The Nucleotide Excision Repair DNA Repair Disorders

Xeroderma pigmentosum (XP) is a multigenic, multiallelic autosomal recessive disease that occurs in the United States at a frequency of about 1 : 250,000, but with higher frequency in Japan and the Mediterranean areas [Cleaver and Kraemer, 1995]. Heterozygotes are unaffected, but homozygotes have severe sun sensitivity that leads to progressive degeneration of sun-exposed regions of the skin and eyes, usually leading to various forms of cutaneous malignancy (melanoma and nonmelanoma) [Kraemer et al., 1989, 1994]. Progressive neurologic degeneration occurs in a significant number of patients, which can be correlated with mutations in specific XP genes.

The disease begins in early life with the first exposures to sunlight, the median age of onset being 1–2 years of age, with skin rapidly exhibiting the signs associated with years of sun exposure. Pigmentation is patchy, and skin shows atrophy and telangiectasia with development of basal and squamous cell carcinomas and melanomas. Cancer incidence for those individuals under 20 years of age is 2,000 times that seen in the general population. There may be a reduction in life span associated with the progression of cancer or neurologic degeneration, but a specific effect on aging itself has not been observed.

CS is an autosomal recessive disease characterized by cachectic dwarfism, retinopathy, microcephaly, deafness, neural defects, and retardation of growth and development after birth. They have a typical facial appearance with sunken eyes and a beaked nose and projecting jaw. CS patients are sun sensitive but do not develop cancers, setting this disease apart from XP. In addition to patients who show combined XP and XP/CS symptoms there are a set of patients who only have CS. These correspond to mutations in one of two genes, CSA and CSB, group A being the more common (Lehmann 1982). Three patients from 2 families are known from XP complementation group B which also show CS symptoms (Weeda et al. 1990). The CS gene products are involved in coupling excision repair to transcription, but their precise function is not yet clear. They may be involved in the ubiquitination and degradation of stalled RNA pol II at damaged sites.

TTD is a rare autosomal recessive disorder characterized by sulfur-deficient brittle hair and ichthyosis (Itin et al. 2001). Hair shafts split longitudinally into small fibers, and this brittleness is associated with levels of cysteine/cystine in hair proteins that are 15 to 50% of those in normal individuals. The hair has characteristic "tiger-tail" banding visible under polarized light. The patients often have an unusual facial appearance, with protruding ears and a receding chin. Mental abilities range from low normal to severe retardation (Lehmann et al. 1988). Several categories of the disease can be recognized on the basis of cellular responses to UV damage and the affected gene. Severe cases have low NER and mutations in XPB or D as described above. A third category involves another unidentified gene called TTDA and lacks major UV sensitivity, and appears to have an unstable TFIIH (Broughton et al. 1990; Itin et al. 2001). Although TTD patients do not exhibit increased incidence of skin cancer, corresponding mice with a human TTD mutation are sensitive to increased UV-induced skin cancer, indicating important differences between the human and mouse models (de Boer et al. 1998).

XP-CS and XP-TTD syndrome

There are several examples of patients who exhibit combined symptoms of XP and other developmental and neurological disorders of CS or TTD. These have generally been found to correspond to mutations in the XPB, XPD or XPG genes.

Cerebro-Oculo-Facio Skeletal (COFS) syndrome [OMIM]

Cerebro-Oculo-Facio-Skeletal (COFS) syndrome is an autosomal, recessively inherited and rapidly progressive, neurologic disorder. The disease leads to brain microcephaly and atrophy with calcifications, cataracts, microcornea, optic atrophy, progressive joint contractures, and growth failure. COFS appears to be a particularly severe developmental and neurological expression of mutations in CSB, XPG and XPD (Graham et al. 2001).