The skin and eye disease in XP and the 1000-fold increased frequency of neoplasms in these sun exposed organs is related to faulty repair of ultraviolet damage to DNA. This results in increased cell killing and increased frequency of mutations in many of the genes in the surviving cells. Accumulation of mutations that activate oncogenes or inhibit tumor suppressor genes in dividing cells eventually leads to cancer.
In the XP patients who develop progressive neurological degeneration the brain is not exposed to ultraviolet radiation. The progressive nature of the degeneration suggests that there might be ongoing damage that is not repaired. Since neurons do not divide, unrepaired DNA damage could result in impaired cellular function and eventually to cell death. An effect of the damage might be to alter the process of transcription so that mutations might be introduced into newly synthesized RNA. This could impair functioning of essential proteins. The NER pathway is present in all cells in the body including those in the nervous system. Recent studies from several laboratories have reported the discovery of some bulky DNA lesions produced by oxidative damage that are substrates for the NER pathway. Unrepaired lesions such as cyclo-deoxyadenine or cyclo-deoxyguanine might accumulate in the DNA of neurons of patients with defective NER and lead to the progressive neurological degeneration 2
. There are many unanswered questions relating to this theory including why only some of the XP patients develop neurological degeneration and why certain parts of the brain are typically affected more than others.
Patients with TTD have neurological defects that appear to be mainly related to impaired development and maturation of the nervous system. They have decreased to absent myelin in the cerebrum. While not proven definitively, it seems that the myelin in these patients never formed properly (dysmyelination) rather than sustaining a loss of normally formed myelin (demyelination). This suggests the presence of a developmental defect as is also seen in the congenital cataracts in the eye, the problems during in utero
growth, and the short stature. In addition TTD patients do not have an increased frequency of skin cancer. TTD patients have defects in XPD
genes. These genes are part of the basal transcription factor, TFIIH as well as in NER. It has been proposed that the specific defects in these genes in TTD patients have a greater effect on the transcription activities of these genes than on their repair activities 5
. A striking example is the finding that mutations in the XPD component of TFIIH result in beta-thalassemia in TTD patients without mutations in hemoglobin genes24
. At present we have no evidence of progressive neurological degeneration in TTD patients.
CS patients have both developmental defects and progressive neurological degeneration. Like TTD patients there is primary involvement of the myelin in the brain. The CSA and CSB proteins have a role in transcription coupled repair and may also be involved in transcription of undamaged genes. CSA and CSB proteins are involved in regulation of recruitment of chromatin remodeling and repair factors to stalled RNA polymerase II after UV damage6
. The transcriptional response after oxidative damage is defective in cells from patients with mutations in the CSB gene13
. Thus the progressive neurological degeneration in CS may involve faulty repair of oxidative damage or of bulky DNA damage as in XP patients. However major questions remain such as the differences in the type of involvement – for example retinal degeneration is present in CS but not in XP - and the differences in cancer susceptibility.