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)

Trichothiodystrophy (TTD) is a rare, autosomal recessive disorder characterized by sulfur-deficient brittle hair and nails, mental retardation, impaired sexual development, and ichthyosis. Photosensitivity has been reported in approximately 50% of the cases, but no skin cancer is associated with TTD. Virtually all photosensitive TTD patients have a deficiency in the nucleotide excision repair (NER) of UV-induced DNA damage that is indistinguishable from that of xeroderma pigmentosum (XP) complementation group D (XP-D) patients. DNA repair defects in XP-D are associated with two additional, quite different diseases; XP, a sun-sensitive and cancer-prone repair disorder, and Cockayne syndrome (CS), a photosensitive condition characterized by physical and mental retardation and wizened facial appearance. One photosensitive TTD case constitutes a new repair-deficient complementation group, TTD-A. Remarkably, both TTD-A and XP-D defects are associated with subunits of TFIIH, a basal transcription factor with a second function in DNA repair. Thus, mutations in TFIIH components may, on top of a repair defect, also cause transcriptional insufficiency, which may explain part of the non-XP clinical features of TTD. Besides XPD and TTDA, the XPB gene product is also part of TFIIH. To date, three patients with the remarkable conjunction of XP and CS but not TTD have been assigned to XP complementation group B (XP-B). Here we present the characterization of the NER defect in two mild TTD patients (TTD6VI and TTD4VI) and confirm the assignment to X-PB. The causative mutation was found to be a single base substitution resulting in a missense mutation (T119P) in a region of the XPB protein completely conserved in yeast, Drosophila, mouse, and man. These findings define a third TTD complementation group, extend the clinical heterogeneity associated with XP-B, stress the exclusive relationship between TTD and mutations in subunits of repair/transcription factor TFIIH, and strongly support the concept of "transcription syndromes."
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PMID:A mutation in the XPB/ERCC3 DNA repair transcription gene, associated with trichothiodystrophy. 901 5

Xeroderma pigmentosum (XP) is a rare inherited disease associated with photosensitivity, a very high susceptibility to develop neoplasm on sun-exposed skin and neurological abnormalities for some patients. We previously reported that diploid cell lines established from XP skin biopsies present an abnormal low level of catalase activity, which is involved in the defense against oxygen free radicals. This biochemical dysfunction, probably involved in the skin cancer formation, has been difficult to be directly related to the nucleotide excision repair (NER) defect in XP. In this paper we report that the retroviral-mediated transduction of XP diploid cells by the XPC and XPD/ERCC2 cDNAs fully and stably corrects the NER defect in terms of survival and unscheduled DNA synthesis (UDS) after ultraviolet (UV) irradiation. The catalase activity in transduced cells was recovered up to normal levels only in cells transduced with repair genes correcting the repair defect. These results imply that: (i) the reduced catalase activity in XP, which might result from cellular depletion of its NADPH cofactor, is directly related to impaired DNA repair, and (ii) this depletion might be one of the multiple cellular consequences of XP inborn defect.
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PMID:Retroviral-mediated correction of DNA repair defect in xeroderma pigmentosum cells is associated with recovery of catalase activity. 950 92

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

Trichothiodystrophy (TTD) is a rare genetic disorder characterized by a hair dysplasia and associated with numerous symptoms affecting mainly organs derived from the neuroectoderm. About half of TTD patients exhibit photosensitivity because their nucleotide-excision repair pathway (NER) does not remove UV-induced DNA lesions efficiently. However, they do not present the skin cancer susceptibility expected from such an NER disorder. Their deficiencies result from phenotype-specific mutations in either XPB or XPD. These genes encode the helicase subunits of TFIIH, a DNA repair factor that is also required for transcription of class II genes. Thus, time- and tissue-specific impairments of transcription might explain the developmental and neurological symptoms of TTD. In a third group of photosensitive patients, TTD-A, no mutation has been identified, although TFIIH amount is reduced.
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PMID:Trichothiodystrophy, a transcription syndrome. 1133 38

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

Cockayne s syndrome is a genetic disorder with a recessive autosomal inheritance, described first by Cockayne in 1936. Patients with this syndrome present failure to thrive, short stature, premature aging, neurological alterations, photosensitivity, delayed eruption of the primary teeth, congenitally absent of some permanent teeth, partial macrodontia, atrophy of the alveolar process and caries. It could be caused by two gene mutations, CNK1 (ERCC8) and ERCC6, located on the 5 and 10 chromosomes respectively, causing two variations of Cockayne s syndrome, CS-A, secondary to a ERCC8 mutation and CS-B with ERCC6 mutation, the last one causes hypersensitivity to the ultraviolet light secondary to a DNA repair defect. The syndrome is also associated with mutations of the XPB, XPD and XPG genes. In this report we present a 9 year and 4 month old patient. He had a height of 94 cm, weight of 8.6 Kg, head circumference of 42 cm. and blood pressure of 120/80. Cachectic habitus, kyphosis, microcephaly, oval face, sunken eyes, a thin and beaklike nose, lack of subcutaneous facial fat (especially in the middle of the face), and large ears give the patient a birdlike appearance. It is notorious the photosensitivity in all the sun-exposed skin. The patient also displays delayed psychomotor skills and mental retardation. In the oral cavity we found deficient hygiene, gingivitis, cervical caries, enamel hipoplasia, abnormal position of the upper and inferior lateral incisors, macrodontia of the upper central teeth, the left one presented a caries. In the x-ray we observed congenital absence of 14, 23 and 24 teeth and mandibular hipoplasia. The aim of this review is to show the dentistry community the characteristics of the Cockayne s syndrome by means of a clinical case.
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PMID:Cockayne's syndrome: a case report. Literature review. 1664 59

Trichothiodystrophy (TTD) is a rare autosomal recessive disorder characterized by brittle hair and also associated with various systemic symptoms. Approximately half of TTD patients exhibit photosensitivity, resulting from the defect in the nucleotide excision repair. Photosensitive TTD is due to mutations in three genes encoding XPB, XPD and p8/TTDA subunits of the DNA repair/transcription factor TFIIH. Mutations in these subunits disturb either the catalytic and/or the regulatory activity of the two XPB, XPD helicase/ATPases and consequently are defective in both, DNA repair and transcription. Moreover, mutations in any of these three TFIIH subunits also disturb the overall architecture of the TFIIH complex and its ability to transactivate certain nuclear receptor-responsive genes, explaining in part, some of the TTD phenotypes.
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PMID:Trichothiodystrophy view from the molecular basis of DNA repair/transcription factor TFIIH. 1980

Trichothiodystrophy (TTD) is an autosomal recessive disorder with symptoms affecting several tissues and organs. The most relevant features are hair abnormalities, physical and mental retardation, ichthyosis, signs of premature aging and cutaneous photosensitivity. The clinical spectrum of TTD varies widely from patients with only brittle, fragile hair to patients with the most severe neuroectodermal symptoms. To date, four genes have been identified as responsible for TTD: XPD, XPB, p8/TTDA, and TTDN1. Whereas the function of TTDN1 is still unknown, the former three genes encode subunits of TFIIH, the multiprotein complex involved in basal and activated transcription and in nucleotide excision repair (NER). Ongoing investigations on TTD are elucidating not only the pathogenesis of the disease, which appears to be mainly related to transcriptional impairment, but also the modalities of NER and transcription in human cells and how TFIIH operates in these two fundamental cellular processes.
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PMID:Trichothiodystrophy: from basic mechanisms to clinical implications. 1993 93

Cerebro-oculo-facio-skeletal (COFS) syndrome is an autosomal recessive inherited disorder characterized by congenital microcephaly, congenital cataracts and/or microphthalmia, arthrogryposis, severe developmental delay, severe postnatal growth failure and facial dysmorphism with prominent nasal root and/or overhanging upper lip. This syndrome is now recognized as a disorder belonging to the spectrum of inherited defects in Nucleotide Excision Repair (NER) resulting in profound photosensitivity. In COFS syndrome, as in Cockayne syndrome, DNA repair is impaired in the transcription-coupled NER pathway, but not in the global genome NER pathway. Fourteen cases so far described as COFS syndrome have been studied at the molecular levels. All mutations have been found in Cockayne syndrome gene, CSB, xeroderma pigmentosum genes, XPD and XPG and ERCC1 gene involved in the transcription-coupled NER pathway.
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PMID:Cerebro-oculo-facio-skeletal syndrome. 2068 8


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