Question

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

Short answer

Answer: The genetic defects in xeroderma pigmentosum (XP) are mutations in one of the following genes: XPA, ERCC3 (XPB), XPC, ERCC2 (XPD), DDB2 (XPE), ERCC4 (XPF), ERCC5 (XPG), and POLH (XPV). These genes are essential for the nucleotide excision repair (NER) pathway, responsible for repairing DNA damage caused by UV radiation. These mutations result in reduced or impaired NER pathway function, leading to an insufficient ability to repair DNA damage. Consequently, the accumulation of unrepaired DNA damage in skin cells increases the risk of skin cancer, skin abnormalities, and potentially neurological issues.

Step-by-step solution

Introduce Xeroderma Pigmentosum (XP)

Xeroderma pigmentosum (XP) is a rare inherited genetic disorder that affects the body's ability to repair DNA damage, particularly damage caused by ultraviolet (UV) radiation from the sun. This results in an increased susceptibility to skin cancer and other skin abnormalities, as well as possible neurological problems.

Explain the cause of XP

XP is caused by mutations in several genes that are essential for the nucleotide excision repair (NER) pathway. The NER pathway is responsible for repairing DNA damage, including damage caused by UV radiation. There are at least eight different complementation groups (XP-A to XP-G and XP-V) of XP, which correspond to mutations in different genes involved in the NER pathway or DNA polymerase.

Detail specific genetic defects

The genetic defects that lead to XP include mutations in one of the following genes: XPA, ERCC3 (XPB), XPC, ERCC2 (XPD), DDB2 (XPE), ERCC4 (XPF), ERCC5 (XPG), and POLH (XPV). These genes are involved in various aspects of the NER pathway, from recognizing DNA damage to repairing the damaged DNA. Mutations in these genes result in reduced or impaired NER pathway function, leading to an insufficient ability to repair DNA damage.

Describe how defects create the phenotypes associated with XP

When the NER pathway is not functioning efficiently due to mutations in one of the genes mentioned above, DNA damage from UV radiation accumulates in the skin cells without being repaired. This accumulation of DNA damage leads to an increased risk of skin cancer, as well as other skin abnormalities such as freckling, pigmentation changes, and premature aging. In some cases, the impaired DNA repair may also affect the nervous system, leading to neurological problems like progressive hearing loss, difficulty walking, and cognitive decline.

Summarize the findings

In conclusion, xeroderma pigmentosum (XP) is a rare genetic disorder caused by mutations in genes involved in the nucleotide excision repair (NER) pathway. These mutations result in an impaired ability to repair DNA damage, specifically damage caused by UV radiation, leading to an increased risk of skin cancer, skin abnormalities, and potentially neurological issues.

Key concepts

Genetic Defects

Xeroderma pigmentosum (XP) is caused by specific genetic defects that affect crucial processes in the body. It is important to understand that these defects are inherited, meaning they are passed down from parents to their children. This genetic disorder is caused by mutations in genes that are part of the DNA repair process, specifically the nucleotide excision repair (NER) pathway.

The genes that can have mutations leading to XP include:

• XPA
• ERCC3 (XPB)
• XPC
• ERCC2 (XPD)
• DDB2 (XPE)
• ERCC4 (XPF)
• ERCC5 (XPG)
• POLH (XPV)

Each of these genes plays a vital role in identifying and correcting DNA damage. When they are mutated, their functioning is compromised, leading to an inability to effectively repair DNA damage. This kind of genetic defect is what primarily results in the symptoms observed in those with xeroderma pigmentosum.

Nucleotide Excision Repair Pathway

The nucleotide excision repair (NER) pathway is a critical system in our cells that is responsible for repairing DNA damage. It plays a significant role in fixing damage caused by harmful UV radiation from the sun.

In simple terms, the NER pathway scans the DNA to spot errors or damage. Once detected, the system removes a small section of the strand that contains the damage. After the faulty piece is taken away, the cell then uses the undamaged complementary strand to refabricate the section, ensuring the DNA is as good as new.

In people with xeroderma pigmentosum, mutations in the genes responsible for NER mean this repair process is faulty or inefficient. Without proper repair capabilities, DNA damage accumulates, leading to severe skin complications and other related issues.

DNA Damage

DNA damage occurs when the DNA structure undergoes physical changes due to environmental factors, such as UV radiation. This is a normal occurrence but usually gets resolved thanks to our body's sophisticated repair systems.

When UV rays penetrate the skin, they can cause damage such as thymine dimers, which are errors that disrupt the genetic code. In healthy individuals, systems like the NER pathway kick in to repair these errors and prevent any long-lasting harm.

For individuals with xeroderma pigmentosum, the accumulation of DNA damage can trigger multiple complications:

• Increased susceptibility to skin cancer
• Frequent sunburns and skin abnormalities
• Potential neurological complications in severe cases

Understanding DNA damage and its repair mechanisms is essential to understanding why disorders like XP have such profound impacts on individuals' health.