Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0349506 (photosensitivity)
4,145 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Xeroderma pigmentosum (XP) complementation group D is a heterogeneous group, containing patients with XP alone, rare cases with both XP and Cockayne syndrome, and patients with trichothiodystrophy (TTD). TTD is a rare autosomal recessive multisystem disorder associated, in many patients, with a defect in nucleotide-excision repair; but in contrast to XP patients, TTD patients are not cancer prone. In most of the repair-deficient TTD patients, the defect has been assigned to the XPD gene. The XPD gene product is a subunit of transcription factor TFIIH, which is involved in both DNA repair and transcription. We have determined the mutations and the pattern of inheritance of the XPD alleles in the 11 cases identified in Italy so far, in which the hair abnormalities diagnostic for TTD are associated with different disease severity but similar cellular photosensitivity. We have identified eight causative mutations, of which four have not been described before, either in TTD or XP cases, supporting the hypothesis that the mutations responsible for TTD are different from those found in other pathological phenotypes. Arg112his was the most common alteration in the Italian patients, of whom five were homozygotes and two were heterozygotes, for this mutation. The presence of a specifically mutated XPD allele, irrespective of its homozygous, hemizygous, or heterozygous condition, was always associated with the same degree of cellular UV hypersensitivity. Surprisingly, however, the severity of the clinical symptoms did not correlate with the magnitude of the DNA-repair defect. The most severe clinical features were found in patients who appear to be functionally hemizygous for the mutated allele.
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PMID:Analysis of mutations in the XPD gene in Italian patients with trichothiodystrophy: site of mutation correlates with repair deficiency, but gene dosage appears to determine clinical severity. 975 21

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.
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PMID: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. 1046 12

Xeroderma pigmentosum (XP) and Cockayne syndrome (CS) are two hereditary disorders in which photosensitivity is associated with distinct clinical and cellular phenotypes and results from genetically different defects. We have identified the primary molecular alteration in two patients in whom clinical manifestations strongly reminiscent of a severe form of XP were unexpectedly associated with the CS cellular phenotype and with a defect in the CSB gene. Sequencing of the CSB -coding region in both cDNA and genomic DNA showed that these patients had identical alterations to those in a patient with the clinical features of the classical form of CS. These data, together with fluorescence in situ hybridization analysis, demonstrated that the two siblings with XP as well as the CS patient were homozygous for the same CSB mutated allele, containing a silent C2830T change and a nonsense mutation C2282T converting Arg735 to a stop codon. The finding that the same inactivating mutation underlies different pathological phenotypes indicates that there is no simple correlation between the molecular defect and the clinical features. Therefore, alterations in the CSB gene give rise to the same repair defect at the cellular level but other genetic and/or environmental factors determine the pathological phenotype.
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PMID:Identical mutations in the CSB gene associated with either Cockayne syndrome or the DeSanctis-cacchione variant of xeroderma pigmentosum. 1076 41

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.
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PMID:Compound heterozygous group A xeroderma pigmentosum patient with a novel mutation and an inherited reciprocal translocation. 1088 56

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.
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PMID:Xeroderma pigmentosum: the role of phototesting. 1097 35

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.
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PMID:Xeroderma pigmentosum variant heterozygotes show reduced levels of recovery of replicative DNA synthesis in the presence of caffeine after ultraviolet irradiation. 1112 Nov 29

We report a Japanese woman with de novo 6p monosomy and 10q trisomy [46,XX,der(6)t(6;10)(p25.1;q25.2)] whose clinical manifestations resemble those of xeroderma pigmentosum (XP) and Cockayne syndrome (CS), known as premature aging syndromes. She had a history of easy sunburning and presented a number of freckles and hypopigmented spots on her face as those of XP. Magnetic resonance imaging and computed tomography scanning demonstrated intracranial abnormalities like those seen in CS. DNA repair studies using the patient's fibroblasts demonstrated hypersensitive responses to ultraviolet (UV). XP, CS, and UV-sensitive syndromes with photosensitivity disturbances have been known as DNA repair abnormalities. However, an association of 6p monosomy with these diseases has not been reported so far. Molecular analysis of the patient we described may contribute to the identification of novel DNA-repair-related gene(s) and/or to the senile mechanism.
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PMID:Woman with UV hypersensitivity and a de novo unbalanced chromosome translocation. 1139 59

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.
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PMID:Cerebro-oculo-facio-skeletal syndrome with a nucleotide excision-repair defect and a mutated XPD gene, with prenatal diagnosis in a triplet pregnancy. 1144 45

The term PIBI(D)S has been used to indicate a rare recessively inherited genetic disorder characterized by photosensitivity, mild non-congenital ichthyosis, brittle sulphur-deficient hair with trichoschisis (trichothiodystrophy), impaired intelligence, occasionally decreased fertility and short stature. To the best of our knowledge, about 20 cases have been reported in the literature. Here we report the characterization of the hair, brain, ultraviolet sensitivity and DNA excision repair defects of a new patient affected by PIBI(D)S. The diagnosis of PIBI(D)S syndrome was made in our patient on the basis of the clinical features and then confirmed by hair microscopy and biochemical analysis. Our patient has increased muscular tone, alteration of the deep tendon reflexes and psychomotor retardation, all consistent with hypomyelination of the brain showed by magnetic resonance imaging and computed tomography. A deficiency of DNA repair capacity was demonstrated in our patient. Furthermore, complementation analysis by cell fusion assigned our patient to xeroderma pigmentosum group D. The nucleotide excision repair defect of the other reported patients with PIBI(D)S falls generally into the same group as xeroderma pigmentosum group D and carry a mutation on the same repair gene (XPD). The relationship between these molecular characteristics and the clinical spectrum of PIBI(D)S is discussed.
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PMID:PIBI(D)S: clinical and molecular characterization of a new case. 1145 10

DNA integrity is threatened by the damaging effects of physical and chemical agents that can affect its function. Nucleotide excision repair (NER) is one of the most known and flexible mechanisms of DNA repair. This mechanism can recognize and remove damages causing DNA double-helix distortion, including the cyclobutane pyrimidine dimers (CPDs) and the pyrimidine-pyrimidone (6-4) photoproducts, promoted by ultraviolet light (UV). The human syndrome xeroderma pigmentosum (XP) is clinically characterized chiefly by the early onset of severe photosensitivity of the exposed regions of the skin, a very high incidence of skin cancers and frequent neurological abnormalities. The xpa gene seems to be involved during UV damage recognition, in both global genome repair (GGR) and transcription-coupled repair (TCR). The modulation of xpa expression may modify the DNA repair rate in the cell genome, providing a valuable contribution to an understanding of the NER process. The controlled expression of the cDNA xpa in XP12RO deficient cells was achieved through the transfection of a muristerone-A inducible vector, pINXA. The INXA15 clone shows good induction of the XPA protein and total complementation of XP12RO cell deficiency. Overexpression of this protein resulted in UV cell survival comparable to normal control human cells. Moreover, low expression of the XPA protein in these cells is sufficient for total complementation in cellular UV sensitivity and DNA repair activity. These data demonstrate that XPA protein concentration is not a limiting factor for DNA repair.
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PMID:Low amounts of the DNA repair XPA protein are sufficient to recover UV-resistance. 1208 27


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