Xeroderma Pigmentosum
Written By: Sonal Gupta
Xeroderma Pigmentosum (XP) is an extremely rare genetic disorder in which UV light, usually from the sun, damages DNA and causes undesirable effects on the skin in the form of third-degree burns and freckles. Damaged DNA causes abnormalities with unexplainable neurological disorders and increases the chances of getting cancer — especially skin cancer. This genetic disorder is inherited autosomal recessively, in which proteins are mutated, causing the damage of DNA or the lack of ability to fix or sense damaged DNA. There are eight different ways to inherit XP, and an individual can inherit it in one or more ways.
One way to obtain XP is through a mutation in the XPA gene, which directly affects the XPA protein by changing its structure and function. Because of its changed state, the protein is unable to carry out its function of attaching DNA repair proteins to damaged DNA sites. Without the fixation of the damaged DNA, it will be expressed in the form of the patient expressing symptoms of XP.
Another way to acquire this disease is through a mutation in the XPB gene, which prevents the XPB protein from unwinding damaged DNA so that it can be repaired. This specific mutation also leads to Cockayne Syndrome (CS), a neurological disorder in which patients are unable to grow and gain weight, have an abnormally small head, have a short stature, and contain signs of delayed development.
The most common way of attaining XP is by a mutation in the XPC protein because it prevents the NER process from occurring. The NER process is a process where damaged DNA by UV light is recognized and fixed.
A mutation in the XPD gene prevents the XPD protein from working with the XPB protein to unwind damaged DNA so it can be replaced later on. This is especially critical because it can lead to XP, CS, XPCS (XP in combination with CS), as well as a disease known as trichothiodystrophy (TTD). TTD is a rare disease causing brittle hair and nails, intellectual impairment, photosensitivity, and lack of fertility.
One can also obtain XP is by a mutation through the XPE gene that prevents the XPE protein from working with a ligase complex for DNA repairment.
XP can also be acquired by a mutation in the XPF gene, which will prevent the XPF protein from working as an endonuclease, an enzyme that separates nucleotides. Without proper function of the XPF protein, damaged DNA will continue to remain on the 5-prime side of DNA.
A mutated XPG protein will have the same effects as the mutation for the XPF protein, but the damaged DNA will remain on the 3-prime side of DNA. However, this mutation will lead to a neurological disease known as Cerebro-oculo-facio-skeletal syndrome (COFS). Symptoms for COFSinclude abnormally shaped body features in the face, chest, and hands, no control over eye movement, and severe intellectual impairments.
Lastly, if a patient contains the XPV gene, this gene will code for a special DNA polymerase that will ensure the replication of damaged DNA during cell division, in order to guarantee that this genetic disorder is passed down from one cell to the next.
There are no treatments for XP and there is very little research available because XP has less than 1000 documented cases. Ways to prevent getting the disorder include avoiding the sun, protective clothing, and sunscreen. Sometimes, XP will create keratosis, or a cancerous skin growth, which can be helped by cryotherapy and fluorouracil. Through cryotherapy, cold temperatures will be applied, and through cryosurgery, cancerous or damaged skin will be removed. Fluorouracil, on the other hand, is most commonly used as an injection to treat cancers but can be converted into an ointment to help patients with XP.
Sources
Petruseva, I O, et al. “Molecular Mechanism of Global Genome Nucleotide Excision Repair.” Acta Naturae, A.I. Gordeyev, Jan. 2014, www.ncbi.nlm.nih.gov/pmc/articles/PMC3999463/#:~:text=Nucleotide%20excision%20repair%20(NER)%20is,damage%20and%20bulky%20chemical%20adducts.
“Trichothiodystrophy.” Wikipedia, Wikimedia Foundation, 27 June 2020, https://en.wikipedia.org/wiki/Trichothiodystrophy#:~:text=5%20See%20also-,Presentation,initials%20of%20the%20words%20involved.
