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N G Jaspers

Publications and source records attributed to N G Jaspers.

70 records · Page 4Linked to original sources
PubMed1988

Genetic complementation analysis of ataxia telangiectasia and Nijmegen breakage syndrome: a survey of 50 patients.

Cultured cells from patients with ataxia telangiectasia (AT) or Nijmegen breakage syndrome (NBS) are hypersensitive to ionizing radiation. After radiation exposure, the rate of DNA replication is inhibited to a lesser extent than in normal cells, whereas the frequency of chromosomal aberrations is enhanced. Both of these features have been used in genetic complementation studies on a limited series of patients. Here we report the results of extended complementation studies on fibroblast strains from 50 patients from widely different origins, using the radioresistant DNA replication characteristic as a marker. Six different genetic complementation groups were identified. Four of these, called AB, C, D, and E (of which AB is the largest), represent patients with clinical signs of AT. Patients having NBS fall into two groups, V1 and V2. An individual with clinical symptoms of both AT and NBS was found in group V2, indicating that the two disorders are closely related. In AT, any group-specific patterns with respect to clinical characteristics or ethnic origin were not apparent. In addition to the radiosensitive ATs, a separate category of patients exists, characterized by a relatively mild clinical course and weak radiosensitivity. It is concluded that a defect in one of at least six different genes may underlie inherited radiosensitivity in humans. To facilitate research on defined defects, a complete list of genetically characterized fibroblast strains is presented.

Ataxia Telangiectasia↗
PubMed1988

A new chromosomal instability disorder confirmed by complementation studies.

Two sisters with a complex clinical pattern, including microcephaly, microgenia, defects of skin pigmentation, anal stenosis/atresia, and combined immunodeficiency together with spontaneous chromosomal instability and cellular hypersensitivity to X-rays and bleomycin are described. Complementation studies on heterokaryons proved that the underlying genetic defect is non-allelic with that of patients with ataxia telangiectasia (complementation groups AB-E) and the Nijmegen breakage syndrome, but identical with the case described by Conley et al. (1986).

Ataxia Telangiectasia↗
PubMed1988

Patients with an inherited syndrome characterized by immunodeficiency, microcephaly, and chromosomal instability: genetic relationship to ataxia telangiectasia.

Fibroblast cultures from six unrelated patients having a familial type of immunodeficiency combined with microcephaly, developmental delay, and chromosomal instability were studied with respect to their response to ionizing radiation. The cells from five of them resembled those from individuals with ataxia telangiectasia (AT) in that they were two to three times more radiosensitive on the basis of clonogenic cell survival. In addition, after exposure to either X-rays or bleomycin, they showed an inhibition of DNA replication that was less pronounced than that in normal cells and characteristic of AT fibroblasts. However, the patients are clinically very different from AT patients, not showing any signs of neurocutaneous symptoms. Genetic complementation studies in fused cells, with the radioresistant DNA synthesis used as a marker, showed that the patients' cells could complement representatives of all presently known AT complementation groups. Furthermore, they were shown to constitute a genetically heterogeneous group as well. It is concluded that these patients are similar to AT patients with respect to cytological parameters. The clinical differences between these patients and AT patients are a reflection of genetic heterogeneity. The data indicate that the patients suffer from a chromosome-instability syndrome that is distinct from AT.

Ataxia Telangiectasia↗
PubMed1987

Sister chromatid exchanges, hyperdiploidy and chromosomal rearrangements studied in cells from melanoma-prone individuals belonging to families with the dysplastic nevus syndrome.

Cytogenetic investigations were performed on 25 individuals belonging to six melanoma-prone families with multiple melanocytic lesions (the dysplastic nevus syndrome, DNS). Patients having DNS with or without a history of melanoma were compared with clinically normal relatives and unrelated normal controls. The results indicate normal frequencies of hyperdiploidy and spontaneous sister chromatid exchanges in the fibroblasts of all individuals studied. Karyotypic analyses were carried out on the members of one family. The patients with DNS had a normal constitutional karyotype. In lymphocytes or fibroblasts from five patients, however, increased frequencies of cells with random chromosomal rearrangements were observed. These abnormalities, mainly translocations and inversions, were not found in two of the patients' spouses and in six clinically normal relatives. In the fibroblast cultures considerable clonal selection of cytogenetically abnormal cells occurred.

Chromosome Aberrations↗
PubMed1985

Complementation analysis of ataxia-telangiectasia.

In a number of laboratories genetic analysis of ataxia-telangiectasia (AT) has been performed by studying the expression of the AT phenotype in fused somatic cells or mixtures of cell-free extracts from different patients. Complementation of the defective response to ionizing radiation was observed frequently, considering four different parameters for radiosensitivity in AT. The combined results from studies on cultured fibroblasts or lymphoblastoid cells from 17 unrelated families revealed the presence of at least four and possibly nine complementation groups. These findings suggest that there is an extensive genetic heterogeneity in AT. More extensive studies are needed for an integration of these data and to provide a set of genetically characterized cell strains for future research of the AT genetic defect.

Ataxia Telangiectasia↗
PubMed1983

Hypersensitivity to ionizing radiation, in vitro, in a new chromosomal breakage disorder, the Nijmegen Breakage Syndrome.

The Nijmegen Breakage Syndrome (NBS) is a new chromosomal instability disorder different from ataxia telangiectasia (AT) and other chromosome-breakage syndromes. Cells from an NBS patient appeared hypersensitive to X-irradiation. X-rays induced significantly more chromosomal damage in NBS lymphocytes and fibroblasts than in normal cells. The difference was most pronounced after irradiation in G2. Further, NBS fibroblasts were more readily killed by X-rays than normal fibroblasts. In addition, the DNA synthesis in NBS cells was more resistant to X-rays and bleomycin than that in normal cells. The reaction of NBS cells to X-rays and bleomycin was similar to that of cells from patients with ataxia telangiectasia. Our results indicate that NBS and AT, which also have similar chromosomal characteristics, must be closely related.

Adolescent↗
PubMed1982

Abnormal levels of UV-induced unscheduled DNA synthesis in ataxia telangiectasia cells after exposure to ionizing radiation.

In cultured cells from normal individuals and from patients having ataxia telangiectasia (AT) the rate of unscheduled DNA synthesis (UDS) induced by UV light was investigated by autoradiography. The number of grains in 6 different AT cell strains was similar to that observed in normal cells. Exposure of normal cells to doses of X-rays up to 20 krad had no influence on the rate of UV-induced UDS. In contrast, the UV-induced UDS was significantly modified in AT cells by treatment with X-rays. In AT cell strains that were reported to have reduced levels of gamma-ray-induced repair DNA synthesis ('excision-deficient' AT cells) the effect of X-rays on UV-induced UDS was inhibitory, whereas UV-induced UDS was stimulated by X-ray exposure in 'excision-proficient' AT cell strains. Different UV and X-ray dose-response relationships were seen in the two categories of AT cell strains. These results strongly suggest that different molecular defects are present in excision-deficient and excision-proficient At cells. They also indicate that the altered levels of repair DNA synthesis after exposure to UV in AT cells may be a secondary consequences of the way such cells handle DNa damage caused by ionizing radiation.

Ataxia Telangiectasia↗
PubMed1982

Genetic heterogeneity in ataxia-telangiectasia studied by cell fusion.

The effect of x-rays on the rate of semiconservative DNA replication was investigated by autoradiography in single cells obtained from normal individuals and from patients having ataxia-telangiectasia (AT). In the five AT cell strains studied, the rate of DNA synthesis was inhibited to a lesser extent that in two normal cell strains. By using this abnormal regulation of DNA replication in AT cells as a marker, an experimental procedure was developed that allowed genetic complementation analysis of AT. After Sendai virus-induced fusion of AT cells, the grains were counted over binucleate cells with both nuclei in S phase. In some cases, the inhibition of DNA synthesis caused by x-rays in the heterodikaryons was more pronounced than that in the parental homodikaryons and was comparable to that in normal binucleate cells, indicating complementation. By using this approach, the five AT cell strains that were investigated could be assigned to three complementation groups. The data suggest that extensive genetic heterogeneity exists in AT.

Ataxia Telangiectasia↗
PubMed1982

Abnormal regulation of DNA replication and increased lethality in ataxia telangiectasia cells exposed to carcinogenic agents.

The effect of different carcinogenic agents on the rate of semiconservative DNA replication in normal and ataxia telangiectasis (AT) cells was investigated. The rate of DNA synthesis in all AT cell strains tested was depressed to a significantly lesser extent than in normal cells after exposure to X-rays under oxia or hypoxia or to bleomycin, agents to which AT cells are hypersensitive. In contrast, inhibition of DNA replication in normal human and AT cells was similar after treatment with some DNA-methylating agents or mitomycin C. Colony-forming ability of AT cells treated with these agents was not different from normal cells. Treatment with 4-nitroquinoline 1-oxide elicited a variable response in both AT and normal cell strains. In some strains, including those shown to be hypersensitive to the drug by other workers, the inhibition of DNA synthesis was more pronounced than in other cell strains, but no significant difference between AT and normal cells could be detected. The rejoining of DNA strand breaks induced by X-rays, measured by DNA elution techniques, occurred within l2 hr after treatment and could not be correlated with the difference in DNA synthesis inhibition in AT and normal cells. After low doses of X-rays, AT cells rejoined single-strand breaks slightly more slowly than did normal cells. The rate of DNA replication in X-irradiation AT and normal cells was not affected by nicotinamide, an inhibitor of poly(adenosine diphosphate ribose) synthesis. These data indicate that the diminished inhibition of DNA replication in carcinogen-treated AT cells (a) is a general characteristic of all AT cell strains, (b) correlates with AT cellular hypersensitivity, (c) is not directly caused by the bulk of the DNA strand breaks produced by carcinogenic agents, and (d) is not based on differences in the induction of poly(adenosine diphosphate ribose) synthesis between X-irradiated AT and normal cells.

4-Nitroquinoline-1-oxide↗
PubMed1982

Genetic complementation analysis of ataxia telangiectasia by somatic cell fusion.

After cells from patients with ataxia telangiectasia (AT) have been exposed to ionizing radiation, the rate of semiconservative DNA replication is inhibited to a significantly lesser extent than in cells from normal individuals. This diminished inhibition of DNA synthesis is a general characteristic of irradiated AT cell strains, irrespective of their capacity to perform repair DNA synthesis after treatment with gamma-rays. Using the abnormal regulation of DNA replication in AT cells as a parameter, a procedure was developed that allows genetic complementation analysis of AT. The five AT cell strains that were investigated in this respect could be assigned to three complementation groups. The results show that an extensive genetic heterogeneity exists in the AT syndrome.

Ataxia Telangiectasia↗
PubMed1981

The rate of DNA synthesis in normal human and ataxia telangiectasia cells after exposure to X-irradiation.

The rate of DNA synthesis was studied in normal cell strains and in strains from patients suffering from the inherited disorder ataxia telangiectasia (AT). After exposure to relatively low doses of oxic X-rays (0-4 krad) DNA synthesis was depressed in AT cell strains to a significantly lesser extent than in normal cells. This response was observed in both an "excision-deficient" and an "excision-proficient" strain. In contrast, there was no difference in DNA-synthesis inhibition between AT and normal cells after UV exposure. After X-irradiation of cells from patients with xeroderma pigmentosum, both complementation group A and XP variants, the observed rate of DNA synthesis was equal to that in normal cells. An exception was the strain XP3BR which has been shown to be X-ray-sensitive. This strain exhibited diminished DNA synthesis inhibition after X-ray doses below 1 krad. These data suggest a relationship between hypersensitivity to X-rays and diminished depression of DNA synthesis.

Ataxia Telangiectasia↗
PubMed1979

A seventh complementation group in excision-deficient xeroderma pigmentosum.

Cells from a xeroderma pigmentosum patient XP2BI who has reached 17 years of age with no keratoses or skin tumours constitute a new, 7th complementation group G. These cells exhibit a low residual level of excision repair, 2% of normal after a UV dose of 5 J/m2 and an impairment of post-replication repair characteristic of excision-defective XPs. They are also sensitive to the lethal effects of UV and defective in host-cell reactivation of UV-irradiated SV40 DNA.

Adolescent↗
PubMed1979

Prenatal diagnosis of xeroderma pigmentosum (group C) using assays of unscheduled DNA synthesis and postreplication repair.

The analysis of DNA repair processes is described in two pregnancies at risk for xeroderma pigmentosum. In both cases, excision repair (measured by unscheduled DNA synthesis) and postreplication repair were analyzed. An affected and an unaffected fetus were identified within 3 weeks after amniocentesis. The cells from the affected fetus were found to be deficient in excision DNA repair, whereas the PRR patterns were intermediate between those of normal and PRR deficient cells. This indicates the possibility of prenatal diagnosis of PRR deficient XP patients (XP variants).

Amniotic Fluid↗