XP is caused by a defect in the ability of cells to repair damage induced in DNA by ultraviolet light. This process (Nucleotide excision repair – NER) is a multi-step pathway, whereby the damage is recognised and subsequently cut out of the DNA. The resulting gap is then repaired (repair synthesis). Eight XP genes have been identified, of which XPA is one. The XPA protein carries out one of the steps in this pathway. All kinds of mutations have been identified in XPA patients. When NER is not functional, because of mutations in one of the XP genes, damage remains in DNA in exposed areas of the skin and the skin hypersensitivity results. The neurological abnormalities are the result of endogenous DNA damage in the brain, which needs to be repaired by NER. In its absence, this damage accumulates, leading to neuronal death and neurological degeneration.
Clinical diagnosis can be confirmed, either by molecular analysis of the XP genes and/or by analysing NER in cultured skin fibroblasts. This is commonly done by measuring the repair synthesis step of NER using a technique known as Unscheduled DNA synthesis.
XPA