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Biomedical subjects

F Giannelli

Publications and source records attributed to F Giannelli.

At least 109 records · Page 6Linked to original sources
PubMed1979

Clinical, genetic and DNA repair studies on a consecutive series of patients with xeroderma pigmentosum.

We report clinical, genetic and biochemical findings in 13 families with the photosensitive genodermatosis, xeroderma pigmentosum. All patients had a defect in repair of DNA damage provoked by ultraviolet radiation. Eleven patients and their three affected sibs were defective in the excision repair of UVR induced DNA lesions while the other two were defective in post-replication repair. One in the former group was diagnosed prior to the development of permanent skin abnormalities and preventive measures succeeded for almost five years in maintaining a normal appearing skin. In addition, two cases were diagnosed prenatally and aborted therapeutically. Some patients' parents showed slightly reduced repair of UVR induced DNA damage. In xeroderma pigmentosum (XP), the defect in the excision of DNA lesions appears to be due to homozygosity for one of at least seven different mutations and, accordingly, XP patients can be assigned to seven so-called complementation groups, A to G. Of these, groups A, C and D are the most common. Somatic cell fusion allowed three of the families reported here to be assigned to group A, four to group C and four to group D. Fibroblasts of patients from these three groups were shown to differ not only in the degree and kinetics of their residual DNA repair but also in the kinetics with which their defect is complemented by fusion with normal or XP cells of other groups. This confirms that mutations of different genes play a role in XP and provides a basis for understanding how such genes interact to secure repair of DNA lesions in normal cells. We discuss the phenotype of XP from different complementation groups in relation to the severe neurological abnormalities which may develop and must be considered in genetic counselling. We also discuss the biochemical anomalies of XP and the cellular effects of physical and chemical agents which damage DNA. In the practical management of XP, the importance of early differential diagnosis and prompt initiation of treatment is emphasized. Lastly we review the relationship between DNA repair and skin cancer in XP.

Adolescent↗
PubMed1978

A human subject with a new defect in repair of ultraviolet damage.

The subject under study (11961) is a child with extreme sun sensitivity. Fibroblasts derived from the child's skin, like those from patients with the disorder xeroderma pigmentosum were hypersensitive to the lethal effects of 254 nm and 310 nm UV-irradiation. Unlike xeroderma pigmentosum cells, however, fibroblasts from our subject were not hypersensitive to the chemical mutagen N-hydroxyacetylaminofluorene but they were hypersensitive to ethylmethanesulfonate. Furthermore, despite the ultra violet light sensitivity, no defects could be detected either in excision or postreplication repair of damaged DNA after UV-irradiation of 11961 cells. This again contrasts with xeroderma pigmentosum cells, which are defective in one or the other of these repair processes. On the basis of these characteristics and the clinical symptoms, we are not at present able to classify this patient as having any of the known sun-sensitive syndromes.

Cell Survival↗
PubMed1978

Xeroderma pigmentosum and the role of DNA repair in oncogenesis.

Biochemical and genetic information on xeroderma pigmentosum (XP) has been briefly reviewed. This indicates that 80 to 90 percent of all XP patients are defective in the excision repair of pyrimidine dimers and are unable to perform the first step of this process as shown, for example, by their inability to undergo the DNA superhelical changes which accompany the initiation of excision repair in normal cells. However, in spite of its apparent biochemical homogeneity, XP is genetically heterogeneous and many genes appear to be responsible for the function of the factor defective in XP. Ten to 20 percent of all XP patients (called XP-variants) are capable of "dimer excision repair" but have difficulties in replicating UV-damaged DNA. The defects of XP and XP-variant affect also the repair of DNA damage caused by a number of chemical mutagens and carcinogens. This has important theoretical and practical implications since it indicates, for example, that the repair systems defective in XP must have broad specificity and that even XP cells not exposed to the harmful effect of light may suffer from poor repair of DNA damage. With regard to cancer, two questions have been considered. Namely, does XP provide a valid general model for UV-carcinogenesis in man and does it show how DNA damage leads to malignant transformation? The first question was answered in the affirmative in view of some clinical but, mainly, of cell biological data indicating that normal and excision defective XP cells differ, more quantitatively than qualitatively, in their response to UV-light. With regard to the second question XP seems to provide some support for various theories on carcinogenesis and, DNA repair defects may favour actinic carcinogenesis in a complex, non-univocous manner. Possibly the most important lesson imparted by XP is that, in man, the stability of the genetic material is dependent on the function of repair systems whose failure may predispose to cancer. In addition, the study of XP has stressed the fact that many genes control DNA metabolism and new evidence is accumulating to show that defects in such genes may contribute significantly to the genetic predisposition to cancer.

Carcinogens↗
PubMed1977

Tumours of the skin.

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Complement System Proteins↗
PubMed1976

DNA repair synthesis in human heterokaryons. III. The rapid and slow complementing varieties of xeroderma pigmentosum.

Patients with Xeroderma pigmentosum and defective DNA excision repair can be distinguished as a rapid (r-XP) and slow (s-XP) complementing variety. When fused with normal cells, fibroblasts from the r-XP are complemented rapidly and in the absence of protein synthesis while those from the s-XP are complemented slowly by a process partly, but not entirely, dependent on protein synthesis. Heterokaryons with different ratios of r-XP to s-XP nuclei (i.e. 1:1-5 and 1-5:1) and control heterokaryons containing one normal and 1-5 r- or s-XP nuclei show that if cell fusion and incubation is conducted in medium preventing protein synthesis, the rXP cells do not complement the s-XP partner at all and, conversely, that the latter is not as effective as normal cells at complementing the rXP partner. On the contrary, if protein synthesis is permitted, the 2 types of XP cells complement each other in a gene dose-dependent manner and to an extent similar to that observed in the control heterokaryons. These findings indicate that the r- and s-XP varieties are caused by mutations at different loci and suggest that the products of these loci interact to produce a functional unit which is present in normal control cells but absent in the XP strains. The relationship between the complementation groups described here and those already reported in the literature being investigated.

Cell Fusion↗
PubMed1975

The erythemal action spectrum and deoxyribonucleic acid repair synthesis in xeroderma pigmentosum.

The reactions to monochromatic radiation of the skin of ten patients with xeroderma pigmentosum were investigated, and eight were abnormal. The abnormalities consisted of papular and vesicular reactions and delay in the development of the minimal erythema dose reaction with wavelengths principally in the 290-320 nm range. Three patients were too young for full action spectra to be obtained but of those patients in whom all wavelengths were tested only one showed a reaction to radiation above 320 nm and this was at 340 nm only. In only one patient was the minimal erythema dose at 300 nm at 24 h lower than normal. In six patients the repair synthesis of deoxyribonucleic acid after ultraviolet radiation was estimated. Reduced levels were seen in five but repair was normal in one patient. The patient with normal repair also had normal reactions to monochromatic radiation. The abnormal reaction of the skin to artificial radiation and the abnormal deoxyribonucleic acid repair synthesis may enable the diagnosis of xeroderma pigmentosum to be made at a very early age. In one of the patients the diagnosis was made at the age of 6 months in a child with photosensitivity but with no other clinical signs of the disease. It is suggested that, by making the diagnosis as early as possible and by protecting the skin from natural sunlight, cutaneous malignancies may be prevented.

Adolescent↗