xeroderma pigmentosum

Definition: XP is characterized by a severe predisposition to skin cancers of various types, mainly squamous cell carcinomas and basal cell carcinomas.

The XP syndrome has an autosomal recessive inheritance and seven distinct groups of genetic complementation groups were identified, named XPA to XPG.

XP patients can be affected in transcription coupled repair, in overall repair, or both. Few patients, known as XP variants (XPV), however, have normal nucleotide excision repair levels and may have a defect on the ability to replicate damaged DNA.

Clinics

Xeroderma pigmentosum (XP) is a disease that is inherited strictly in an autosomal-recessive mode. XP has a worldwide distribution. The incidence varies from about 1 in 250,000 in Western countries to as high as 1 in 40,000 in Japan.

Although the severity varies in different patients, cutaneous symptoms such as marked skin burning on minimal sun exposure can be detected as early as the first sun exposure within weeks of birth. The eyelids, conjunctiva and cornea are frequently affected because of ultraviolet radiation exposure, especially in very sunny climates. Oral abnormalities also occur for similar reasons. Even the tip of the tongue may show signs of sun damage.

The estimated incidence of cutaneous basal cell carcinoma and squamous cell carcinoma is elevated more than 1000-fold in individuals with XP under 20 years of age and is elevated more than 100,000-fold for squamous cell carcinoma of the tip of the tongue. An association of the cutaneous manifestations of XP with various neurological phenotypes is observed in about 20% of cases.

Individuals with XP have a high incidence of premalignant actinic keratoses (proliferative lesions in the skin, which signal impending neoplastic change), as well as benign and malignant skin tumours. The median age of onset of skin cancer is 8 years, nearly 50 years younger than in the general US population.

This is the earliest onset of neoplasia documented for any recessive human hereditary disease and reflects the importance of DNA repair in the prevention of these cancers in the general population.

Neoplasms are predominantly basal cell and squamous cell carcinomas of the skin, but also include melanomas, keratoacanthomas (tumours that arise from cells of the skin appendages, such as hair follicles), angiomas and sarcomas.

The cutaneous features of XP are essentially identical in patients with XP-AXP-G, although XP-E patients tend to have milder symptoms and a later onset of cancer, and XP-C patients are less frequently afflicted neurologically.

History

The human autosomal recessive hereditary disease XP was first described during the late nineteenth century by the Austro-Hungarian physician Moritz Kaposi (of Kaposi sarcoma fame) and his colleague Ferdinand Hebra. During the late 1960s, James Cleaver and Richard B. Setlow independently showed that cells from patients with XP are defective in NER.

Since then, a wealth of published data has confirmed this molecular phenotype both in vitro and in vivo providing unequivocal evidence that the inability to repair base damage, in particular the type of base damage resulting from exposure to UV radiation, results in an enhanced mutational burden in cells and eventually to neoplastic transformation.

The genetic complexity of XP was elaborated by fusing cells from different patients and observing the phenotypic correction (complementation) of defective repair synthesis in fused cells with nuclei from two patients (heterodikaryons). In this manner, seven genetic complementation groups (designated XP-AXP-G) have been established, and genes defective in each group (XPAXPG) have been cloned.

Loss of function of an eighth gene called XPV also results in XP, including skin cancer predisposition, but is not associated with defective NER. Instead, it results in a defect in a different cellular response to DNA damage, which requires the accurate replicational bypass of UV-radiation-induced base damage.

Hence, XP fundamentally results from the accumulation of mutations in the DNA of skin cells after exposure to sunlight. Mutations can accumulate either because photoproducts in DNA are not removed by NER, or because of defective replicative bypass of these lesions.

The elucidation of the molecular pathology of both XP that is associated with defective NER, and that associated with incorrect replicational bypass of base damage, provides convincing support for the somatic mutation theory of cancer in humans, and for the role of DNA repair genes as important tumour suppressors or ’caretakers’ of the genome.

Synopsis

 sunlight hypersensitivity
 high incidence of skin cancer
 frequent neurological anomalies
 premature aging
 hypersensitive to UV
 DNA hypermutability by UV and some chemical agents.
 8 complementation groups: XPA, XPB, XPC, XPD, XPE, XPF, XPG and XPV)

Pathogeny

 XP individuals are highly sensitive, presenting dramatic pigmentary skin disturbances, specially at regions exposed to sunlight. There is a great increase in the incidence of both benign and malignant skin tumors and frequently these clinical features are accompanied by neurological abnormalities and premature aging.

 Fibroblasts from these patients are sensitive to UV light and have reduced levels of nucleotide excision repair. They also show an increased frequency of mutagenesis after UV, which correlates well with the patient clinical feature of increased skin carcinogenesis.

 The XP syndrome has an autosomal recessive inheritance and seven distinct groups of genetic complementation groups were identified, named XPA to XPG. Few patients, known as XP variants (XPV), however, have normal nucleotide excision repair levels and may have a defect on the ability to replicate damaged DNA (Bootsma and Hoeijmakers, 1991).

 The genes related to XP have recently been cloned, except for XPE and XPV, and have revealed strong homologies with DNA repair genes from other eukaryotic organisms.

 The XPA protein in association with RPA protein is responsible for the binding to the damaged DNA. The XPA-RPA complex also has interactions with TFIIH, XPF-ERCC1 and XPG, that play different roles on DNA repair. Thus, the complex might constitute the nucleation component for the remaining subunits of excision repair.

 The fact that XPB and XPD proteins are subunits of the RNA polymerase II transcription factor TFIIH is in agreement with the discovery of the preferential nucleotide excision repair of transcriptionally active genes made by Bohr and his colleagues in 1985.

This kind of repair has been denominated "transcription coupled repair" in order to differentiate from the repair of the rest of the genome, known as overall or general repair.

The most likely function of TFIIH in transcription is promoter clearance, which is the reaction encompassing the phosphorylation of C-terminal domain of RNA polymerase II, the disruption of the initiation complex and the synthesis of a transcript 30-50 nucleotides in length.

For the excision repair, TFIIH participates in the formation of the pre-incision complex after its recruitment by XPA protein to the damaged site. It seems that the helicase activities of XPB (3’-5’ direction) and XPD (5’-3’) may be important functions necessary for the role of TFIIH on DNA repair.

The XPC protein participates in general DNA repair: cells mutated on the XPC gene carry out normal transcription coupled repair, but are defective in overall repair.

Results of in vitro experiments indicate that the presence of XPC protein is not fundamental for repair, but in this circumstance both the excised oligomer and the damaged strand in the pre-incision complex are extensively degraded. This protein also associates with the TFIIH and has a high nonspecific DNA affinity.

These data lead to the reasonable assumption that XPC can help stabilize the pre-incision subassemblies on nucleosomal DNA, while protecting the rest of the DNA. In transcribed DNA, an elongation complex stalled at a lesion obviates the need for XPC.

Once the damage is recognized and prepared for repair, the DNA is nicked in both sides of the lesion. The XPF and the XPG proteins are implicated in this process: the incision at 5’of the lesion is made by the XPF protein (complexed with the ERCC1 protein) and at 3’ by the XPG protein (Matsunaga et al., 1995). After the incision and excision of the damaged DNA strand, the synthesis of the" new" DNA by DNA polymerases d or e occurs and the final nick is removed by DNA ligase.

Classification

Pathology

XPA	MIM.611153	XPA	MIM.611153
XPB	MIM.610651	ERCC3	MIM.133510
XPC	MIM.278720	XPC	MIM.278720
XPD	MIM.278730	ERCC2	MIM.126340
XPE	MIM.610965	ERCC4	MIM.133520
XPF	MIM.278760	ERCC4	MIM.133520
XPG	MIM.278780	ERCC5	MIM.278780

Subtypes

 xeroderma pigmentosum with anormal DNA repair rates

• XPA - xeroderma pigmentosum complementation group A
• XPB - xeroderma pigmentosum complementation group B
• XPC - xeroderma pigmentosum complementation group C
• XPD - xeroderma pigmentosum complementation group D
• XPG - xeroderma pigmentosum complementation group G

 xeroderma pigmentosum with normal DNA repair rates (MIM.278750) caused by mutations in the DNA polymerase eta gene (POLH) (MIM.603968)

XPV

The eighth genetic complementation group for XP is called XPV (for the variant form of the disease). XPV patients are clinically indistinguishable from those with classical XP, but are fully proficient for NER.

This conundrum was recently solved when it was shown that the product of the XPV gene is an unusual DNA polymerase called DNA polymerase.

This polymerase is highly error prone when copying normal DNA (the measured error rate is about 6,000 times higher than that of the high-fidelity polymerases involved in DNA replication).

High-fidelity replicative DNA polymerases, however, cannot replicate through sites of base damage. By contrast, DNA polymerase can bypass such lesions, and does so by incorporating nucleotides opposite sites of base damage.

The error rate is less than 5%, so the generation of mutations is avoided most of the time. The specific catalytic attributes of an enzyme such as DNA polymerase that facilitates the correct reading of templates in which bases have an abnormal structure is an area of intense interest and research activity.

Tumoral predisposition

 melanoma
 cutaneous squamous cell carcinoma
 squamous cell carcinoma of the conjunctiva (17378688)
 atypical fibroxanthoma (17378688)

Animal models

 With the advent of targeted gene replacement in mouse embryonic stem (ES) cells (mouse gene-knockout technology), mutational inactivation of several mouse XP genes has been achieved, generating mouse models for the human disease.

 In general, these accurately mimic the marked predisposition to UV-radiation-induced skin cancer. But they have also been informative with respect to other aspects of NER and its relationship to cancer predisposition that could not be appreciated from human studies.

 Xpa mutant mice are prone to tumours of the skin, lymphoid system and liver associated with exposure to the chemical carcinogen benz[a]pyrene, and to skin cancer following painting with 7,12-dimethylbenzanthracene (DMBA), another potent chemical carcinogen.

 Similarly, both benign and malignant tumours of the liver and lung occur more frequently in Xpc mice exposed to the carcinogen N-acetoxy-acetylaminofluorene (AAF) or its metabolically activated derivative N-hydroxyacetyl aminofluorene (N-OH AAF).

See also

 DNA repair diseases

• nucleotide excision repair diseases
  • xeroderma pigmentosum
  • Cockayne disease
  • trichothiodystrophie

References

 Cleaver JE. Cancer in xeroderma pigmentosum and related disorders of DNA repair. Nat Rev Cancer. 2005 Jul;5(7):564-73. PMID: 16069818