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.

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).

[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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.