Xeroderma Pigmentosum, Variant Type

A number sign (#) is used with this entry because of evidence that the variant form of xeroderma pigmentosum (XPV) is caused by mutations in the DNA polymerase eta gene (POLH; 603968).

Description

Xeroderma pigmentosum is an autosomal recessive disorder characterized by increased sensitivity to sunlight and defects in DNA repair. For a general overview of the disorder, see XPA (278700).

Some patients with xeroderma pigmentosum have been found to have normal DNA excision repair, but defective postreplication repair (Lehman et al., 1975). This XP 'variant' class is characterized by a defect in conversion of newly synthesized DNA from low to high molecular weight after UV irradiation (Masutani et al., 1999).

So-called 'pigmentary xerodermoid' is apparently identical to the XP variant, which is characterized by loss of a gene product that permits normal cells to replicate DNA without interruption at UV-damaged sites (Cleaver et al., 1980).

Clinical Features

Fujiwara et al. (1981) reported studies of cultured cells from an 8-year-old boy, the son of first-cousin parents, who, they suggested, had a 'new' form of photodermatosis with a defect in the recovery of post-UV DNA synthesis. He had sun sensitivity, but no growth retardation, microcephaly, congenital malformations, or other abnormalities. Cells derived from the patient showed normal nucleotide excision repair after UV irradiation, but defective recovery of DNA synthesis. The biochemical findings distinguished this XP variant from the 7 known XP complementation groups, which show defects in nucleotide excision repair.

Diagnosis

Itoh et al. (1996) reported a method for the diagnosis of XPV that utilized the measurement of 3 cellular markers of DNA repair by autoradiography: unscheduled DNA synthesis (UDS), recovery of RNA synthesis (RRS), and recovery of replicative DNA synthesis (RDS) after UV irradiation. Fibroblasts from XPV patients exhibited normal UDS and RRS but diminished RDS, which was exacerbated by exposure to caffeine. Itoh et al. (2000) used this method to characterize cells of 2 XPV patients and their heterozygous parents. Cells from heterozygous parents showed normal levels of UDS, RRS, and RDS, but RDS was reduced in the presence of 1 mM caffeine (53 +/- 8% relative to the normal control). Furthermore, the cells showed normal UV survival without caffeine, but slightly reduced UV survival with 1 mM caffeine present. These results suggest that xeroderma pigmentosum variant heterozygotes can be identified by their sensitivity to ultraviolet irradiation in the presence of nontoxic levels of caffeine.

Pathogenesis

Despite having the clinical characteristics of XP, including increased frequency of skin cancer, cells from patients with variant XP are only slightly more UV-sensitive than normal cells, but are significantly more sensitive to its mutagenic effect. Wang et al. (1991) transfected an XP variant cell line with a UV-irradiated shuttle vector carrying a gene as a target for mutation, allowed replication of the plasmid, and determined the frequency and spectrum of mutations induced. Mutants in XPV cells increased linearly with dose with a slope 5 times steeper than that seen with normal cells. Most of the mutants contained base substitutions and substitutions involving a dipyrimidine; 28% of the mutations involved AT basepairs as compared to 11% in normal cells. The findings suggested that XPV cells were less likely to incorporate dAMP opposite thymidine bases involved in UV photoproducts (TT dimers) during DNA replication, which would contribute to hypermutability with UV radiation.

DNA polymerase eta (POLH; 603968) performs translesion synthesis past UV photoproducts and is deficient in cancer-prone XPV syndrome. The slight sensitivity of XPV cells to UV is dramatically enhanced by low concentrations of caffeine. Using DNA combing, Despras et al. (2010) showed that translesion synthesis defect led to a strong reduction in the number of active replication forks and a high proportion of stalled forks in human cells. Extensive regions of single-strand DNA were formed during replication in irradiated XPV cells, leading to an overactivation of ATR/CHK1 (601215/603078) pathway after low UVC doses. Addition of a low concentration of caffeine post-irradiation significantly decreased CHK1 activation and abrogated DNA synthesis in XPV cells. While inhibition of CHK1 activity by 7-hydroxystaurosporine (UCN-01) prevented UVC-induced S-phase delay in wildtype cells, it aggravated replication defect in XPV cells by increasing fork stalling. Consequently, UCN-01 sensitized XPV cells to UVC as caffeine did. The authors concluded that POLH acts at stalled forks to resume their progression, preventing the requirement for efficient replication checkpoint after low UVC doses. In the absence of POLH, CHK1 kinase becomes essential for replication resumption by alternative pathways, via fork stabilization.

Molecular Genetics

Masutani et al. (1999) identified the POLH gene and determined that it is the human homolog of yeast Rad30. The authors identified mutations in the POLH gene (603968.0001-603968.0005) in cell lines derived from patients with XPV.

Johnson et al. (1999) independently cloned the human homolog of S. cerevisiae Rad30 and identified protein truncation mutations (603968.0006-603968.0011) in patients with XPV.