A summary of mutations in the UV-sensitive disorders: Xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy

Abstract

The human diseases xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy are caused by mutations in a set of interacting gene products, which carry out the process of nucleotide excision repair. The majority of the genes have now been cloned and many mutations in the genes identified. The relationships between the distribution of mutations in the genes and the clinical presentations can be used for diagnosis and for understanding the functions and the modes of interaction among the gene products. The summary presented here represents currently known mutations that can be used as the basis for future studies of the structure, function, and biochemical properties of the proteins involved in this set of complex disorders, and may allow determination of the critical sites for mutations leading to different clinical manifestations. The summary indicates where more data are needed for some complementation groups that have few reported mutations, and for the groups for which the gene(s) are not yet cloned. These include the Xeroderma pigmentosum (XP) variant, the trichothiodystrophy group A (TTDA), and ultraviolet sensitive syndrome (UVs) groups. We also recommend that the XP-group E should be defined explicitly through molecular terms, because assignment by complementation in culture has been difficult. XP-E by this definition contains only those cell lines and patients that have mutations in the small subunit, DDB2, of a damage-specific DNA binding protein.

The genetics of hair shaft disorders

“…77,78,80 It has been theorized that different XP gene mutations cause varying defects in DNA repair and/or gene transcription, leading to the pathognomonic presentations in each syndrome. 34,35,59,[81][82][83][84][85][86][87][88][89][90][91][92][93] In a small group of patients, elevated temperatures can cause in vitro instability of TFIIH. 35,79,88,94 It has been suggested that fever may cause worsening of TTD features in subgroups of patients.…”

XPD Common Variants and their Association with Melanoma and Breast Cancer Risk

“…Individuals with the rare inherited syndrome xeroderma pigmentosum (XP) have an approximate 1000-fold increased incidence of skin malignancies, including melanoma [3]. There are several genes associated with XP and these include ERCC2, ERCC3, XP-G and XP-F [3,4]. The XPD (ERCC2) gene product has a dual function in basal transcription and in nucleotide excision repair [5,6].…”

Characterization of tiger tail banding and hair shaft abnormalities in trichothiodystrophy

“…The majority of TTD patients have a defect in XPD, the gene defective in patients with XP complementation group D (XP-D). 4,7 XPD is a component of the transcription factor TFIIH that regulates two distinct DNA-metabolizing functions, namely, repair and transcription. It is now believed that clinical features of XP are linked to mutations in the repair function of nucleotide excision repair (NER) genes, while mutations affecting the transcription-related function of NER genes results in the TTD phenotype.…”