The name ‘tree man illness’ is a reference to the yellow-brown growths, as seen in Figure 1, which resemble tree bark that develop as a symptom of Epidermodysplasia verruciformis (EV) (Swati, et al., 2017). EV is a disease that results from a mutation on the EVER genes (McDermott, et al., 2009). Mutations that occur in DNA have advantages and disadvantages. They may result in new encoded proteins that can be beneficial to the organism for survival, and these mutations are crucial for evolution. However, sometimes mutations result in genetic disorders and cancers, and these are considered harmful mutations (Loewe and Hill, 2010). An example of a harmful mutation is mutation in the EVER genes, resulting in EV (McDermott, et al., 2009). EV is a genetic, heterogenous disease with evidence of autosomal recessive and X-linked inheritance patterns (McDermott, et al., 2009). It is a very rare disease in which the patient becomes highly susceptible to Human Papillomavirus (HPV) infections (McDermott, et al., 2009). By 2017, there were only 500 cases of EV reported in literature (Myers, Kwan and Fillman, 2021). HPV is a DNA virus, which promotes cellular proliferation and infects the mucosal and cutaneous epithelia (White, 2019). HPV is responsible for many of the symptoms associated with EV, such as lesions and warts (Kalińska-Bienias, Kowalewski and Majewski, 2016). Moreover, lesions develop into cancers in 30–60% of EV patients (Swati et al., 2017).
EV is a result of a homozygous nonsense mutation in the EVER1 and EVER2 genes (Lodish, et al., 2000). The EVER genes are located on the 17q25 chromosome (Kalińska-Bienias, Kowalewski and Majewski, 2016). It has been suggested that the EVER proteins which are encoded by the EVER genes may be responsible for regulating cellular zinc balance (Kalińska-Bienias, Kowalewski and Majewski, 2016). Studies have shown that mutations in EVER genes were only found in 75% of EV patients. There were no mutations found in 25% of affected patients, which could indicate genetic heterogeneity of EV. Thus, there may be additional genes responsible for the development of this disease (McDermott, et al., 2009).
EVER proteins interact with zinc transporters to form a ZnT-1/EVER complex (Sharma, et al., 2014). This complex is responsible for the transfer of zinc from the cytoplasm to the endoplasmic reticulum. The mutations in the EVER genes result in the instability of the ZnT-1/EVER complex, interrupting its function (Sharma, et al., 2014). This leads to a flux of zinc in the reverse direction, towards the cytoplasm and nucleus (Sharma, et al., 2014). It has been hypothesized that the regulation of zinc composes a protective barrier, which limits access to zinc ions that are available for viral replications (Kalińska-Bienias, Kowalewski and Majewski, 2016). Mutations in the EVER genes result in impairment of the ZnT-1/EVER complex, which leads to increased zinc levels, allowing for EV replication and sensitivity to HPV infections (Kalińska-Bienias, Kowalewski and Majewski, 2016).
EV is a lifelong disease with no cure; therefore, patients continue to suffer from its associated symptoms (Swati, et al., 2017). There is very little known about EV and mutations on the EVER genes, and therefore, there are no effective treatment options available. Though it is a rare disease, due to the severity of EV and its associated symptoms, further research on EVER genes and mutations is crucial. This would provide us with a better understanding of the biological mechanisms involved in EV, how its symptoms occur, and how to best treat or cure the disease.
Works Cited
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Kalińska-Bienias, A., Kowalewski, C. and Majewski, S., 2016. The EVER genes – the genetic etiology of carcinogenesis in epidermodysplasia verruciformis and a possible role in non-epidermodysplasia verruciformis patients. Advances in Dermatology and Allergology, 33(2), pp.75–80. https://doi.org/10.5114/ada.2016.59145.
Lodish, H., Berk, A., Zipursky, S.L., Matsudaira, P., Baltimore, D. and Darnell, J., 2000. Mutations: Types and Causes. Molecular Cell Biology. 4th edition. [online] Available at: <https://www.ncbi.nlm.nih.gov/books/NBK21578/> [Accessed 25 Mar. 2021].
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Myers, D.J., Kwan, E. and Fillman, E.P., 2021. Epidermodysplasia Verruciformis. In: StatPearls. [online] Treasure Island (FL): StatPearls Publishing. Available at: <http://www.ncbi.nlm.nih.gov/books/NBK534198/> [Accessed 1 Apr. 2021].
Sharma, S., Barman, K.D., Sarkar, R., Manjhi, M. and Garg, V.K., 2014. Efficacy of oral zinc therapy in epidermodysplasia verruciformis with squamous cell carcinoma. Indian Dermatology Online Journal, 5(1), pp.55–58. https://doi.org/10.4103/2229-5178.126034.
Swati, S., Sowjanya, K., Lakuma, R., Sunaina, S.A., Srividya, G. and Rohitha, V., 2017. Epidermodysplasia verruciformis-A genetic disorder. Systematic Reviews in Pharmacy, 8(1), pp.71–75. https://doi.org/10.5530/srp.2017.1.12.
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