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)

Bloom syndrome and ataxia-telangiectasia are autosomal recessive human disorders characterized by immunodeficiency, genome instability and predisposition to develop cancer. Recent data reveal that the products of these two genes, BLM and ATM, interact and function together in recognizing abnormal DNA structures. To investigate the function of these two molecules in DNA damage recognition, we generated double knockouts of ATM(-/-) BLM(-/-) in the DT40 chicken B-lymphocyte cell line. The double mutant cells were viable and exhibited a variety of characteristics of both ATM(-/-) and BLM(-/-) cells. There was no evidence for exacerbation of either phenotype; however, the more extreme radiosensitivity seen in ATM(-/-) and the elevated sister chromatid exchange seen in BLM(-/-) cells were retained in the double mutants. These results suggest that ATM and BLM have largely distinct roles in recognizing different forms of damage in DNA, but are also compatible with partially overlapping functions in recognizing breaks in radiation-damaged DNA.
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PMID:Disruption of the BLM gene in ATM-null DT40 cells does not exacerbate either phenotype. 1498

Immune responses to a 7-valent pneumococcal conjugate vaccine were determined in 10 patients with ataxia-telangiectasia who are at high risk for pneumococcal disease because of immunodeficiency. Pneumococcal antibody titers for 7 serotypes measured increased 2.0- to 7.5-fold after immunization.
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PMID:Immunogenicity of the seven valent pneumococcal conjugate vaccine in patients with ataxia-telangiectasia. 1501 8

Ataxia-telangiectasia (A-T) is a human autosomal recessive disease caused by mutations in the gene encoding ataxia-telangiectasia mutated (ATM). A-T is characterized by progressive cerebellar degeneration, variable immunodeficiency, and a high incidence of leukemia and lymphoma. Recurrent sino-pulmonary infections secondary to immunodeficiency and hematopoietic malignancies are major causes of morbidity and mortality in A-T patients. In mice, an introduced mutation in Atm leads to a phenotype that recapitulates many of the symptoms of A-T, including immune system abnormalities and susceptibility to malignancy. Here we show that the replacement of the bone marrow compartment in Atm knockout mice (Atm(-/-)) using a clinically relevant, nonmyeloablative host-conditioning regimen can be used to overcome the immune deficiencies and prevent the malignancies observed in these mice. Therefore, bone marrow transplantation may prove to be of therapeutic benefit in A-T patients.
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PMID:Bone marrow transplantation restores immune system function and prevents lymphoma in Atm-deficient mice. 1504 55

Oxidative DNA damage has been reported in fetal tissues by exposure to 3'-azido-3'-deoxythymidine (AZT). AZT has been used effectively for the treatment of human immunodeficiency virus-1 (HIV-1) and AIDS. It showed in vitro to block the nucleoside-binding site of the viral reverse transcriptase and to inhibit DNA replication by chain termination. It incorporates into both nuclear and mitochondrial DNA and is shown to cause cancer in vivo and in vitro. This study was designed to examine the interaction of AZT with DNA in aqueous solution at physiological condition, using different drug/DNA (phosphate) molar ratios (r) of 1/80 to 1/2 and constant DNA concentration of 12.5 mM (phosphate). Capillary electrophoresis, FTIR, and UV-visible difference spectroscopic methods and molecular modeling were used to determine the drug binding sites, the binding constants and the effects of the AZT complexation on DNA conformation. Structural analysis showed that AZT binds to DNA through G-C and A-T base pairs and the backbone PO(2) groups with two binding constants of K(1) = 2.60 x 10(5) M(-1) and K(2) = 1.20 x 10(5) M(-1). The drug distributions are 50% with G-C, 15% with A-T and 35% with the backbone phosphate group. AZT-DNA interaction is associated with a partial B- to A-DNA conformational transition.
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PMID:AZT-DNA interaction. 1506 82

Immunodeficiency is a characteristic feature of ataxia-telangiectasia (A-T). Humoral immunodeficiency generally consists of hypogammaglobulinemia and impaired antibody response to bacterial and viral antigens. We previously observed defective antibody response to 23-valent pneumococcal polysaccharide vaccine (PPV) in 96% of 29 patients with A-T. In this study, we investigated the antibody response to a seven-valent pneumococcal conjugate vaccine, PCV7, in 14 patients with A-T. IgG antibody levels to four pneumococcal serotypes, 6B, 14, 19F, 23F, which were included in PCV7, were measured by ELISA in pre- and postimmunization serum samples. Antibody titers against each individual Streptococcus pneumoniae serotype was considered to be positive when serotype specific pneumococcal antibody titer was higher than 10% (>10 U/mL) of the reference plasma pool level. However, when the fold increase (FI) in postimmunization antibody titer was less than two, the subject was determined to be unresponsive to the given serotype. The values were compared with the results obtained in age- and ethnic-matched children after one dose of PPV. Only two patients produced antibodies to one serotype each; one to serotype 19 with a fold increase of <2, and the other to serotype 23F with a fold increase of 5.7 based on the above criteria, although the differences between pre- and postvaccine antibody titers for serotypes 14, 19, and 23 appeared to be statistically significant. In conclusion, A-T patients failed to respond to one dose of PCV7 vaccine. Two or more doses of conjugated vaccine may be required to recruit the help of T lymphocytes in A-T patients.
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PMID:Antibody response to a seven-valent pneumococcal conjugated vaccine in patients with ataxia-telangiectasia. 1516 97

This objective of this study was to evaluate patients with immunodeficiency syndromes who had developed malignant solid tumors and to examine survival rates and prognosis with respect to type of immunodeficiency disease. Twenty-two patients who were diagnosed with malignant solid tumors and immunodeficiency syndromes between January 1972 and February 2003 were analyzed retrospectively. There were 12 (55%) patients with non-Hodgkin lymphoma, 8 (37%) with Hodgkin disease, 1 (5%) with mucinous adenocarcinoma of the colon, and 1 (5%) with brain stem glioma. Fifteen (68%) patients had ataxia-telangiectasia, 3 (14%) had common variable immunodeficiency disease, 2 (9%) had Bloom syndrome, 1 (5%) had combined immunodeficiency, and 1 (5%) had selective immunoglobulin A deficiency. Out of the 15 patients with ataxia-telangiectasia 9 patients had non-Hodgkin lymphoma, 5 had Hodgkin disease, and 1 had brain stem glioma. Two patients with common variable immunodeficiency disease had non-Hodgkin lymphoma and 1 had Hodgkin disease. One of the patients with Bloom syndrome had Hodgkin disease and 1 had colon carcinoma. The overall survival for the whole group was 24%. Overall survival rates in non-Hodgkin lymphoma, Hodgkin disease, colon carcinoma, and brain stem glioma were 17, 44, 0, and 0% (p =.25), respectively. Overall survival in ataxia-telangiectasia patients was 20%. In this series, most of the patients had ataxia-telangiectasia (68%). The survival rates of the malignant diseases were very poor in immunodeficiency. Overall survival in non-Hodgkin lymphoma patients was relatively worse than Hodgkin disease patients.
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PMID:Malignant solid tumors associated with congenital immunodeficiency disorders. 1520 88

Inherited biallelic mutations of the ATM (ataxia-telangiectasia mutated) gene in humans cause ataxia-telangiectasia, a rare autosomal recessive disorder associated with progressive neuro-degeneration, cancer predisposition, immunodeficiency, and hypersensitivity to ionizing radiation. The ATM gene is highly conserved across a wide range of species. In an attempt to establish a zebrafish (Danio rerio) model of ataxia-telangiectasia, we cloned the coding sequence of the catalytic domain of the zebrafish homologue of ATM and found it to contain an open reading frame encoding 907 amino acids at the carboxyl terminus of the zebrafish ATM (zATM). The catalytic domain of zATM shares 67% and 66% homology with human ATM (hATM) and mouse ATM (mATM), respectively. The full-length mRNA encoding zATM is found to be approximately 11 kb by Northern hybridization, and the expression of zATM is observed in different adult and embryonic tissues. Overexpression of a kinase-inactive zATM domain in human cells has a dominant-negative effect against hATM function. Expression of the altered zATM in ZF4 cells leads to an A-T-like phenotype in response to ionizing radiation. These results taken together indicate that zATM is the homologue of hATM. Furthermore, using the kinase-inactive form of zATM should allow manipulation of zATM function in fish cells.
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PMID:Molecular cloning and characterization of the catalytic domain of zebrafish homologue of the ataxia-telangiectasia mutated gene. 1523 10

The Nijmegen Breakage Syndrome (NBS) is a rare autosomal recessive disorder associated with microcephaly, immunodeficiency, chromosome instability and cancer proneness. The mutated gene that results in NBS codes for nibrin (Nbs1/p95), a DNA repair protein that is functionally linked to ATM, the kinase protein product of the gene responsible of ataxia-telangiectasia (A-T). We report the clinical, cytogenetic and molecular characterization of a second case of NBS in Chile detected by us. The patient is a 7 year old Chilean boy from a consanguineous marriage, with microcephaly, immunodeficiency and acute non lymphocytic leukemia (ANLL). As NBS shares chromosomal and cellular features with A-T, the cytogenetic studies of this patient also included 3 A-T patients. Our results showed that the frequency of spontaneous and X rays induced chromosomal aberrations in NBS are higher than in A-T cells. DNA analysis revealed that the patient is homozygous for the Slavic mutation 657del5 in the NBS1 gene. This finding and the absence of nibrin in patient's cells, confirmed the clinical diagnosis of NBS in our patient.
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PMID:[Clinical, cytogenetic and molecular characterization of a new case of Nijmegen breakage syndrome in Chile]. 1544 58

Eukaryotic cells have evolved a complex mechanism for sensing DNA damage during genome replication. Activation of this pathway prevents entry into mitosis to allow for either DNA repair or, in the event of irreparable damage, commitment to apoptosis. Under conditions of replication stress, the damage signal is initiated by the ataxia-telangiectasia-mutated and Rad3-related kinase ATR. We recently demonstrated that the human immunodeficiency virus type 1 (HIV-1) gene product viral protein R (Vpr) arrests infected cells in the G(2) phase via the activation of ATR. In the present study, we show that the activation of ATR by Vpr is analogous to activation by certain genotoxic agents, both mechanistically and in its downstream consequences. Specifically, we show a requirement for Rad17 and Hus1 to induce G(2) arrest as well as Vpr-induced phosphorylation of histone 2A variant X (H2AX) and formation of nuclear foci containing H2AX and breast cancer susceptibility protein 1. These results demonstrate that G(2) arrest mediated by the HIV-1 gene product Vpr utilizes the cellular signaling pathway whose physiological function is to recognize replication stress. These findings should contribute to a greater understanding of how HIV-1 manipulates the CD4(+)-lymphocyte cell cycle and apoptosis induction in the progressive CD4(+)-lymphocyte depletion characteristic of HIV-1 pathogenesis.
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PMID:Human immunodeficiency virus type 1 Vpr-mediated G2 arrest requires Rad17 and Hus1 and induces nuclear BRCA1 and gamma-H2AX focus formation. 1548 98

The 'ataxia telangiectasia mutated' (Atm) gene maintains genomic stability by activating a key cell-cycle checkpoint in response to DNA damage, telomeric instability or oxidative stress. Mutational inactivation of the gene causes an autosomal recessive disorder, ataxia-telangiectasia, characterized by immunodeficiency, progressive cerebellar ataxia, oculocutaneous telangiectasia, defective spermatogenesis, premature ageing and a high incidence of lymphoma. Here we show that ATM has an essential function in the reconstitutive capacity of haematopoietic stem cells (HSCs) but is not as important for the proliferation or differentiation of progenitors, in a telomere-independent manner. Atm-/- mice older than 24 weeks showed progressive bone marrow failure resulting from a defect in HSC function that was associated with elevated reactive oxygen species. Treatment with anti-oxidative agents restored the reconstitutive capacity of Atm-/- HSCs, resulting in the prevention of bone marrow failure. Activation of the p16(INK4a)-retinoblastoma (Rb) gene product pathway in response to elevated reactive oxygen species led to the failure of Atm-/- HSCs. These results show that the self-renewal capacity of HSCs depends on ATM-mediated inhibition of oxidative stress.
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PMID:Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. 1549 26


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