobile EDS, an autosomal dominant pattern of inheritance is observed. This means a person only needs to have a mutation in only one copy of the disease-causing gene in each cell. In some cases, a person with these forms of EDS inherits the mutation from an affected parent. Other cases may result from new mutations in the gene and these cases occur in people with no family history of EDS. Each child of a person with autosomal dominant EDS has a 50% chance of inheriting the mutation.

PERSONAL ENCOUNTER CARING FOR PATIENT WITH hEDS.

I once had the opportunity to work with a patient who has hEDS and it’s so sad to see the day to day struggle of trying to avoid dislocations and subluxations at almost every joint of the body due to excessive flexibility and range of motion. Patients can be restricted to use multiple braces a lot of the time to secure and support several joints of the body during the hours of the day and are only taken off when it’s time to sleep. The activities of daily living become almost impossible without assistance. In some cases, patient is restricted to moving around in a wheel chair.

HOW hEDS RELATE TO PODIATRY

There are about 26 bones, 30 small joints, more than 100 muscles, ligaments and tendons that must work together for the proper functioning of the foot. In a patient with hEDS, there is low production of tenascin–X which interpret to weak joints, weak ligaments and weak tendons in the lower extremities which compromises the foot and ankle. This leaves joints of the ankle and the feet incapable to withstand stress (when walking or running) and support the weight of the body (when standing) freely without any external support.

PODIATRY RELATED MEDICAL CONDITIONS PECULIAR WITH hEDS PATIENTS

There are some foot related medical conditions observed in patients with hEDS. However, there is little science to support why some of these conditions exist in hEDS patients. Some of these diseases/conditions are, low-arched foot/flat foot, high arched foot, skin callus, clawing of toes, lower limb pain, lower limb disability, Plantar Fasciitis, Bunion, Verruca Pedis, Tinea Pedis, Delayed Healing etc. It has also been observed that hEDS patient tends to have a lot of feet and ankle issues than a person without the disease.

HOW TNXB GENE IS RELATED TO THE OPG GENE (pod member’s gene)

The OPG (osteoprotegerin) gene encodes for OPG receptor protein which plays a vital role in bone metabolism. This OPG protein inhibits osteoclast differentiation and activity by acting as a decoy receptor that RANKL (Receptor activator of nuclear factor kappa-b ligand) binds to. Bruhn- Olszewska et al 2017. When a malfunction of this complex bone metabolism occurs, Charcot Arthropathy/ Charcot Neuroosteoathropathy seems to be the disease seen in patients. The disease has been discovered to arise due to single nucleotide polymorphism (SNPs) in the OPG gene. Charcot Arthropathy is also seen in serious cases of diabetes mellitus. Bruhn- Olszewska et al 2017.

Relating the diseases (hEDS and Charcot Arthropathy) caused by both respective genes (TNXB gene and OPG gene), it can easily be said that these diseases can be of great concern in the field of podiatry. When critically examined, the two diseases share similarities as they tend to affect the strength of the bones and joints in the body, most especially in the lower extremity, which could lead to life threatening medical complications if not well taken care of.

CONCLUSION

There are no treatments for hEDS yet, however the disease can be managed in different ways. Firstly, patients need to be educated about their condition which will help a lot with self-management. It is more likely that patients will take better decisions when it comes to taking care of themselves when they understand implications of doing otherwise. Patients can self-manage their condition by wearing comfortable shoes. Silipos/hosiery can also be used to protect deformed joint and cover skin tissue at risk of breakdown. Above all, washing the feet and wearing of clean socks would go along way in improving the hygiene of the feet.

A podiatrist would also recomend to patients to get orthoses, do some stretching & strengthening exercises, use braces and in some case, get surgery.

REFERENCES

1. Bristow, James, William Carey, David Egging, and Joost Schalkwijk. “Tenascin-X, Collagen, Elastin, and the Ehlers-Danlos Syndrome.” American Journal of Medical Genetics. Part C, Seminars in Medical Genetics 139C, no. 1 (November 15, 2005): 24–30. https://doi.org/10.1002/ajmg.c.30071.
2. Bruhn-Olszewska, Bożena, Anna Korzon-Burakowska, Grzegorz Węgrzyn, and Joanna Jakóbkiewicz-Banecka. “Prevalence of Polymorphisms in OPG , RANKL and RANK as Potential Markers for Charcot Arthropathy Development.” Scientific Reports 7, no. 1 (March 29, 2017): 1–9. https://doi.org/10.1038/s41598-017-00563-4.
3. “Footcare in Hypermobile Ehlers-Danlos Syndrome – The Ehlers-Danlos Support UK.” Accessed August 22, 2019. https://www.ehlers-danlos.org/information/footcare-in-hypermobile-ehlers-danlos-syndrome/.
4. Mao, Jau-Ren, and James Bristow. “The Ehlers-Danlos Syndrome: On beyond Collagens.” The Journal of Clinical Investigation 107, no. 9 (May 1, 2001): 1063–69. https://doi.org/10.1172/JCI12881.
5. Schalkwijk, Joost, Manon C. Zweers, Peter M. Steijlen, Willow B. Dean, Glen Taylor, Ivonne M. van Vlijmen, Brigitte van Haren, Walter L. Miller, and James Bristow. “A Recessive Form of the Ehlers–Danlos Syndrome Caused by Tenascin-X Deficiency.” Research-article. http://dx.doi.org/10.1056/NEJMoa002939, August 20, 2009. https://doi.org/10.1056/NEJMoa002939.
6. The Ehlers Danlos Society. “The Types of EDS.” Accessed November 22, 2019. https://www.ehlers-danlos.com/eds-types/.
7. Reference, Genetics Home. “Ehlers-Danlos Syndrome.” Genetics Home Reference. Accessed November 20, 2019. https://ghr.nlm.nih.gov/condition/ehlers-danlos-syndrome.