Biomedical subjects

P Lagomarsini

Publications and source records attributed to P Lagomarsini.

14 recordsLinked to original sources

PubMed1997

Chromosomal fragility in the cancer-prone disease xeroderma pigmentosum preferentially involves bands relevant for cutaneous carcinogenesis.

Spontaneous and folate-induced chromosomal fragility was analyzed in peripheral blood lymphocytes from 6 patients affected by the cancer-prone disease xeroderma pigmentosum (XP), from the parents of 4 of the patients, and from 12 normal subjects. All XP patients were defective in nucleotide-excision repair; 4 belonged to group C and 1 each to groups A and D. A tendency toward increased spontaneous chromosomal fragility was observed in the XP family members, and lesions indicating substantial chromosomal damage, which were not observed in any healthy donors, were frequently found. The spontaneous lesion sites in lymphocytes from homozygous and heterozygous carriers of XP defects appeared to be significantly associated with those observed in normal skin fibroblasts from the same subjects. These XP spontaneous fragility sites showed a statistically significant association with the rearrangement breakpoints reported in skin pre-tumoral and tumoral lesions from normal and unrelated XP donors. Under conditions of folate deprivation, the chromosomal fragility level, the pattern and the frequency of expression of fragile sites in XP patients and in their parents were similar to normal. However, XP patients generally showed a higher susceptibility to breakage at sites described as mutagen and carcinogen targets.

Adolescent↗

PubMed1993

Genetic heterogeneity of the excision repair defect associated with trichothiodystrophy.

Trichothiodystrophy (TTD) is a rare autosomal recessive disease characterized by brittle hair with reduced sulfur content, mental and physical retardation, a peculiar face and ichthyosis. Photosensitivity has been reported in approximately 20% of the cases in the literature. DNA repair investigations demonstrated that clinical photosensitivity is usually associated with an enhancement of the cellular UV-sensitivity and that the repair defect is in the same gene as in patients from group D of xeroderma pigmentosum (XP). In this paper we describe the characterization of 13 further TTD patients; a defect in the nucleotide-excision repair was observed in fibroblast strains from 10 patients, confirming that TTD is frequently associated with DNA repair defects. Genetic analysis based on complementation studies demonstrated the presence of the XP-D defect in seven repair-defective TTD cases, indicating definitively that the concurrence of TTD with XP-D is not a sporadic or casual event. However, three further cell strains (TTD4VI and TTD6VI from two French siblings and TTD1BR from an English patient) showed restoration of normal UV-induced DNA repair synthesis after fusion with XP or TTD cells belonging to XP group D. These observations, which give the first indication that TTD is associated with repair defects behaving differently in the functional test of complementation, suggest some kind of causal connection between defective excision-repair factors and clinical features diagnostic for TTD. A peculiar aspect of TTD in which repair deficiencies are not related to an increased susceptibility to cancer is confirmed also in all the repair-defective TTD patients investigated in this paper.

Abnormalities, Multiple↗

PubMed1992

[Clinical and cellular studies in a patient with Cockayne syndrome].

Hypersensitivity to the lethal effect of ultraviolet light (UV) and other DNA-damaging agents has been observed in cells from patients affected by Cockayne syndrome, suggesting that this syndrome is deficient in the capability to repair damage in cellular DNA. We report a case showing the main clinical features of Cockayne syndrome in which the clinical and cellular photosensitivity described as typical for Cockayne syndrome is not present. These cytological results suggest that there is considerable clinical and cellular heterogeneity in Cockayne syndrome and that cellular sensitivity to UV might not be as essential for the diagnosis of Cockayne syndrome as previously thought.

Adolescent↗

PubMed1990

Search for consanguinity within and among families of patients with trichothiodystrophy associated with xeroderma pigmentosum.

The association of two rare hereditary disorders, trichothiodystrophy (TTD) and xeroderma pigmentosum (XP), was found in four patients from three families, apparently unrelated but living in the same geographical area. In order to test the hypothesis of a common ancestor, consanguinity within and among the families was checked using three different approaches: reconstruction of genealogical trees, typing of blood markers, and surname analysis. The results of the three types of analyses strengthen the hypothesis that, in at least two out of the three families, the genetic defect determining the TTD/XP phenotype is identical by descent, as a consequence of remote inbreeding. This implies that if two mutations are responsible for the two diseases they are at linked loci or affect the same gene.

Blood Group Antigens↗

PubMed1989

Clonal chromosome rearrangements in a fibroblast strain from a patient affected by xeroderma pigmentosum (complementation group C).

We report the results of DNA repair studies and cytogenetic investigations in a patient presenting acute phothosensitivity and cancerous skin lesions. In lymphocytes and fibroblasts a reduced level of unscheduled DNA synthesis after UV irradiation was found and the presence of xeroderma pigmentosum, complementation group C, mutation was demonstrated by complementation analysis. In lymphocyte and fibroblast cultures the frequency of spontaneous chromosome gaps and breaks was normal, whereas the frequency of chromosome rearrangements was higher than expected. In fibroblasts from the 4th to the 18th passage of the culture, 4 reciprocal translocations with a clonal distribution were identified. The rearranged chromosomes were Nos. 2, 13, 14 and 15, Nos. 2 and 13 being both involved in 3 different translocations with breakpoints at 2q21, 2q31, 2p23 and 13q31, 13q12 or 3. The biological significance of this finding is discussed in view of a possible correlation with the DNA repair defect and a possible relevance in tumor development of specific chromosome rearrangements.

Adult↗

PubMed1989

Chromosome instability in lymphocytes from a patient with Werner's syndrome is not associated with DNA repair defects.

Different cellular parameters used to detect genetic instability were analyzed in lymphocytes from a patient affected by Werner's syndrome (WS). Cytogenetic studies indicated the presence of structural and numerical chromosomal abnormalities and the occurrence of variegated translocation mosaicism. The baseline mutation frequency was similar to that observed in normal donor samples. DNA repair investigations showing a normal capability to perform UV-induced DNA repair synthesis and a normal sensitivity to various mutagens (UVC light, mono- and bi-functional alkylating agents) indicate that different DNA repair mechanisms act normally in WS. In this feature, WS appears to differ from the other genetically determined syndromes in which chromosomal instability is associated with a marked hypersensitivity to specific DNA-damaging agents.

Cells, Cultured↗

PubMed1988

Trichothiodystrophy without photosensitivity. Biochemical, ultrastructural and DNA repair studies.

A case of trichothiodystrophy (TTD) without photosensitivity is reported in an 8-year-old girl. Electron microscopic (EM) examination of the keratinocytes showed fibrillary bundles in the cytoplasm thinner and less electron dense than those of the normal cells and large membrane-bound vacuoles filled with granular-filamentous material. These findings could indicate a disturbance in the protein metabolism in tissues of ectodermal origin, explaining also the functional abnormalities of the central nervous system in TTD patients. The results of cellular DNA repair studies after UV irradiation in cultured fibroblasts showed normal levels of unscheduled DNA synthesis. This finding indicates that UV hypersensitivity is not constantly present in TTD.

Amino Acids↗

PubMed1988

Chromosome and blood marker studies in families of patients affected by xeroderma pigmentosum and trichothiodystrophy.

Chromosome and blood marker studies were performed in the families of 4 patients in which the association of 2 rare recessive Mendelian disorders, xeroderma pigmentosum (XP-D) and trichothiodystrophy (TTD), was present. Blood genotypes did not indicate any linkage with the pathologic condition, nor any segregation anomaly. Cytogenetic analysis using high-resolution banding techniques showed a normal karyotype both in the heterozygous and in the homozygous individuals. These findings lead us to exclude a cytologically detectable chromosome rearrangement, such as a microdeletion, as a possible cause of the association of XP-D and TTD in our patients.

Blood Group Antigens↗

PubMed1988

Normal sensitivity to mutagens, spontaneous chromosome breakage, and mutation frequency in nevoid basal cell carcinoma syndrome.

Genetic instability in nevoid basal cell carcinoma syndrome (NBCCS) was investigated by measuring in lymphocytes obtained from four patients the level of UV-induced DNA repair synthesis, the DNA replication rate after treatment with different mutagens (UV light, mono- and bifunctional alkylating agents), the baseline mutation frequency, and the spontaneous chromosome breakage. All the parameters analyzed showed normal values; only the response to mitogens in NBCCS lymphocytes was delayed in comparison to that in normal donors. Our findings indicate that chromosomal instability and cellular UV hypersensitivity described in some NBCCS patients are not distinctive and constant features of NBCCS.

Adolescent↗

PubMed1987

Complementation studies in cells from patients affected by trichothiodystrophy with normal or enhanced UV photosensitivity.

A normal level of UV-induced DNA-repair synthesis (UDS) was observed in fibroblasts from a patient affected by trichothiodystrophy (TTD) without photosensitivity. This finding indicates that the hypersensitivity to UV light and the reduced UDS due to the presence of xeroderma pigmentosum complementation group D mutation (XP-D), described in photosensitive TTD patients, are not constantly associated with TTD. Complementation analysis in heterokaryons, obtained by fusion of repair-proficient with repair-deficient TTD cells, demonstrates that cells from the patient showing normal photosensitivity are able to restore UDS in UV-hypersensitive TTD cells.

Cell Fusion↗

PubMed1987

Response of mammalian ADP-ribosyl transferase to lymphocyte stimulation, mutagen treatment and cell cycling.

The inhibitors of the nuclear enzyme ADP-ribosyl transferase (ADPRT) had been shown to block the stimulation of quiescent lymphocytes with mitogens suggesting the involvement of the enzyme in the control of gene expression and cell differentiation. By means of the activity-gel assay we have analysed the intensity and the molecular mass of the catalytic bands of the enzyme at early and late times after stimulation of human lymphocytes by phytohemagglutinin. We observed that the increase in the activity of ADPRT is concurrent with the onset of DNA synthesis and is maintained for up to 10 days after lymphocyte stimulation, when DNA replication is over but the capacity to perform repair synthesis is still elevated. The analysis of ADPRT in stimulated lymphocytes by Western blots indicated that the increase in enzyme activity is due to the de novo synthesis of enzyme protein. The response of ADPRT to the treatment of human lymphocytes with DNA-damaging agents was studied at various dose-ranges, using the activity-gel technique. The results obtained indicate that dimethyl sulfate is 10 times as active as methyl methane sulfonate in stimulating ADPRT activity and that, at very high doses, the activity band of the enzyme tends to disappear. Very similar observations were obtained when Chinese hamster ovary cells were treated with the same agents, although the concentrations of the mutagens eliciting maximal ADPRT activation were 10 times higher than in human lymphocytes. When analysed by Western blots, no significant difference of the protein band of the enzyme was observed in comparing control and treated cells. This suggests that the activity-gel system can detect two different phenomena: the increase in enzyme protein, as in the case of stimulated lymphocytes, and the enzyme-activating effect of DNA-damaging agents, which occurs without changing the number of enzyme molecules. Of particular interest is the observation that mitomycin C is capable of activating ADPRT in human lymphocytes, thus suggesting that cross-linking agents are involved in promoting ADP-ribosylation reactions. We have also analysed the variations of the enzyme throughout the cell cycle in HeLa cells synchronized in S phase or in mitosis. No significant changes in the levels of the enzyme activity were revealed by the activity-gel assay during the progression of the cycle, although an overall increase of active polypeptides of larger size in concomitance with the S period was observed.

Cell Cycle↗

PubMed1986

Xeroderma pigmentosum (complementation group D) mutation is present in patients affected by trichothiodystrophy with photosensitivity.

We studied the response to UV irradiation in cells from four patients, from three apparently unrelated families, affected by trichothiodystrophy (TTD). They showed all the symptoms of this rare autosomal recessive disorder (brittle hair with reduced sulfur content, mental and physical retardation, ichthyosis, peculiar face) together with photosensitivity. We found a decreased rate of duplicative DNA synthesis in stimulated lymphocytes, reduced survival in fibroblasts, and very low levels of unscheduled DNA synthesis (UDS) in Go lymphocytes and fibroblasts after UV irradiation. Complementation studies showed that normal values of UDS are restored in heterokaryons obtained by fusion of TTD cells with normal and xeroderma pigmentosum (XP)-complementation group A-cells. In contrast the defect is not complemented by fusion with XP-complementation group D-fibroblasts.

Cells, Cultured↗

PubMedDate not supplied

The basal and the mutagen-induced levels of ADP-ribosyl transferase activity are not modified in Fanconi's anemia cells.

The activity of ADP-ribosyl transferase, an enzyme thought to be involved in several basic functions of the chromatin and in DNA repair, has been investigated in normal and Fanconi's anemia (FA) cells. Fibroblasts and lymphoblasts treated with alkylating (dimethyl sulfate) or cross-linking (mitomycin C, psoralen plus UVA) agents were compared to untreated cells. The basal level of the enzymatic activity was found to be the same in normal and FA cells and the enzymatic response to treatments with DNA-damaging agents was similar in both cell types. Consequently it is unlikely that the molecular defect in FA cells is due to a decreased activity in ADP-ribosyl transferase.

Anemia, Aplastic↗

PubMedDate not supplied

Xeroderma pigmentosum: clonal chromosomal rearrangements in a pre-cancerous skin lesion.

In cells from a papulonodular formation of a patient with the clinical and cellular phenotype of the variant form of xeroderma pigmentosum (XP-V), clonal rearrangements involving different chromosomes were observed. This finding confirms the literature data suggesting that multiple non-specific chromosome anomalies are typical of pre-malignant and malignant skin lesions.

Adult↗