1/72. Molecular studies of Japanese patients with group A xeroderma pigmentosum using polymerase chain reaction and restriction fragment length polymorphism and nonradioactive single strand conformation polymorphism analyses.xeroderma pigmentosum is an autosomal recessive disease characterized by extreme sensitivity of the skin to ultraviolet light, which results in a high incidence of early skin cancer. We report here the molecular analysis of the xeroderma pigmentosum group A complementing genes of five Japanese patients with group A xeroderma pigmentosum and their families, by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis, and by PCR and non-radioactive single strand conformation polymorphism (SSCP) analysis using the Pharmacia PhastSystem. Four of the five patients were found to be homozygous for a known splicing mutation of intron 3. One patient was found to be heterozygous for the splicing mutation of intron 3 and a known nonsense mutation of exon 6. This nonradioactive PCR-SSCP technique was as useful for the molecular diagnosis of patients with group A xeroderma pigmentosum as was PCR-RFLP analysis.- - - - - - - - - - ranking = 1keywords = sensitivity (Clic here for more details about this article) |
2/72. xeroderma pigmentosum variant associated with multiple cancers.A 62-year-old Japanese man with xeroderma pigmentosum (XP) variant is reported. The patient had developed at least 6 basal cell carcinomas, a squamous cell carcinoma, and a malignant melanoma on sun-exposed areas, and an atypical carcinoid on the right lung. In vivo phototesting showed a normal response. The minimal erythema dose of ultraviolet B (UVB) was not lowered and no delayed peaking of the erythema reaction was observed. His skin fibroblasts exhibited higher sensitivity to UV irradiation, but a normal level of unscheduled DNA and rna synthesis. Cell fusions with XP group A, C, D, E, F, and G cells after UV irradiation were all complemented. Previous reports together with this case suggest that older XP variant patients have a high frequency of not only skin cancers, but also internal malignancies.- - - - - - - - - - ranking = 1keywords = sensitivity (Clic here for more details about this article) |
3/72. A newly identified patient with clinical xeroderma pigmentosum phenotype has a non-sense mutation in the DDB2 gene and incomplete repair in (6-4) photoproducts.We report here a patient (Ops1) with clinical photosensitivity, including pigmented or depigmented macules and patches, and multiple skin neoplasias (malignant melanomas, basal cell carcinomas, and squamous cell carcinomas in situ) in sun-exposed areas. These clinical features are reminiscent of xeroderma pigmentosum. As cells from Ops1 showed normal levels in dna repair synthesis in vivo (unscheduled DNA synthesis and recovery of rna synthesis after ultraviolet irradiation), we performed a postreplication repair assay and recovery of replicative DNA synthesis after ultraviolet irradiation to investigate if Ops1 cells belonged to a xeroderma pigmentosum variant pattern. Ops1 cells were normal, but there was an incomplete pattern repair in (6-4) photoproducts in contrast to a normal pattern repair in cis-syn cyclobutane pyrimidine dimers by repair kinetics using the enzyme-linked immunosorbent assay. Moreover, Ops1 cells were defective in a damage-specific DNA binding protein and carried a non-sense mutation in the DDB2 gene. These results suggest that (i) the DDB2 gene is somewhat related to skin carcinogenesis, photoaging skin, and the removal of (6-4) photoproducts; (ii) although it is believed that cyclobutane pyrimidine dimers are the principal mutagenic lesion and (6-4) photoproducts are less likely to contribute to ultraviolet-induced mutations in mammals, Ops1 is one of the ultraviolet-induced mutagenic models induced by (6-4) photoproducts.- - - - - - - - - - ranking = 1.0022247989311keywords = sensitivity, contrast (Clic here for more details about this article) |
4/72. Cancer protection in xeroderma pigmentosum variant (XP-V).We describe herein a brother and sister diagnosed with xeroderma pigmentosum variant (XP-V) in early adult life, who presented with increased sensitivity to sunlight and with cutaneous carcinomas on sun-damaged skin. The 27-year-old male farmer (Case 1.) was diagnosed with advanced squamous cell carcinoma (SCC) and multiple actinic lesions. Surgical removal of these lesions was performed. Three months later he died of multiple pelvic metastases of SCC. His 29-year-old sister (Case 2.) was operated on for different tumors, histologically SCC-s or basal cell carcinomas (BCC), or praecancerous conditions many times. After a two year interval she was treated with low dose isotretinoin (2 mg/body weight). Diagnosis of XP-V was based on unscheduled DNA analysis (USD) and on clinical symptoms. We observed that during the long lasting isotretinoin treatment the tumor frequency dropped to a quarter. Therefore, the isotretinoin treatment seems to be a good approach for cancer prevention in conditions with high predisposition to skin cancer, such as in XP-V.- - - - - - - - - - ranking = 1keywords = sensitivity (Clic here for more details about this article) |
5/72. Compound heterozygous group A xeroderma pigmentosum patient with a novel mutation and an inherited reciprocal translocation.The severity of neurological abnormalities in Japanese group A xeroderma pigmentosum (XP-A) patients correlates with the sites of non-sense mutation in the XP-A gene. We describe a patient who presented with a more severe photosensitivity and neurological abnormality than those in typical Japanese XP-A patients with a splicing mutation in intron 3. The patient was compound heterozygous for the splicing mutation in intron 3, which resulted in formation of a non-sense codon in exon 4, and a novel non-sense mutation at codon 208 in exon 5, a C to T transition creating a stop codon TAG. Although the combination of these mutations might have been thought to cause only mild neurological signs, the longer truncated XP-A proteins than those of typical XP-A patients may have resulted in severe neurological symptoms. This phenomenon may be explained by a translocation of chromosome (1;10)(q25.3;q22.3) inherited from his father.- - - - - - - - - - ranking = 1keywords = sensitivity (Clic here for more details about this article) |
6/72. xeroderma pigmentosum: the role of phototesting.We report three patients newly diagnosed as having xeroderma pigmentosum (XP). Previous photobiological studies have implicated ultraviolet (UV) B as the activating waveband in XP, causing a delayed and prolonged erythemal response. This characteristic reaction pattern has been used as a quick screening test in patients suspected of having XP, while awaiting confirmatory dna repair studies. Two of our patients showed no abnormal erythemal responses, and one showed severe photosensitivity from 330 to 400 nm but normal UVB responses, with a peak erythema at 24 h. We conclude that the erythemal responses in XP are highly variable and cannot be considered as a reliable screening test in the diagnosis of XP.- - - - - - - - - - ranking = 1keywords = sensitivity (Clic here for more details about this article) |
7/72. Four radiation hypersensitivity cases and their implications for clinical radiotherapy.BACKGROUND AND PURPOSE: Over a 20 year period, four out of 2000 paediatric radiotherapy patients, treated at St. Bartholomew's Hospital (three with lymphoma, one with angiosarcoma), have revealed extreme/fatal clinical hypersensitivity in normal tissues. patients AND methods: Cellular hypersensitivity was confirmed in vitro and attributed to the ataxia-telangiectasia (A-T) gene in cases I and II, a newly described defect in the DNA ligase 4 gene in case III, and a novel and as yet incompletely defined, molecular defect in case IV who presented with xeroderma pigmentosum (XP). RESULTS: The severe clinical hypersensitivity preceded the cellular and molecular analysis, but did not manifest as a clinically exaggerated normal tissue reaction until 3 weeks after the start of a conventionally fractionated course of radiotherapy, by which time the latent damage had been inflicted. There were no clinical stigmata to alert the clinician to a predisposing syndrome in two patients (cases I and II). We point out that approximately 20% of A-T patients are classified as variants with delayed expression of clinical symptoms, and case II falls into this category. CONCLUSIONS: As lymphoma (incidence, one in 100000 children) constituted the majority of the diagnoses, questions arise as to: (1), the probability of other centres having experienced and being presented in the future with similar problems (particularly bearing in mind that other oncologically predisposing radiosensitivity syndromes have not been not represented in our experience); and (2), the appropriateness, efficiency and applicability of predictive assays. Unambiguous cellular radiosensitivity would have been apparent from clonal assays on fibroblast cultures from all four cases prior to treatment, but such assays take 4-6 weeks to produce results. While estimates of chromosome damage or clonal assays on pre-treatment blood derived cells would be faster, there is a health economics issue as to the general applicability of such 'screening' assays.- - - - - - - - - - ranking = 9keywords = sensitivity (Clic here for more details about this article) |
8/72. xeroderma pigmentosum variant heterozygotes show reduced levels of recovery of replicative DNA synthesis in the presence of caffeine after ultraviolet irradiation.patients with xeroderma pigmentosum variant show clinical photosensitivity, skin neoplasias induced by ultraviolet light, and defective postreplication repair, but normal nucleotide excision repair. We recently reported an alternative, simple method for the diagnosis of xeroderma pigmentosum variant that measures by autoradiography three cellular markers for dna repair after ultraviolet irradiation: unscheduled DNA synthesis, recovery of rna synthesis, and recovery of replicative DNA synthesis. Among hereditary photosensitive disorders, including other xeroderma pigmentosum groups, cockayne syndrome, and a newly established ultraviolet-sensitive syndrome, only xeroderma pigmentosum variant cells exhibited normal unscheduled DNA synthesis, normal recovery of rna synthesis, but reduced recovery of replicative DNA synthesis (51 /- 6% the rate relative to normal controls). This reduction of recovery of replicative DNA synthesis was enhanced in the presence of a nontoxic level of caffeine to 36 /- 5%. In this study we assess the cellular markers in two independent families that included two photosensitive patients that were identified as xeroderma pigmentosum variant. cells from heterozygotic parents showed normal levels of unscheduled DNA synthesis, recovery of rna synthesis, and recovery of replicative DNA synthesis, but reduced rates of recovery of replicative DNA synthesis in the presence of 1 mM caffeine (53 /- 8% relative to the normal control). Furthermore, with a colony-forming assay, the cells showed normal survival by ultraviolet without caffeine, but slightly reduced survival by ultraviolet with 1 mM caffeine present. In one family, we confirmed inheritance of two heterozygous mis-sense mutations. One mutation is an A-->G transition at nucleotide 1840 that generates a K535E mis-sense mutation. Another mutation is an A-->C transversion at nucleotide 2003 that generates a K589 mis-sense mutation. Each of these mutations were absent in 52 unrelated Japanese individuals. These results suggest that xeroderma pigmentosum variant heterozygotes can be identified by their sensitivity to ultraviolet irradiation in the presence of nontoxic levels of caffeine.- - - - - - - - - - ranking = 2keywords = sensitivity (Clic here for more details about this article) |
9/72. Studies on a new case of xeroderma pigmentosum (XP3BR) from complementation group G with cellular sensitivity to ionizing radiation.XP3BR is a fibroblast strain derived from a xeroderma pigmentosum patient exhibiting severe mental retardation in addition to the typical changes in the skin. No tumours have been observed by 6 years of age. cells from this patient had no detectable excision repair of u.v. damage. The defect in daughter strand repair was also characteristic of excision-defective XP's. The material was assigned to complementation group G and is the second (unrelated) example from this group. XP3BR cells were more sensitive than normal cells to the lethal action not only of u.v. but also of gamma irradiation, in contrast to all other XP cells tested to date including XP2BI, the other representative of complementation group G. The u.v. sensitivity was similar to that of strains from complementation groups A and D, confirming the correlation between extreme u.v. sensitivity and the presence of neurological defects. Following treatment with u.v., XP3BR, and other XPs gave more 6-thioguanine resistant mutants than normal cells whether the comparison was made per unit of dose or per lethal event. After low doses of gamma irradiation XP3BR cells were more mutable than normal or XP2BI cells.- - - - - - - - - - ranking = 6.0022247989311keywords = sensitivity, contrast (Clic here for more details about this article) |
10/72. Cerebro-oculo-facio-skeletal syndrome with a nucleotide excision-repair defect and a mutated XPD gene, with prenatal diagnosis in a triplet pregnancy.Cerebro-oculo-facio-skeletal (COFS) syndrome is a recessively inherited rapidly progressive neurologic disorder leading to brain atrophy, with calcifications, cataracts, microcornea, optic atrophy, progressive joint contractures, and growth failure. cockayne syndrome (CS) is a recessively inherited neurodegenerative disorder characterized by low to normal birth weight, growth failure, brain dysmyelination with calcium deposits, cutaneous photosensitivity, pigmentary retinopathy and/or cataracts, and sensorineural hearing loss. Cultured CS cells are hypersensitive to UV radiation, because of impaired nucleotide-excision repair (NER) of UV-induced damage in actively transcribed DNA, whereas global genome NER is unaffected. The abnormalities in CS are caused by mutated CSA or CSB genes. Another class of patients with CS symptoms have mutations in the XPB, XPD, or XPG genes, which result in UV hypersensitivity as well as defective global NER; such patients may concurrently have clinical features of another NER syndrome, xeroderma pigmentosum (XP). Clinically observed similarities between COFS syndrome and CS have been followed by discoveries of cases of COFS syndrome that are associated with mutations in the XPG and CSB genes. Here we report the first involvement of the XPD gene in a new case of UV-sensitive COFS syndrome, with heterozygous substitutions-a R616W null mutation (previously seen in patients in XP complementation group D) and a unique D681N mutation-demonstrating that a third gene can be involved in COFS syndrome. We propose that COFS syndrome be included within the already known spectrum of NER disorders: XP, CS, and trichothiodystrophy. We predict that future patients with COFS syndrome will be found to have mutations in the CSA or XPB genes, and we document successful use of dna repair for prenatal diagnosis in triplet and singleton pregnancies at risk for COFS syndrome. This result strongly underlines the need for screening of patients with COFS syndrome, for either UV sensitivity or DNA-repair abnormalities.- - - - - - - - - - ranking = 3keywords = sensitivity (Clic here for more details about this article) |
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