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Chapter 28 : Nucleotide Excision Repair Syndromes: Xeroderma Pigmentosum, Cockayne Syndrome, and TrichothiodystrophyThis text is a complete revision of Chapter 148, Xeroderma Pigmentosum and Cockayne Syndrome, in the 7th edition of Metabolic and Molecular Bases of Inherited Diseases. Part of this chapter is an updated version of Hoeijmakers JHJ: Human nucleotide excision repair syndromes: Molecular clues to unexpected intricacies, Eur J Cancer 30A(13):1912, 1994; used with permission from Elsevier Science, Ltd., The Boulevard, Lanfordlane, Kidlington OX5 1GB, UK.

Authors: Dirk Bootsma, Kenneth H. Kraemer, James E. Cleaver, Jan H. J. Hoeijmakers

Three rare autosomal recessive syndromes are associated with a nucleotide excision repair (NER) defect: xeroderma pigmentosum (XP), Cockayne syndrome (CS), and the photosensitive form of trichothiodystrophy (TTD). A common denominator of all three conditions is an extreme sensitivity to sunlight. XP patients exhibit in addition to photosensitivity a greater than thousand-fold increased frequency of sunlight-induced skin cancers. Other features include progressive degenerative alterations of the skin and eyes and in some cases accelerated neurologic degeneration due to increased neuronal death. Patients with CS have a combination of sun sensitivity, short stature, severe neurologic abnormalities due to dysmyelination, cataracts, dental caries, a wizened appearance, and a characteristic bird-like facies. They do not display cancer predisposition. The hallmark of TTD is sulfur-deficient brittle hair and nails. Patients also have ichthyosis and many symptoms characteristic of CS. About half of TTD patients are hypersensitive to ultraviolet (UV) light, and they have a NER defect. As in CS, there are no indications for an increased risk of cancer. In addition to the preceding, rare patients showing combined XP-CS symptoms have been described.

The NER pathway removes a remarkably wide array of structurally unrelated DNA lesions. Among these are numerous helix-distorting chemical adducts induced by carcinogens such as benz[a]pyrene, as well as cyclobutane pyrimidine dimers (CPD) and [6-4]pyrimidine-pyrimidone photoproducts (6-4PP) produced in human skin by the shortwave UV component of the solar spectrum. This explains why patients with inherited deficiencies in the NER process display marked hypersensitivity to sun exposure. Defective repair also results in genetic instability leading to increased chromosome abnormalities and mutagenesis and in many cases predisposition to cancer. At least two NER subpathways exist: a rapid transcription-coupled repair (TCR) pathway responsible for the efficient elimination of lesions from the transcribed strand of active genes that permits rapid resumption of the vital process of transcription and for some lesions a less efficient global genome repair (GGR) subpathway that surveys the entire genome.

Complementation analysis by cell fusion has allowed a further genetic classification of XP, CS, and TTD patients. In XP, seven different complementation groups are distinguished, representing seven distinct defective genes involved in NER in XP: XP-A, -B, -C, -D, -E, -F, and -G. In addition, another class of XP patients (XP variant) appears to be deficient in a gene product that in normal cells permits semiconservative replication of previously damaged sites in the DNA template (postreplication repair). Similarly, complementation analysis has revealed two complementation groups in CS, CS-A and CS-B, and three in TTD, of which two overlap with XP groups: TTD-A, XP-B, and XP-D. Patients with combined XP-CS have been assigned to three XP complementation groups: XP-B, XP-D and XP-G.

The NER defect in the cells of most XP and TTD patients is located in the core of the NER mechanism and affects both transcription-coupled and global genome repair. In XP-C cells the defect is limited to the global genome repair system, whereas in CS only the transcription-coupled repair pathway is impaired.

All XP, CS, and TTD genes, except TTD-A and XP-variant, have been cloned, and their functions in the NER mechanism are known or in the process of being clarified. Disease-causing mutations have been identified in most of the corresponding genes.

Several of the protein (complexes) involved in NER participate in other DNA transactions as well. All NER genes associated with TTD:XP-B, XP-D, and TTD-A—are simultaneously implicated in basal transcription. The XP-F complex probably has a dual involvement in a mitotic recombination pathway, and later steps in NER are shared with replication. The notion of function sharing has important implications for the clinical consequences of inherited mutations in these NER proteins. It is likely that the symptoms, which are not easy to explain on the basis of an NER defect per se (e.g., the brittle hair and nerve dysmyelination), are caused by subtle insufficiencies in basal transcription.

Mouse models for NER deficiencies have been generated. They provide excellent tools for understanding the complex relationships between DNA repair defects and clinical consequences.

Prenatal diagnosis for XP, CS, and TTD is possible if an unequivocal NER defect or the responsible mutations in the family have been demonstrated.


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