Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nijmegen Breakage Syndrome (NBS) is a very rare autosomal recessive chromosomal instability disorder characterized by microcephaly, growth retardation, immunodeficiency and a high incidence of malignancies. Cells from NBS patients are hypersensitive to ionizing radiation (IR) and display radioresistant DNA synthesis (RDS). NBS is caused by mutations in the NBS1 gene on chromosome 8q21 encoding a protein called nibrin. This protein is a component of the hMre11/hRad50 protein complex, suggesting a defect in DNA double-strand break (DSB) repair and/or cell cycle checkpoint function in NBS cells. We established SV40 transformed, immortal NBS fibroblasts, from primary cells derived from a Polish patient, carrying the common founder mutation 657del5. Immortalized NBS cells, like primary cells, are X-ray sensitive (2-fold) and display RDS following IR. They show an increased sensitivity to bleomycin (3.5-fold), etoposide (2.5-fold), camptothecin (3-fold) and mitomycin C (1.5-fold), but normal sensitivity towards UV-C. Despite the clear hypersensitivity towards DSB-inducing agents, the overall rates of DSB-rejoining in NBS cells as measured by pulsed field gel electrophoresis were found to be very similar to those of wild type cells. This indicates that the X-ray sensitivity of NBS cells is not directly caused by an overt defect in DSB repair.
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PMID:Immortalization and characterization of Nijmegen Breakage syndrome fibroblasts. 1037 45

Immune deficiency and chromosome fragility are hallmarks of two human diseases, ataxia telangiectasia and Nijmegen breakage syndrome. The genes mutated in these diseases, ATM and NBS1, have been cloned and there has been considerable recent progress on deciphering the function of the protein products implicated in these disorders and how their absence in the disease states relates to the immunodeficiency and chromosome fragility observed. The function of the two protein products, Atm and Nibrin, in effecting DNA repair and cell cycle checkpoints in response to genomic insult provides a framework for understanding the cellular response to DNA damage.
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PMID:Chromosomal breakage syndromes. 1044 47

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disorder characterized by microcephaly, combined immunodeficiency, and a high incidence of lymphoid tumor. Cells from NBS patients show chromosomal instability, hypersensitivity to ionizing radiation and abnormal p53-mediated cell cycle regulation. We cloned the underlying gene for NBS, designated NBS1, by complementation-assisted positional cloning from the candidate region 8q21. Large genomic sequencing, as well as a search using computer programs, provides a powerful approach for identifying the underlying gene for a disease. The NBS1 gene encodes a protein of 754 amino acids that has FHA and BRCT domains which often are conserved in cell-cycle checkpoint proteins. The gene has weak homology to the yeast (Saccharomyces cerevisiae) Xrs2 protein in the N-terminus region. Like yeast Xrs2, the NBS1 protein forms a complex with hRAD50/hMRE11, and the complex is condensed as foci in the nucleus after irradiation, indicative that this triple-complex is a crucial factor in DNA repair. Functional analysis of the NBS1 protein is in progress and it should provide further clues to understanding the repair mechanism of radiation-induced DNA double-strand breaks.
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PMID:Positional cloning and functional analysis of the gene responsible for Nijmegen breakage syndrome, NBS1. 1083 6

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disorder which belongs to the group of inherited chromosomal instability syndromes. The clinical characteristics include severe microcephaly, a dysmorphic facies, and immunodeficiency with predisposition to malignancies. While the cellular characteristics of ataxia teleangiectasia (AT) and NBS are similar, the clinical findings are quite distinct. NBS patients show characteristic microcephaly, which is rare in association with AT and they do not develop ataxia and teleangiectasia. Recently, the gene mutated in NBS has been identified. Here we report a 5-year-old Bosnian boy with severe microcephaly. Because of multiple structural aberrations involving chromosomes 7 and 14 typical for AT (MIM 208900) and NBS (MIM 251260), AT was diagnosed. We suggested the diagnosis of NBS because of the boy's remarkable microcephaly, his facial appearance, and the absence of ataxia and teleangiectasia. DNA analysis was performed and revealed that the boy is homozygous for the major mutation (657de15) in the NBS1 gene. This finding confirms the diagnosis of NBS in our patient and offers the possibility to perform a most reliable prenatal diagnosis in a further pregnancy.
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PMID:Clinical presentation and mutation identification in the NBS1 gene in a boy with Nijmegen breakage syndrome. 1085 73

Nijmegen breakage syndrome (NBS) is a chromosomal instability disorder, clinically characterised by microcephaly, immunodeficiency, radiosensitivity and a very high predisposition to lymphoid malignancy. Recently, it was demonstrated that mutations in the NBS1 gene are responsible for NBS. Most of the NBS patients known so far are of Slav origin and carry a major founder mutation 657del5 in exon 6 of the NBS1 gene. In this study we estimated the prevalence of the 657del5 mutation in the Czech Republic, Poland and the Ukraine. We found an unexpectedly high carrier frequency of the 657del5 mutation (1/177) in the three Slav populations, a factor that may contribute to cancer frequency in those countries. In addition, we show that NBS patients are often diagnosed late and therefore receive inappropriate therapy.
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PMID:Clinical ascertainment of Nijmegen breakage syndrome (NBS) and prevalence of the major mutation, 657del5, in three Slav populations. 1109 81

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive human disease whose clinical features include growth retardation, immunodeficiency, and increased susceptibility to lymphoid malignancies. Cells from NBS patients exhibit gamma-irradiation sensitivity, S-phase checkpoint defects, and genomic instability. Recently, it was demonstrated that this chromosomal breakage syndrome is caused by mutations in the NBS1 gene that result in a total loss of full-length NBS1 expression. Here we report that in contrast to the viability of NBS patients, targeted inactivation of NBS1 in mice leads to early embryonic lethality in utero and is associated with poorly developed embryonic and extraembryonic tissues. Mutant blastocysts showed greatly diminished expansion of the inner cell mass in culture, and this finding suggests that NBS1 mediates essential functions during proliferation in the absence of externally induced damage. Together, our results indicate that the complex phenotypes observed in NBS patients and cell lines may not result from a complete inactivation of NBS1 but may instead result from hypomorphic truncation mutations compatible with cell viability.
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PMID:Targeted disruption of the Nijmegen breakage syndrome gene NBS1 leads to early embryonic lethality in mice. 1123 Nov 26

Nijmegen breakage syndrome (NBS) and ataxia telangiectasia (AT) are rare autosomal recessive hereditary disorders characterized by radiosensitivity, chromosomal instability, immunodeficiency and proneness to cancer. Although the clinical features of both syndromes are quite distinct, the cellular characteristics are very similar. Cells from both NBS and AT patients are hypersensitive to ionizing radiation (IR), show elevated levels of chromosomal aberrations and display radioresistant DNA synthesis (RDS). The proteins defective in NBS and AT, NBS1 and ATM, respectively, are involved in the same pathway, but their exact relationship is not yet fully understood. Stumm et al. (Am. J. Hum. Genet. 60 (1997) 1246) have reported that hybrids of AT and NBS lymphoblasts were not complemented for chromosomal aberrations. In contrast, we found that X-ray-induced cell killing as well as chromosomal aberrations were complemented in proliferating NBS-1LBI/AT5BIVA hybrids, comparable to that in NBS-1LBI cells after transfer of a single human chromosome 8 providing the NBS1 gene. RDS observed in AT5BIVA cells was reduced in these hybrids to the level of that seen in immortal NBS-1LBI cells. However, the level of DNA synthesis, following ionizing radiation, in SV40 transformed wild-type cell lines was the same as in NBS-1LBI cells. Only primary wild-type cells showed stronger inhibition of DNA synthesis. In summary, these results clearly indicate that RDS cannot be used as an endpoint in functional complementation studies with immortal NBS-1LBI cells, whereas the cytogenetic assay is suitable for complementation studies with immortal AT and NBS cells.
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PMID:Complementation of chromosomal aberrations in AT/NBS hybrids: inadequacy of RDS as an endpoint in complementation studies with immortal NBS cells. 1126 29

We report on an 11-year-old Japanese girl with combined immunodeficiency and chromosomal instability. She had postnatal growth deficiency and microcephaly, preaxial polydactyly of the left hand, and susceptibility to infections. Immunological studies showed marked lymphocytopenia (around 500/ll), reduced lymphocyte response to various mitogens, and reduced or absent serum IgA, IgG, and IgM. Cell biological studies of her primary skin fibroblasts demonstrated spontaneous chromosome aberrations and radiation hypersensitivity. The combination of immunodeficiency, chromosomal instability, and radiation hypersensitivity as seen in the girl is present in both ataxia-telangiectasia and Nijmegen breakage syndrome. Ataxia-telangiectasia was excluded because of differences in clinical features and laboratory data. Likewise, Nijmegen breakage syndrome is unlikely to be the case because the characteristic face, hyperpigmented spots, and mental retardation present in the syndrome were missing in the girl. Sequence analysis of a Nijmegen breakage syndrome responsible gene, NBS1, revealed no mutations. A normal NBS1 product was also demonstrated by immunoblot analysis using an anti-NBS1 antibody. We propose that the disorder in the girl represents a new combination of combined immunodeficiency and chromosomal instability.
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PMID:Combined immunodeficiency, chromosomal instability, and postnatal growth deficiency in a Japanese girl. 1133 42

Nijmegen breakage syndrome (NBS) is a rare chromosomal-instability syndrome associated with defective DNA repair. Approximately 90% of NBS patients are homozygous for a truncating mutation of the NBS1 gene. As development of the immune system relies on recombination, which involves repair of DNA breaks, one might predict that mutations in the NBS1 gene could cause immunodeficiency. We immunologically investigated the world's largest series of NBS patients (n = 74), confirmed immunodeficiency, and found a discrepancy between relatively normal IgM concentrations, and decreased IgG and IgA concentrations. In addition, a significant relation between low IgA and low IgG levels was found. These data are compatible with a defective class switching in NBS and can be explained by a role of the NBS1 protein in DNA repair, signal transduction, cell cycle regulation or apoptosis.
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PMID:Decreased immunoglobulin class switching in Nijmegen Breakage syndrome due to the DNA repair defect. 1175

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disorder characterized by microcephaly, immunodeficiency, and predisposition to hematopoietic malignancy. The clinical and cellular phenotypes of NBS substantially overlap those of ataxia-telangiectasia (A-T). NBS is caused by mutation of the NBS1 gene, which encodes a member of the Mre11 complex, a trimeric protein complex also containing Mre11 and Rad50. Several lines of evidence indicate that the ataxia-telangiectasia mutated (ATM) kinase and the Mre11 complex functionally interact. Both NBS and A-T cells exhibit ionizing radiation (IR) sensitivity and defects in the intra S phase checkpoint, resulting in radioresistant DNA synthesis (RDS)-the failure to suppress DNA replication origin firing after IR exposure. NBS1 is phosphorylated by ATM in response to IR, and this event is required for activation of the intra S phase checkpoint (the RDS checkpoint). We derived a murine model of NBS, the Nbs1(DeltaB/DeltaB) mouse. Nbs1(DeltaB/DeltaB) cells are phenotypically identical to those established from NBS patients. The Nbs1(DeltaB) allele was synthetically lethal with ATM deficiency. We propose that the ATM-Mre11 complex DNA damage response pathway is essential and that ATM or the Mre11 complex serves as a nexus to additional components of the pathway.
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PMID:A murine model of Nijmegen breakage syndrome. 1196 51


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