Question

What genetic defects result in the disorder xeroderma pigmentosum \((\mathrm{XP})\) in humans? How do these defects create the phenotypes associated with the disorder?

Short answer

Answer: Xeroderma pigmentosum (XP) is a rare genetic disorder characterized by the body's impaired ability to repair DNA damage caused by ultraviolet (UV) radiation. This leads to increased sensitivity to sunlight, resulting in skin abnormalities and an increased risk of skin cancer. The disorder is mainly caused by mutations in genes related to the nucleotide excision repair (NER) pathway, which is responsible for detecting and repairing DNA damage caused by UV radiation. The genetic defects in XP disrupt the NER pathway, leading to the accumulation of DNA damage in skin cells and the associated phenotypes, such as sun sensitivity, sunburns, and increased risk of skin cancers. Additionally, some forms of XP can lead to neurological abnormalities due to the accumulation of DNA damage in neuronal cells.

Step-by-step solution

Xeroderma Pigmentosum (XP) Overview

Xeroderma pigmentosum is a rare genetic disorder in which the body's ability to repair DNA damage caused by ultraviolet (UV) radiation is impaired. This results in a heightened sensitivity to sunlight, leading to skin abnormalities such as sunburn, freckling, premature aging, and an increased risk of skin cancer. Additionally, some individuals with XP may have neurological abnormalities.

Genetic Defects in XP

XP is mainly caused by mutations in genes related to the nucleotide excision repair (NER) pathway. The NER pathway is responsible for detecting and repairing DNA damage caused by UV radiation. There are at least eight complementation groups (XP-A to XP-G and a variant form) that have been identified, each resulting from mutations in a different gene. These genes are: XPA, ERCC3 (XPB), XPC, ERCC2 (XPD), DDB2 (XPE), ERCC4 (XPF), ERCC5 (XPG), and POLH (XPV). All of these genes play essential roles in the NER pathway and DNA damage recognition.

Phenotypes Associated with XP

The genetic defects in XP disrupt the NER pathway, leading to the phenotypes associated with the disorder. The impaired NER pathway cannot effectively remove DNA damage caused by UV radiation, leading to the accumulation of DNA damage in skin cells. This results in increased sun sensitivity, sunburns, freckling, and pigmentation changes, as well as a significantly heightened risk of developing skin cancers such as basal cell carcinoma, squamous cell carcinoma, and melanoma. Furthermore, some forms of XP (specifically those caused by mutations in the XPA, XPD, or XPG genes) can lead to neurological abnormalities. The NER pathway is also crucial for the proper functioning and maintenance of neurons. Disruption of the NER pathway can lead to the accumulation of DNA damage in neuronal cells, which can result in progressive neurodegenerative diseases, intellectual disability, and other neurological issues.