Xeroderma pigmentosum (XP), an uncommon autosomal recessive disorder, is caused by mutations in eight different genes (XPA through G and XPV). It results in changes of pigment in the skin and an alarming rate of incidence of skin cancers (Lehmann, McGibbon, & Stefanini, 2011). In fact, individuals suffering from this disease have more than a 1,000 chance of acquiring cancer if they don't follow their physician's recommendations. Neurological alterations may also be experienced by a selective few. The disease is more prevalent in certain areas such as Japan, where about 1 million people carry an XPA founder mutation (Rouanet et al., 2013; Lehmann et al., 2011).
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It is the XPA protein's job to make sure that all of the proteins involved are where they are supposed to be (Cleaver, Lam & Revet, 2009). The damaged region is then cut out by XPF and XPG. The gap that is left is filled by undamaged DNA. Mutations in any of these essential proteins have proven to be detrimental and lead to XP because of how the pathway is coordinated (DiGiovanna & Kramer, 2012).
Individuals with the XP-V subtype have a mutation in the HPV gene, which is also called POLH. Mutations in XPV are not associated with NER. Instead, they are closely related to DNA polymerase η (Ortega-Recalde et al., 2013). POLH is responsible for encoding DNA polymerase η, a specialized polymerase that is able to replicate DNA damaged by UV exposure. A mutation in XPV decreases DNA synthesis of damaged sections of DNA by UV light (Lehmann et al., 2011). Ortega-Recalde et al. (2013) found a homozygous nonsense mutation in XPV that results in the disease.
XP-A to XP-G are seven different groups of genetic complementation that correspond to the mutations in XPA, XPB (also known as ERCC3), XPC, XPD (also known as ERCC2), XPF (also known as ERCC4), and XPG (also known as ERCC5). The eighth one is the subtype XPV (Cleaver et al., 2009). About 50% of individuals with XP have XPC mutations, making it the most common cause of this disorder (Rouanet et al., 2013).There are a great variety of symptoms that depend on the type of mutation an individual has. Skin sensitivity, freckles, and early onset of tumors in areas where the skin was exposed to the sun characterize all forms of XP. Individuals in approximately 60% of cases display strong sensitivity to sunlight in the first weeks after they are born. In other cases, signs of XP don't surface until around two years of age and may not be diagnosed properly as XP at first. Freckle-like pigmentations called lentigines may appear in regions of the skin that have been exposed to sunlight (Lehmann et al., 2011).
In about 25% of individuals with XP, neurological degeneration is a problem that can begin between the age of two and middle age (Lehmann et al., 2011). The cause of this is not well known but has been associated with oxidative processes that involve the mitochondria that create free radicals (DiGiovanna et al., 2012). High frequency hearing loss and the loss of deep tendon reflexes are the first signs. Intellectual deficiency can later result and may lead to slurred speech, difficulty in swallowing, among other things (DiGiovanna & Kraemer, 2013). Patients with XP may also have problems with abnormalities of the eyes. The structures of the eye that are commonly affected are those that are mostly exposed to UV light. These may include the eyelids, cornea, and the conjunctiva. Continuous exposure to UV light can result in keratitis and may even lead to neoplasms (Lehmann et al., 2011).
Skin cancer in XP patients residing in the United States typically develops in the first ten years of life. More...