Xeroderma pigmentsum?

Xeroderma pigmentsum is a very rare, inheritated disorder. Individuals who have this disorder may suffer from various pigmentation abnormalities and develop skin cancers very readily, particulary after exposure to sunlight. Can you suggest a biological explantion for the predisposition of these individuals to develop skin cancers so readily? (Developing hypotheses)

Xeroderma pigmentsum?
Pathophysiology: The basic defect in XP is in nucleotide excision repair (NER), leading to deficient repair of DNA damaged by UV radiation. This extensively studied process consists of the removal and the replacement of damaged DNA with new DNA. Two types of NER exist: global genome (GG-NER) and transcription coupled (TC-NER). The last decade has seen the cloning of the key elements of NER, and the process has been reconstituted in vitro.





Seven XP repair genes, XPA through XPG, have been identified. These genes play key roles in GG-NER and TC-NER. Both forms of NER include a damage-sensing phase, performed in GG-NER by the product of the XPC gene complexed to another factor. In addition, the XPA gene product has been reported to have an affinity for damaged DNA. Therefore, XPA likely plays a role in the damage-sensing phase as well.





Following detection of DNA damage, an open complex is formed. The XPG gene product is required for the open complex formation. The XPB and XPD gene products are part of a 9-subunit protein complex (TFIIH) that is also needed for the open complex formation. Subsequently, the damaged DNA is removed.





The XPG and XPF genes encode endonucleases; however, the XPF gene product functions as an endonuclease when complexed to another protein. The resulting gap is filled in with new DNA by the action of polymerases. An XP-variant has been described. The defect in this condition is not in NER but is instead in postreplication repair.





Seven complementation groups, XPA-XPG, corresponding to defects in the corresponding gene products of XPA-XPG genes, have been described. These entities occur with different frequencies (eg, XPA is relatively common, whereas XPE is fairly rare), and they differ with respect to disease severity (eg, XPG is severe, whereas XPF is mild) and clinical features. Cockayne syndrome can rarely occur with XPB, XPD, and XPG.





In addition to the defects in the repair genes, UV-B radiation also has immunosuppressive effects that may be involved in the pathogenesis of XP.





Although typical symptoms of immune deficiency, such as multiple infections, are not usually observed in patients with XP, several immunologic abnormalities have been described in the skin of patients with XP. Clinical studies of the skin of patients with XP indicate prominent depletion of Langerhans cells induced by UV radiation. Various other defects in cell-mediated immunity have been reported in XP.





These defects include impaired cutaneous responses to recall antigens, decreased circulating T-helper cells-to-suppressor cells ratio, impaired lymphocyte proliferative responses to mitogen, impaired production of interferon in lymphocytes, and reduced natural killer cell activity.

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