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

Verified step by step guidance

1. Understand that xeroderma pigmentosum (XP) is caused by mutations in genes responsible for nucleotide excision repair (NER), a DNA repair pathway that fixes damage caused by ultraviolet (UV) light.
2. Identify the key genes involved in XP, such as XPA, XPB, XPC, XPD, XPE, XPF, and XPG, which encode proteins that recognize and excise UV-induced DNA lesions like thymine dimers.
3. Explain that defects in these genes impair the NER pathway, leading to an inability to properly repair UV-induced DNA damage, resulting in accumulation of mutations in skin cells.
4. Connect the accumulation of unrepaired DNA damage to the clinical phenotypes of XP, including extreme sensitivity to sunlight, freckling, pigmentation abnormalities, and a high predisposition to skin cancers.
5. Summarize that the genetic defects cause a failure in DNA repair mechanisms, which leads to cellular damage and the characteristic symptoms of XP due to increased mutagenesis and cell death in UV-exposed tissues.

Key Concepts

Nucleotide Excision Repair (NER) Pathway

NER is a DNA repair mechanism that removes bulky DNA lesions, such as those caused by UV light-induced thymine dimers. It involves recognition, excision, and resynthesis of damaged DNA segments. Defects in NER genes impair this process, leading to accumulation of DNA damage.

Genetic Mutations in XP-Related Genes

Xeroderma pigmentosum results from mutations in genes encoding proteins essential for NER, such as XPA, XPB, XPC, and others. These mutations reduce or eliminate repair activity, causing cells to be hypersensitive to UV-induced DNA damage.

Phenotypic Consequences of DNA Repair Defects

Failure to repair UV-induced DNA damage leads to mutations, genomic instability, and cell death. Clinically, this manifests as extreme UV sensitivity, skin abnormalities, pigmentation changes, and a high risk of skin cancers characteristic of XP patients.