Question

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

Short answer

Answer: Xeroderma pigmentosum (XP) is caused by genetic mutations in genes responsible for DNA repair, particularly those encoding for proteins of the nucleotide excision repair (NER) pathway. These defects compromise the NER pathway's function, leading to an accumulation of unrepaired DNA damage, particularly in regions exposed to ultraviolet (UV) light. The accumulation of DNA damage results in various phenotypes, including extreme sensitivity to sunlight, irregular skin pigmentation, skin aging, increased risk of skin cancer, neurological abnormalities, and eye problems.

Step-by-step solution

Identify the genetic defects responsible for xeroderma pigmentosum

Xeroderma pigmentosum (XP) is caused by genetic mutations in the genes responsible for DNA repair. In particular, the defects occur in genes encoding for proteins of the nucleotide excision repair (NER) pathway. There are eight complementation groups (XP-A to XP-G and XP-V), and each group represents a different affected gene in the pathway involved in repairing DNA damage caused by exposure to ultraviolet (UV) light.

Defects compromising the NER pathway

The primary function of the nucleotide excision repair pathway is to identify and remove damaged DNA segments, and then resynthesize the correct DNA sequence. When the genes encoding the proteins of the NER pathway are mutated, the pathway's function is compromised, which leads to an inability to repair DNA damage effectively.

Accumulation of DNA damage

Due to defects in the NER pathway, individuals with XP accumulate unrepaired DNA damage, particularly in regions of the DNA exposed to ultraviolet (UV) light. The unrepaired DNA damage results in an increased susceptibility to mutations, which can lead to various types of skin cancer and other skin abnormalities.

Phenotypes associated with xeroderma pigmentosum

The phenotypes associated with XP result from the accumulation of DNA damage, which then leads to the following manifestations: 1. Extreme sensitivity to sunlight (photosensitivity): Individuals with XP are highly susceptible to sunburn and skin damage because their cells cannot effectively repair UV-induced DNA damage. 2. Freckle-like skin pigmentation: Despite minimal sun exposure, individuals with XP often develop freckles and irregular pigmentation patterns due to the accumulation of DNA damage. 3. Skin aging (xerosis): The skin's inability to repair damage effectively causes premature skin aging and dryness. 4. An increased risk of developing skin cancer: Individuals with XP have a significantly higher risk of developing basal cell carcinoma, squamous cell carcinoma, and melanoma due to the inability to repair UV-induced DNA damage. 5. Neurological abnormalities: In some cases of XP, the accumulation of DNA damage can also affect the nervous system, leading to progressive neurological degeneration. 6. Eye abnormalities: Many XP patients experience eye problems, including inflammation, clouding of the cornea, and increased risk of ocular tumors. By understanding the genetic defects responsible for xeroderma pigmentosum and knowing the consequences of these defects, we can effectively explain the appearance of the phenotypes associated with the disorder.

Key concepts

DNA Repair Genes

When delving into the world of genetics, DNA repair genes have a crucial role in maintaining the integrity and stability of our genetic information. Each cell in our bodies is equipped with mechanisms to correct errors that occur in our DNA, arising from various factors, including environmental insults. These repair genes produce proteins that identify and fix any damage that has been caused to the DNA.

In the case of xeroderma pigmentosum (XP), the repair genes that are implicated belong to the nucleotide excision repair pathway. A defect in any of these genes means that the person with XP cannot repair UV-induced damage effectively, resulting in highly increased sensitivity to sunlight. Over time, the accumulation of DNA damage leads to noticeable and often severe consequences, like abnormal skin pigmentation and an elevated risk of skin cancer.

Nucleotide Excision Repair Pathway

The nucleotide excision repair pathway (NER) is a vital DNA repair mechanism that operates like a molecular surveillance system. It detects and removes a wide range of DNA lesions, which can include UV-induced photoproducts, such as thymine dimers.

Once damage is detected, the NER machinery excises the damaged DNA strand and uses the complementary strand as a template to synthesize a correct version. This process involves multiple steps and different proteins working together. Considering the importance of this pathway, it's not surprising that its compromise, as seen in XP, can lead to a host of serious health issues. The mutation of any of the proteins involved in the NER can prevent proper DNA repair, leading to an increase in mutation frequency which is a precursor to cancer development.

UV-Induced DNA Damage

Exposure to ultraviolet (UV) radiation is a common environmental stressor that can cause significant DNA damage. UV light can induce the formation of covalent bonds between adjacent pyrimidine bases in the DNA, creating photoproducts like cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) pyrimidone photoproducts (6-4 PPs). These products cause distortion in the DNA structure which can interfere with transcription and replication.

In healthy individuals, the nucleotide excision repair pathway swiftly manages these issues, but in XP patients, these lesions accumulate, leading to errors in the DNA that increase the potential for malignant transformations. Avoidance of UV exposure is incredibly important for individuals with XP to prevent exacerbating the effects of their condition.

Skin Cancer Risks

The risks of skin cancer are a major concern for individuals with xeroderma pigmentosum. Since they cannot effectively repair the cells damaged by UV radiation, these individuals have a heightened risk of developing several types of skin cancer, including basal cell carcinoma, squamous cell carcinoma, and melanoma.

This elevated risk underlines the need for XP patients to take very strict protective measures against UV exposure, which includes using high-SPF sunscreens, wearing protective clothing, and avoiding the sun during peak hours. Despite the limitation on sun exposure, regular dermatological check-ups are crucial for early detection of skin changes that could indicate the onset of skin cancer. The significance of understanding skin cancer risks in relation to UV-induced DNA damage in XP cannot be overstated, as this knowledge directly relates to the proactive measures required to manage the condition.