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.

Key concepts

Genetic Disorders

Genetic disorders are ailments that arise due to abnormalities in an individual's DNA. These disorders can occur if a single gene is mutated, if there are changes in chromosome structures, or if entire chromosome numbers are altered. In the case of Xeroderma Pigmentosum (XP), it is classified as a genetic disorder since it primarily results from mutations in genes responsible for repairing DNA damage. These mutations hinder the body’s natural ability to repair itself, particularly from ultraviolet-induced damage.

Understanding genetic disorders involves not just identifying the affected genes, but also recognizing the domino effect these abnormalities have on bodily functions. Genetic disorders can be inherited in different patterns, such as autosomal recessive or dominant, which can affect how the disorder is passed through families.

• Autosomal recessive: Both parents must carry one copy of the mutated gene, which is often the case with XP.
• Autosomal dominant: Only one parent needs to carry the mutation for it to be passed on.

DNA Repair Mechanisms

Our DNA is constantly exposed to damaging agents like radiation and chemicals. To counteract this, cells have built-in repair mechanisms to maintain genetic stability. These mechanisms detect and fix various damages that might occur within the DNA strands.

There are several types of DNA repair processes, including:

• Base Excision Repair (BER)
• Nucleotide Excision Repair (NER)
• Homologous Recombination (HR)
• Non-Homologous End Joining (NHEJ)

The NER pathway, notably implicated in XP, identifies and corrects damage caused by ultraviolet radiation by removing a small section of the DNA strand surrounding the damage. These pathways involve a complex interplay of proteins and enzymes that recognize DNA disturbances, excise the faulty sections, and synthesize the correct sequences in their place.

Nucleotide Excision Repair

The Nucleotide Excision Repair (NER) mechanism is crucial in maintaining the integrity of DNA, especially when exposed to ultraviolet radiation. NER works by identifying and rectifying lesions that distort the DNA helix. This includes bulky adducts such as thymine dimers, which can form due to UV radiation exposure.

The NER process involves several key steps:

• Damage Recognition: The initial identification of the distortion in the DNA strand.
• Excision: Removal of the damaged section using endonucleases.
• Synthesis: DNA polymerases fill in the gap with correct nucleotides.
• Ligase Action: Seals the newly synthesized DNA into the existing strand.

In individuals with XP, mutations in genes responsible for the NER pathway hinder these steps, preventing effective repair of UV-induced damage. This inefficiency leads to accumulated DNA damage, manifesting in the form of skin and potentially neurological anomalies.

Ultraviolet Radiation

Ultraviolet (UV) radiation is part of the electromagnetic spectrum emitted by the sun. While it plays important roles, such as aiding in vitamin D synthesis, excessive exposure can be harmful. UV radiation can cause damage to the DNA within skin cells, leading to mutations and, over time, potentially resulting in skin cancers. There are three types of UV rays: UVA, UVB, and UVC.

• UVA: Has the longest wavelength and can prematurely age the skin cells.
• UVB: Mostly responsible for causing sunburn and can directly damage DNA, potentially leading to cancer.
• UVC: The shortest wavelength, mostly absorbed by the Earth's atmosphere, and does not significantly reach the surface.

In XP, individuals lack the effective DNA repair capability to counteract UV-induced damage, leading to a rapid accumulation of mutations and the development of skin abnormalities.

Neurological Abnormalities

Neurological abnormalities in XP occur when the same genomic imperfections affecting skin cells also disrupt neuronal cells. Not all XP cases exhibit neurological symptoms, but when present, they significantly affect patients' quality of life. These abnormalities arise because neurons share similar DNA repair capabilities and vulnerabilities as skin cells. Damage to neurons can lead to:

• Progressive neurodegenerative diseases
• Intellectual disabilities
• Coordination problems and loss of motor functions

Typically, mutations in genes like XPA, XPD, and XPG not only affect skin cells but also lead to increased vulnerability in brain cells. The failure to effectively repair DNA damage hampers neuronal development and function, potentially resulting in these severe neurological manifestations.