What is the specific mutation?
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Xeroderma pigmentosum is a rare autosomal recessive genetic defect. The mutation occurs in nucleotide excision repair (NER) by affecting the ATP dependent DNA helicase XP. The ERRC2 protein known as XPD in NER is also damaged. Essentially, the mutation causes NER to malfunction and no longer recognize and replace damaged DNA. In turn, this causes unrepaired DNA damage which builds up over time, specifically from UV radiation, and the development of cancerous tumors (U.S. National Library of Medicine, 2017).
What are the symptoms of the disease?
The primary symptom of the disease is ultra-sensitivity to ultraviolet radiation, particularly from the sun and fluorescent light bulbs. The most severe impact can be seen on the skin. Even a brief skin exposure to the sun results in severe burns which can take a prolonged time to heal. Also, this results in the onset of lentigo or freckling of the skin before the age of two.
This is a sign of unrepaired ultraviolet damage on the skin and can be accompanied by xerosis, poikiloderma, telangiectasia, and skin atrophy. Ocular effects include photophobia and conjunctivitis inflamed by sunlight. There is a 25% chance of developing progressive neurodegeneration, muscle weakness, and cognitive impairment. Less than 40% of people with the disorder survive past the age of 20 and have an extremely high chance of acquiring non-melanoma skin cancer and some prominence of internal types of cancer (National Organization for Rare Disorders, 2017).
How was the relationship between the mutation and the disease discovered?
The first records of the disease originated in Vienna in 1874, describing the physical symptoms of xeroderma, which lead to the development of tumors. Through the late 1800s and early 20th century, the disease was identified and classified with no known causes other than exposure to sunlight. In 1968, a report by Cleaver outlined the DNA repair deficiency in Xeroderma pigmentosum cells. DNA photoproducts were not efficiently removed. In 1972, cell fusion studies proved the disease’s heterogeneity. It was also shown that there were different complementation groups because the cells taken from different patients were able to fix each other’s DNA. Finally, after two decades of research, the set of genes responsible for the various complementation groups A through G were discovered in the 1990s (DiGiovanna & Kraemer, 2012).
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How does this mutation impact DNA replication and repair and how is this different from normal DNA replication?
Xeroderma pigmentosum does not specifically impact DNA replication. However, it is an autosomal recessive genetic disorder, therefore in order for the disease to be active, the person must receive two copies of the same gene from each parent. Genes affected are ranged from XP-A to XP-G located on chromosomes 2,3,6,9,13,16, and 19. In a normal expression of the genes, the created proteins result in effective DNA damage recognition and repair by replacing the incorrect sequence gaps.
In Xeroderma pigmentosum the process of nucleotide excision repair is malfunctioning. As abnormalities form in the DNA, the cells begin to die or become cancerous. In addition, a variant of the disease directly impacts the DNA polymerase POLH gene which protects cells from UV-induced damage (U.S. National Library of Medicine, 2017).
How does this mutation impact transcription and translation and how is this different from normal transcription and translation?
The XPD and XPB proteins play a role not only in DNA repair but also in basal transcription TFIIH. A varying mutation can result in an active Xeroderma pigmentosum. Alternatively, if it begins to affect transcription, it leads to Trichothiodystrophy, also a genetic disease. TFIHH is required in all transcription of the RNA polymerase II, therefore if XPD and XPB are affected, it results in abnormalities in transcription. In addition, XP phenotypes destroy the repair function of TFIIH which may influence helicase activity (Menck & Munford, 2014).
How does this problem in DNA replication lead to one symptom of the disease?
The most prominent symptom of this illness is sensitivity to ultraviolet radiation resulting in skin damage and eventually cancers. The cells affected by Xeroderma pigmentosum are unable to repair the DNA mutations and damage that occurs after exposure. The defects in the molecular composition of these cells due to the affected genes are the cause of the elevated rate of mutations in the skin exposed to ultraviolet. As mutations occur, they result in changes in pigmentation and cancer development in the skin. The molecular deficiencies are connected to oxidative damage and DNA lesions which are also unrepairable. Xeroderma pigmentosum provides a unique medical combination of genetic and environmental factors leading to cancer (National Organization for Rare Disorders, 2017).
Give two examples of how genetic engineering technology could be used to learn more about, detect earlier, or treat this disease? Be sure to include a description of what genetic engineering is.
Genetic engineering is the process of modifying the DNA composition of an organism so that the genes can result in a certain physiological effect. This can include traits, including resistance or cure to certain diseases. In modern medicine, the concept of using a genetic modification for treatment purposes is commonly expressed as gene therapy (Doudna, J., 2015).
The demethylating treatment which consists of using genetically engineered nucleases insensitive to CpG methylation leads to the successful XP protein re-expression and recovery of NER functions (Dupuy et al., 2013). Another similar example shows that a specifically designed transcription activator-like effector nuclease corrects a 2bp deletion which results in sustainable DNA repair. Even though the gene is corrected, it remains in the same position in the human genome with the “regulation of its physiological promoter, ” and that is encouraging to the development of gene therapy for Xeroderma pigmentosum patients (Dupuy & Sarasin, 2015).
DiGiovanna, J., & Kraemer, K. (2012). Shining a light on Xeroderma pigmentosum. Journal of Investigative Dermatology, 132(302), pp. 785-796. doi: 10.1038/jid.2011.426
Dupuy, A. et al. (2013). Targeted gene therapy of Xeroderma pigmentosum cells using meganuclease and TALEN™. PLoS One, 8(11).
Dupuy, A., & Sarasin, A. (2015). DNA damage and gene therapy of Xeroderma pigmentosum, a human DNA repair-deficient disease. Mutuation Research, 776, pp. 2-8. doi: 10.1016/j.mrfmmm.2014.08.007
Doudna, J. (2015). Genomic engineering and the future of medicine. Journal of the American Medical Association, 313(8), pp. 791-792. doi: 10.1001/jama.2015.287
Menck, C., & Munford, V. (2014). DNA repair diseases: what do they tell us about cancer and aging? Genetics and Molecular Biology, 37(1).
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National Organization for Rare Disorders. (2017). Xeroderma pigmentosum.
U.S. National Library of Medicine. (2017). Xeroderma pigmentosum.