PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “Xeroderma Pigmentosum”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 55 records · Page 3Linked to original sources
PubMed1989

[DNA repair defect in xeroderma pigmentosum].

Xeroderma pigmentosum (XP) is an autosomal recessive human disease, clinically characterized by the early onset of severe photosensitivity of exposed skin to sunlight, a very high incidence of skin cancers and frequent neurological abnormalities. Cells from XP patients are hypersensitive to killing by UV-light, because they have a defect in repair of UV-light induced DNA damage. Genetic complementation analysis by cell fusion has led to the identification of at least ten genetic complementation groups, designated as group A through I, and a variant. However, the genetic basis of the physiological defect of XP has not yet been characterized. For isolation of the gene responsible for XP complementation group A, the pSV2gpt and genomic DNA from a mouse embryo were co-transfected into XP2OSSV group A XP cells. Two primary UV-resistant XP transfectants were isolated from about 1.6 X 10(5) pSV2gpt transformed XP colonies. The pSV2gpt and genomic DNA from the primary transfectants were again co-transfected into XP2OSSV cells, and a secondary UV-resistant XP transfectant was obtained by screening about 4.8 X 10(5) pSV2gpt transformed XP colonies. The secondary transfectant retained fewer mouse repetitive sequences. A mouse gene that complements the defect of XP2OSSV cells was cloned into EMBL3 vectors from the secondary transfectant. Transfections of the cloned DNA also conferred UV-resistance on another group A XP cell line, but not on group C, D, F or G XP cell lines, suggesting that the cloned DNA repair gene is specific for group A XP and may be the mouse counterpart of the group A XP human gene.

Animals↗
PubMed2001

Association between DNA repair-deficiency and high level of p53 mutations in melanoma of Xeroderma pigmentosum.

Xeroderma pigmentosum (XP) is an inheritable disease characterized by sun-sensitivity and a high frequency of skin cancers including melanoma. We have analyzed two different groups of XP: the XP complementation group C (XP-C), deficient in global nucleotide excision repair but proficient in transcription-coupled repair and associated with a very early onset of skin cancers; and the XP variant (XPV), deficient in the bypass of DNA photoproducts. To get new insights into the biology of melanoma in XP patients, we studied 20 melanomas from four XP-C and two XPV patients in terms of pathology, immunohistochemistry of p53, mutations in exons 4-9 of the p53 gene, and polymorphisms of the p53 gene at codon 72. All statistical tests were two-sided. The majority of the XP melanomas were of the lentigo maligna melanoma (LMM) type, as found in the elderly. p53 point mutations were found in 60% of XP-C melanomas and in only 10% of XPV melanomas, this latter frequency being similar to what has been reported in the general population. Mutations show the specific UV-signature because the majority were CC to tandem and C to T transitions located at the bipyrimidine sites known to be hotspots of UV-induced DNA lesions. All DNA lesions giving rise to mutations in XP-C melanomas were located on the nontranscribed strand of the p53 gene, demonstrating that these patients' cells were able to carry out preferential repair in vivo. The LMMs found in XP-C are associated with an accumulation of unrepaired DNA lesions and may represent a good model for the LMM induction in the elderly.

Adolescent↗
PubMed1984

DNA repair protects against cutaneous and internal neoplasia: evidence from xeroderma pigmentosum.

Xeroderma pigmentosum (XP), is a rare, autosomal recessive disease with sun sensitivity and multiple neoplasms in association with reduced DNA repair. As a reflection of the clinical consequences of deficient DNA repair, XP serves as a model for determining the effects of proficient DNA repair. To estimate the risk of developing neoplasms in XP, we abstracted reports of 726 XP patients (from 41 countries) published from 1874 to 1982. Despite limitations of a literature survey, the XP patients under age 20 years had an estimated 2000-fold increase in frequency of basal cell and squamous cell carcinoma of the skin, of cutaneous melanoma, of cancer of the anterior eye, and of cancer of the anterior tongue, in comparison to the general population. These sites are all potentially exposed to u.v. radiation, a strong carcinogen which produces DNA damage that is poorly repaired by XP cells. XP patients under age 20 years also had an estimated 12-fold increase in occurrence of neoplasms in sites not exposed to u.v. radiation. Among the XP patients under age 40 years with internal cancer, there was a disproportionate representation of malignant neoplasms of the brain (especially sarcomas), and oral cavity (excluding tongue) compared to US whites under age 40 years. These internal neoplasms may be related to exposure to chemical environmental carcinogens that cause DNA damage which, like u.v.-induced damage, is poorly repaired by XP cells. These reports provide no evidence of an increase in XP of common lethal neoplasms such as lymphomas, or female genital tract or endocrine system cancers. These findings suggest that DNA repair plays a role in protection against u.v.-induced neoplasia and in protection against some internal neoplasms in the general population.

Adolescent↗
PubMed2001

Effect of topically applied T4 endonuclease V in liposomes on skin cancer in xeroderma pigmentosum: a randomised study. Xeroderma Pigmentosum Study Group.

BACKGROUND: In patients with xeroderma pigmentosum the frequency of all forms of skin cancer is higher than in the general population, owing to a genetic defect in DNA repair. The bacterial DNA repair enzyme, T4 endonuclease V, delivered intracellularly, increases the rate of repair of sunlight-induced DNA damage in human cells. We tested the ability of this enzyme in a liposomal delivery vehicle applied topically (T4N5 liposome lotion) to lower the rate of new skin cancers in patients with xeroderma pigmentosum. METHODS: 30 patients were enrolled in this prospective, multicentre, double-blind study. Patients were randomly assigned T4N5 liposome lotion or a placebo liposome lotion, to be applied daily for 1 year. At 3-monthly visits, new actinic keratoses and basal-cell carcinomas were identified and removed. Analyses were by intention to treat. FINDINGS: 20 patients were assigned T4N5 liposome lotion and ten placebo lotion; one placebo-group patient withdrew before treatment and one withdrew with progressive disease at 9 months. The annualised rate of new actinic keratoses was 8.2 among the patients assigned T4N5 liposome lotion and 25.9 among those assigned placebo (difference 17.7 [95% CI 11.8-26.5]; p=0.004 by Poisson modelling). For basal-cell carcinoma, the annualised rates of new lesions were 3.8 in the treatment group and 5.4 in the placebo group (difference 1.6 [0.38-2.82]). No significant adverse effects were found among any of the patients. INTERPRETATION: DNA damage has an important role in the development of skin cancer and precancerous skin lesions. The topical application of DNA repair enzymes to sun-damaged skin of patients with xeroderma pigmentosum lowered the rate of development of two forms of these lesions during a year of treatment.

Administration, Topical↗
PubMed1996

DNA repair and ultraviolet mutagenesis in cells from a new patient with xeroderma pigmentosum group G and cockayne syndrome resemble xeroderma pigmentosum cells.

Xeroderma pigmentosum (XP)/Cockayne syndrome (CS) complex is a combination of clinical features of two rare genetic disorders in one individual. A sun-sensitive boy (XP20BE) who had severe symptoms of CS, with dwarfism, microcephaly, retinal degeneration, and mental impairment, had XP-type pigmentation and died at 6 y with marked cachexia (weight 14.5 lb) without skin cancers. We evaluated his cultured cells for characteristic CS or XP DNA-repair abnormalities. The level of ultraviolet (UV)-induced unscheduled DNA synthesis was less than 5% of normal, characteristic of the excision-repair defect of XP. Cell fusion studies indicated that his cells were in XP complementation group G. His cells were hypersensitive to killing by UV, and their post-UV recovery of RNA synthesis was abnormally low, features of both CS and XP. Post-UV survival of plasmid pSP189 in his cells was markedly reduced, and post-UV plasmid mutation frequency was higher than with normal cells, as in both CS and XP. Sequence analysis of the mutated plasmid marker gene showed normal frequency of plasmids with multiple base substitutions, as in CS, and an abnormally increased frequency of G:C-->A:T mutations, a feature of XP. Transfection of UV-treated pRSVcat with or without photoreactivation revealed that his cells, like XP cells, could not repair either cyclobutane pyrimidine dimers or non-dimer photoproducts. These results indicate that the DNA-repair features of the XP20BE (XP-G/CS) cells are phenotypically more like XP cells than CS cells, whereas clinically the CS phenotype is more prominent than XP.

Cell Survival↗
PubMed1989

Stimulated production of ATP by H2O2 disproportionation in extracts from normal and xeroderma pigmentosum skins, and from normal, xeroderma pigmentosum, ataxia telangiectasia and simian virus 40 transformed cell lines.

It has been previously shown that xeroderma pigmentosum (XP) skin biopsies and their established cell lines exhibit a decrease in catalase activity and enhanced formation of photo-produced H2O2. Several in vivo and in vitro thermodynamic results suggest that the energy of H2O2 disproportionation produced by catalase could be sufficient to synthesize ATP with or without the help of intact mitochondria. In this paper, we first studied the properties of H2O2-stimulated ATP production in extracts of normal and pathological XP skin biopsies and cell lines. In acellular extracts of normal skin biopsies and/or cell lines, ATP production can be increased 2- to 3-fold, but only with a narrow range of H2O2 concentration. In contrast, in extracts of pathological skins or cells, ATP production was only observed when using 10- to 1000-fold less H2O2 concentration as defined for normal extracts. Similar results were noted with two cell lines derived from patients afflicted with ataxia telangiectasia (AT), and with simian virus 40 (SV40) transformed lines of normal, XP and AT cells, Although we have no proof that such a process may exist in vivo, we would like to suggest that both H2O2-stimulated ATP production and catalase activity are good indicators of the degree of normality or abnormality of skin biopsies and/or cell lines.

Adenosine Triphosphate↗
PubMed2001

Impaired ultraviolet-B-induced cytokine induction in xeroderma pigmentosum fibroblasts.

Xeroderma pigmentosum is a rare, autosomal recessive disease in which patients develop excessive solar damage at an early age and have a 1000-fold increased risk of developing cutaneous neoplasms. Xeroderma pigmentosum can be classified into seven complementation groups (A-G) with defects in different DNA nucleotide excision repair genes. Xeroderma pigmentosum patients also have impaired immune function including reduced natural killer cell activity and impaired induction of interferon-gamma. We hypothesized that altered cytokine induction may contribute to the immune defect in xeroderma pigmentosum patients. We examined cytokine mRNA expression after ultraviolet B irradiation using reverse transcriptase polymerase chain reaction in fibroblasts derived from five xeroderma pigmentosum patients in complementation groups A, C, and D and in complemented XP-A and XP-D cells. Cytokines interleukin-1beta and interleukin-6 displayed impaired ultraviolet B induction whereas interleukin-8 had normal induction in the xeroderma pigmentosum fibroblasts. Stable complementation of XP-A and XP-D cell lines increased ultraviolet-B-induced interleukin-1beta and interleukin-6 expression. These results demonstrate a deficient response of xeroderma pigmentosum fibroblasts to ultraviolet B in terms of cytokine interleukin-1beta and interleukin-6 induction but normal interleukin-8 induction and exhibit a role for DNA repair in cytokine induction.

Cell Line↗
PubMed1997

The molecular basis of xeroderma pigmentosum.

BACKGROUND: Xeroderma pigmentosum is an extremely rare, autosomal recessive disease characterized by a more than 1000-fold increase in nonmelanoma skin cancer. Individuals with this disease can be divided into eight complementation groups: A-G and V for variant. Each one represents a different genetic defect in DNA repair. OBJECTIVE: To review the molecular basis of xeroderma pigmentosum. RESULTS: Deficiencies in various gene products in the nucleotide excision repair pathway cause xeroderma pigmentosum in complementation groups A-G. The molecular basis of the variant group remains to be elucidated. CONCLUSIONS: Research into the genetic defects underlying xeroderma pigmentosum have led to an increased understanding of nucleotide excision repair.

Abnormalities, Multiple↗
PubMed2003

Molecular genetics of Xeroderma pigmentosum variant.

Xeroderma pigmentosum (XP) is an autosomal recessive disease characterized by sun sensitivity, early onset of freckling and subsequent neoplastic changes on sun-exposed skin. Skin abnormalities result from an inability to repair UV-damaged DNA because of defects in the nucleotide excision repair (NER) machinery. Xeroderma pigmentosum is genetically heterogeneous and is classified into seven complementation groups (XPA-XPG) that correspond to genetic alterations in one of seven genes involved in NER. The variant type of XP (XPV), first described in 1970 by Ernst G. Jung as 'pigmented xerodermoid', is caused by defects in the post replication repair machinery while NER is not impaired. Identification of the XPV gene was only achieved in 1999 by biochemical purification and sequencing of a protein from HeLa cell extracts complementing the PRR defect in XPV cells. The XPV protein, polymerase (pol)eta, represents a novel member of the Y family of bypass DNA polymerases that facilitate DNA translesion synthesis. The major function of (pol)eta is to allow DNA translesion synthesis of UV-induced TT-dimers in an error-free manner; it also possesses the capability to bypass other DNA lesions in an error-prone manner. Xeroderma pigmentosum V is caused by molecular alterations in the POLH gene, located on chromosome 6p21.1-6p12. Affected individuals are homozygous or compound heterozygous for a spectrum of genetic lesions, including nonsense mutations, deletions or insertions, confirming the autosomal recessive nature of the condition. Identification of POLH as the XPV gene provides an important instrument for improving molecular diagnostics in XPV families.

DNA-Directed DNA Polymerase↗
PubMed1995

Molecular and cellular analysis of the DNA repair defect in a patient in xeroderma pigmentosum complementation group D who has the clinical features of xeroderma pigmentosum and Cockayne syndrome.

Xeroderma pigmentosum (XP) and Cockayne syndrome (CS) are quite distinct genetic disorders that are associated with defects in excision repair of UV-induced DNA damage. A few patients have been described previously with the clinical features of both disorders. In this paper we describe an individual in this category who has unusual cellular responses to UV light. We show that his cultured fibroblasts and lymphocytes are extremely sensitive to irradiation with UV-C, despite a level of nucleotide excision repair that is 30%-40% that of normal cells. The deficiency is assigned to the XP-D complementation group, and we have identified two causative mutations in the XPD gene: a gly-->arg change at amino acid 675 in the allele inherited from the patient's mother and a -1 frameshift at amino acid 669 in the allele inherited from his father. These mutations are in the C-terminal 20% of the 760-amino-acid XPD protein, in a region where we have recently identified several mutations in patients with trichothiodystrophy.

Cells, Cultured↗
PubMed1993

High prevalence of the point mutation in exon 6 of the xeroderma pigmentosum group A-complementing (XPAC) gene in xeroderma pigmentosum group A patients in Tunisia.

Xeroderma pigmentosum (XP) patients in Tunisia who belong to the genetic complementation group A (XPA) have milder skin symptoms than do Japanese XPA patients. Such difference in the clinical features might be caused by the difference in the site of mutation in the XP A-complementing (XPAC) gene. The purpose of this study is to identify the genetic alterations in the XPAC gene in the Tunisian XPA patients and to investigate the relationship between the clinical symptoms and the genetic alterations. Three sites of mutation in the XPAC gene have been identified in the Japanese XPA patients, and about 85% of them have a G-->C point mutation at the splicing acceptor site of intron 3. We found that six (86%) of seven Tunisian XPA patients had a nonsense mutation in codon 228 in exon 6, because of a CGA-->TGA point mutation, which can be detected by the HphI RFLP. This type of mutation is the same as those found in two Japanese XPA patients with mild clinical symptoms. Milder skin symptoms in the XPA patients in Tunisia than in those in Japan, despite mostly sunny weather and the unsatisfactory sun protection in Tunisia, should be due to the difference in the mutation site.

Adolescent↗
PubMed1989

Late onset of skin cancers in 2 xeroderma pigmentosum group F siblings and a review of 30 Japanese xeroderma pigmentosum patients in groups D, E and F.

Sib patients with xeroderma pigmentosum (XP), XP90TO (42 years old, male) and XP92TO (40 years old, female, were assigned to group F by the complementation analysis in hybridized heterodikaryons. The XP90TO and XP92TO fibroblasts exhibited the typical XPF characteristics of a threefold higher sensitivity to the lethal effect of 254 nm UV and a reduced level of 12% unscheduled DNA synthesis (UDS) compared with normal cells. Clinically, both patients manifested moderate to severe acute sun sensitivity by age 8, pigmented freckles by age 10 and skin malignancies at higher ages (6 basaliomas at 42 years in XP90TO; 1 basalioma at 41 years in XP92TO). Despite the still currently sun-sensitive state, the patients showed normal minimal erythema dose (MED) at monochromatic wavelengths of 290, 300 and 305 nm but abnormally delayed peaking of erythema reaction at 48 h after exposure. After irradiation with more than 3 MED, XP92TO showed a long persistence of induced erythema for at least 7 days. A review of the 16 reported XPF patients indicated mild skin manifestations, no neurological abnormalities, and more delayed skin carcinogenesis at a lower frequency than that in XPA patients. In addition, we have collected clinical information from Japanese XP patients in rare complementation groups D and E and reviewed their clinical and photobiological characteristics.

Adult↗
PubMed2005

Transcription-associated breaks in xeroderma pigmentosum group D cells from patients with combined features of xeroderma pigmentosum and Cockayne syndrome.

Defects in the XPD gene can result in several clinical phenotypes, including xeroderma pigmentosum (XP), trichothiodystrophy, and, less frequently, the combined phenotype of XP and Cockayne syndrome (XP-D/CS). We previously showed that in cells from two XP-D/CS patients, breaks were introduced into cellular DNA on exposure to UV damage, but these breaks were not at the sites of the damage. In the present work, we show that three further XP-D/CS patients show the same peculiar breakage phenomenon. We show that these breaks can be visualized inside the cells by immunofluorescence using antibodies to either gamma-H2AX or poly-ADP-ribose and that they can be generated by the introduction of plasmids harboring methylation or oxidative damage as well as by UV photoproducts. Inhibition of RNA polymerase II transcription by four different inhibitors dramatically reduced the number of UV-induced breaks. Furthermore, the breaks were dependent on the nucleotide excision repair (NER) machinery. These data are consistent with our hypothesis that the NER machinery introduces the breaks at sites of transcription initiation. During transcription in UV-irradiated XP-D/CS cells, phosphorylation of the carboxy-terminal domain of RNA polymerase II occurred normally, but the elongating form of the polymerase remained blocked at lesions and was eventually degraded.

Cockayne Syndrome↗
PubMed1987

6-Methylguanine and 6-methylguanosine inhibit colony-forming ability in a malignant xeroderma pigmentosum cell line but not in other xeroderma pigmentosum and normal human fibroblast strains after treatment with 1-(2-chloroethyl)-1-nitroso-3-(2-hydroxyethyl)-urea.

The XP cell strain XP29MA, its malignant counterpart XP29MAmal and a normal human fibroblast strain were tested for colony-forming ability after treatment with HECNU in the presence of m6G, m6Gua, and he7G. In XP29MAmal, inhibition of post-HECNU colony-forming ability was 35% when 0.25 mM of either m6G or m6Gua were present, whereas in XP29MA and the normal fibroblast strain no inhibition was detected. The he7G caused a similar but smaller inhibitory effect in XP29MAmal, but failed to do so in XP29MA. HECNU predominantly exerts its killing effect by alkylating O-6 of DNA-bound guanine and causing DNA interstrand crosslinks. Alkylation of O-6 of guanine can be repaired by 6-methylguanine-DNA methyltransferase. From our experiments we conclude that in XP29MAmal this methyltransferase was inhibited in the presence of the 6-alkylguanines, thus leaving more 2-chloroethylated sites in DNA unrepaired. This results in sensitization in terms of decreased colony-forming ability observed only in the malignant cell line.

Cell Division↗
PubMed1980

Repair of DNA damage after exposure to 4-nitroquinoline-1-oxide in heterokaryons derived from xeroderma pigmentosum cells.

Xeroderma pigmentosum (XP) cells are deficient in the repair of damage induced by ultraviolet irradiation. Excision-repair-deficient XP cell strains have been classified into 7 distinct complementation groups, according to results of studies on cell fusion and UV irradiation. XP cells are not only abnormally sensitive to UV, but also to a variety of chemical carcinogens, including 4-nitro-quinoline-1-oxide (4NQO). Complementation analysis with XP strains from 4 different complementation groups with respect to the repair of 4NQO-induced DNA damage revealed that the classification of the strains into complementation groups with respect to 4NQO-induced repair coincides with the classification based on the repair of UV damage.

4-Nitroquinoline-1-oxide↗