Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043346 (xeroderma pigmentosum)
 2,924 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The xeroderma pigmentosum complementation group D is defined by more than 30 unrelated individuals of whom less than half show major abnormalities of the central nervous system, once considered to be the hallmark of the group. Fibroblasts from the great majority of these individuals show very considerable sensitivity to UV light in vitro despite the fact that the cells carry out what appears to be substantial excision repair, as judged from repair synthesis and incision activity. This article reviews the XPD group and the defects in cellular DNA repair and examines the lack of correlation between repair and the appearance of neurological abnormalities. The article also discusses the recent awareness that at least some members of two other inherited conditions, trichothiodystrophy and Cockayne's Syndrome, carry mutations in the XPD gene.
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PMID:The XPD complementation group. Insights into xeroderma pigmentosum, Cockayne's syndrome and trichothiodystrophy. 137 8

Xeroderma pigmentosum (XP) is a rare autosomal recessive disease characterized by photosensitivity, a high incidence of cancer in sun-exposed portions of the skin and a reduced capacity to repair the u.v.-induced DNA damage. One of the XP mutations (XP-D) has also been identified in patients affected by trichothiodystrophy (TTD), a rare autosomal recessive disease characterized by brittle hair, mental and physical retardation, peculiar face and ichthyosis. However, in these patients there is no evidence of increased skin tumour incidence. Since an impairment of cell-mediated immunity has been proposed as a co-factor in the cancer proneness of XP patients, we investigated the involvement of immune defect(s) in five XP patients, five TTD patients, their parents, and 24 TTD relatives. We evaluated the phenotype of circulating lymphocytes, natural killer (NK) cell lytic activity, target cell binding of NK cells at single cell level and the effect of interferons (IFN) alpha and beta on NK cell activity. The relative proportion of CD3+ and CD4+ circulating lymphocytes was reduced in XP but not in TTD patients. NK cell lytic activity was decreased in XP patients and their mothers, but their fathers showed normal lytic activity. NK activity varied among TTD families: four out of five patients and their relatives presented low NK cell activity, and one family was normal. In TTD family members, NK activity increased after incubation with IFN-alpha or IFN-beta, but never reached normal values. In contrast, in XP patients and their mothers, the defect was almost completely corrected after in vitro incubation with IFN-alpha or IFN-beta. Our study indicates impaired NK lytic activity in the majority of TTD and XP patients and that this defect is present also in members of their families. In addition, XP patients present a low number of circulating T cells. These multiple abnormalities, together with DNA repair defects, could be related to the increased cancer risk in XP patients.
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PMID:Immune defects in families and patients with xeroderma pigmentosum and trichothiodystrophy. 153 35

Xeroderma pigmentosum (XP) and trichothiodystrophy (TTD) are two recessively transmitted human diseases characterized by DNA repair deficiency. While XP is associated with a very high incidence of cancer on skin exposed to sunlight, TTD is not a cancer-prone disease. Therefore, unrepaired UV-induced DNA lesions do not appear to be enough to give rise to tumors. In order to understand the differences between these two syndromes, we measured catalase activity in cellular extracts, UV irradiated or not, and quantified H2O2 production following in vitro UV irradiation. We confirmed on 21 different XP diploid fibroblast lines that catalase activity was decreased on average by a factor of five as compared to controls, while XP heterozygote lines exhibited intermediary responses. All seven TTD lines we tested were deficient in UV-induced lesion repair and exhibited a high level of catalase activity. However, molecular analysis of catalase transcription showed no difference between normal, XP and TTD cell lines. This was confirmed by Western blots where the amount of catalase subunits was identical in all cell lines studied. Finally, UV irradiation induces five and three times more H2O2 production in XP lines compared with TTD or controls respectively. These striking differences between TTD and XP indicate that UV light, directly or indirectly, together with defective oxidative metabolism may increase the initiation and/or the progression steps in the XP environment compared to TTD. This may partly explain the different tumoral phenotype observed between the two diseases.
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PMID:Striking differences in cellular catalase activity between two DNA repair-deficient diseases: xeroderma pigmentosum and trichothiodystrophy. 154 19

Symptoms of xeroderma pigmentosum, a hereditary disease characterized by accelerated light-induced ageing of the skin, are due to deficiencies in the repair of damaged DNA. Following UV irradiation a high incidence of thioguanine-resistant mutations have been observed, which may be a model for the abnormally high incidence of freckling and benign and malignant transformation observed in these patients. Cells from patients with Cockayne's syndrome and trichothiodystrophy have also been shown to be hypermutable by UV radiation with a similar DNA repair defect, but unlike xeroderma pigmentosum patients they do not experience a higher incidence of skin cancer or freckling. An immunological defect may be a further crucial factor determining the dermatological symptoms of xeroderma pigmentosum patients. Much can be learned about the way normal individuals function from a study of aberrant functioning of individuals with defined genetic deficiencies. In the field of senescence of the skin, the disease xeroderma pigmentosum (XP) has been of particular value, as the exposed skin of these sun-sensitive individuals shows at an early age many of the features of aged sun-exposed skin of normal individuals. These features of XP skin include hyperkeratosis, freckling, benign lesions and malignant tumours, including melanomas. A full discussion of this syndrome has been given by Kraemer et al.
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PMID:Sunlight-induced cancer: some new aspects and implications of the xeroderma pigmentosum model. 218 79

DNA repair in mammals consists of a large family of genes that encode a variety of mutually interacting gene products. These gene products coordinately locate and prepare damaged sites in chromatin for eventual excision and replacement and interact with transcriptionally active and replicating regions. Subsets of repair genes are represented by the complementation groups of xeroderma pigmentosum (XP), Cockayne syndrome, trichothiodystrophy and the ERCC series, which overlap one another to varying degrees. Cloned DNA sequences or whole chromosomes correct the UV-sensitive phenotype of XP by only 6-50%, which may be informative for the precise mechanisms of complementation and repair and for the relative importance of various UV photoproducts. Repair deficiencies in vivo are associated with increases in the toxic effects of UV damage and chronic expression of damage-inducible genes, with consequent implications for viability, development, neurological and immunological function, and carcinogenesis.
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PMID:Do we know the cause of xeroderma pigmentosum? 218 96

Photosensitive genodermatoses associated with established defects of DNA repair currently include the autosomal recessive diseases xeroderma pigmentosum (XP), Cockayne's syndrome (CS), trichothiodystrophy (TTD), and Bloom's syndrome (BS). XP is a heterogeneous disorder associated with defective excision repair or daughter strand repair of ultraviolet (UV)-induced DNA damage. It is characterized by cutaneous and ocular abnormalities predominantly on sun-exposed sites and in some cases, neurological features resulting from progressive neuronal loss. Skin involvement includes easy sunburning, pigmentary abnormalities, telangiectasia, dryness, scarring, and susceptibility to multiple benign and malignant neoplasms. In CS, defective repair of actively transcribing DNA is clinically associated with acute photosensitivity, growth retardation, demyelinating neurological abnormalities, and pigmentary retinal degeneration, but without increased cancer susceptibility. TTD is characterized by sulphur-deficient brittle hair, variable growth delay, mental retardation, ichthyosis, and in some cases photosensitivity. Although in some patients there is a deficiency of DNA excision repair identical to that in certain xeroderma pigmentosum patients, no increased cancer risk is present in trichothiodystrophy. In BS, deficient cellular DNA ligase is associated with congenital telangiectasia, photosensitivity, growth retardation, immune deficiency, increased susceptibility to infection, and predominantly internal rather than cutaneous malignancy. Immunological factors may at least determine the varying susceptibility to malignancy of these conditions.
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PMID:DNA repair deficient photodermatoses. 220 44

There is evidence for defective DNA repair in xeroderma pigmentosum, Cockayne's syndrome, and trichothiodystrophy, but for increased cancer risk only in xeroderma pigmentosum. Natural and adaptive immune surveillance and mutant frequency to 6-thioguanine resistance in circulating T-lymphocytes were studied in five patients with xeroderma pigmentosum, two with Cockayne's syndrome, and one with trichothiodystrophy. Forty-eight-hour cutaneous hypersensitivity responses to recall antigens excluded anergy and circulating CD3+, CD4+, CD8+, and CD16+ cell numbers were within normal limits in all patients tested, as were proliferative lymphocyte responses to PHA, except in the trichothiodystrophy patient. Proliferative responses to recall antigens (PPD, SKSD, and Candida) showed that all patients responded to one or more antigens. Direct natural killer cytotoxicity measured against the human erythromyeloid leukaemia cell line K562 using a 4-h 51Cr release assay was significantly reduced in xeroderma pigmentosum (specific cytotoxicity less than mean +/- SD greater than 17.4 +/- 9.4 per cent, with effector:target cell ratio of 50:1) compared to normal controls (45.8 +/- 17.8), but normal in Cockayne's syndrome and trichothiodystrophy. Generation of lymphokine activated killer cell activity was normal in the two xeroderma pigmentosum lines tested. The mutant frequency in the xeroderma pigmentosum donors was significantly increased (p less than 0.01) and was elevated in the two Cockayne's syndrome donors, taking age into account. No mutants were observed from the single trichothiodystrophy donor. These findings suggest that reduced natural killer cell activity may contribute to the greatly increased susceptibility to skin cancer in xeroderma pigmentosum.
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PMID:Immune function, mutant frequency, and cancer risk in the DNA repair defective genodermatoses xeroderma pigmentosum, Cockayne's syndrome, and trichothiodystrophy. 238 95

The association of two rare hereditary disorders, trichothiodystrophy (TTD) and xeroderma pigmentosum (XP), was found in four patients from three families, apparently unrelated but living in the same geographical area. In order to test the hypothesis of a common ancestor, consanguinity within and among the families was checked using three different approaches: reconstruction of genealogical trees, typing of blood markers, and surname analysis. The results of the three types of analyses strengthen the hypothesis that, in at least two out of the three families, the genetic defect determining the TTD/XP phenotype is identical by descent, as a consequence of remote inbreeding. This implies that if two mutations are responsible for the two diseases they are at linked loci or affect the same gene.
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PMID:Search for consanguinity within and among families of patients with trichothiodystrophy associated with xeroderma pigmentosum. 230 51

Chromosome and blood marker studies were performed in the families of 4 patients in which the association of 2 rare recessive Mendelian disorders, xeroderma pigmentosum (XP-D) and trichothiodystrophy (TTD), was present. Blood genotypes did not indicate any linkage with the pathologic condition, nor any segregation anomaly. Cytogenetic analysis using high-resolution banding techniques showed a normal karyotype both in the heterozygous and in the homozygous individuals. These findings lead us to exclude a cytologically detectable chromosome rearrangement, such as a microdeletion, as a possible cause of the association of XP-D and TTD in our patients.
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PMID:Chromosome and blood marker studies in families of patients affected by xeroderma pigmentosum and trichothiodystrophy. 339 68

A normal level of UV-induced DNA-repair synthesis (UDS) was observed in fibroblasts from a patient affected by trichothiodystrophy (TTD) without photosensitivity. This finding indicates that the hypersensitivity to UV light and the reduced UDS due to the presence of xeroderma pigmentosum complementation group D mutation (XP-D), described in photosensitive TTD patients, are not constantly associated with TTD. Complementation analysis in heterokaryons, obtained by fusion of repair-proficient with repair-deficient TTD cells, demonstrates that cells from the patient showing normal photosensitivity are able to restore UDS in UV-hypersensitive TTD cells.
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PMID:Complementation studies in cells from patients affected by trichothiodystrophy with normal or enhanced UV photosensitivity. 360 Jun 93


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