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 (BS) is a rare genetic disorder characterized by small body size, sunsensitivity, immunodeficiency and a high predisposition to various types of cancer. BLM was identified as the causative gene for BS, and BLM protein is homologous to DNA helicase. In 1995 the causative gene for BS was identified using somatic crossover point mapping and termed BLM. BLM is a 4437 bp cDNA that encodes a 1417 amino acid peptide which is homologous to ATP-dependent DNA helicases. DNA helicases are the enzymes which catalyze the unwinding of double-stranded DNA to provide single- stranded templates for the processes of replication, repair, recombination and transcription. BLM is a member of the RecQ helicase family, consisting of human WRN, RECQL and yeast Sgs1. The BLM protein translocates into the nucleus and the distal arm of the bipartite basic residues in the C-terminus of the BLM protein is essential for targeting the nucleus. Here, we also describe relationship between the BLM gene and the cancer.
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PMID:[Bloom syndrome]. 1092 24

Ataxia-telangiectasia (AT) is an uncommon genetic disorder characterized by cerebellar ataxia, oculocutaneous telangiectasias, progressive immunodeficiency, and a predisposition to lymphoid malignancy. The genetic defect in AT predisposes not only to malignancy but also to severe toxicity from anti-neoplastic therapies. It is important to consider the diagnosis of AT in any child with a lymphoid malignancy at a younger than expected age, or who has a pre-existing ataxia, to anticipate unusually severe toxicities from the antineoplastic therapy, to avoid confusing the development of ataxia with toxicity from therapy, and to provide appropriate genetic counseling. We describe two children at a young age with a lymphoid malignancy diagnosed before the diagnosis of AT. One patient had severe toxicity from his chemotherapy, requiring truncation of the planned course of treatment. The other child was able to tolerate his entire planned course of therapy, but ataxia that was initially interpreted as toxicity from chemotherapy rather than as a sign of his AT developed. Lymphoid malignancy may be the presenting sign of AT. Making this diagnosis may influence therapy of the malignancy. The neurologic manifestations of the disease can be misinterpreted as toxicities of the chemotherapy, and diagnosis of AT allows appropriate genetic counseling for the family.
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PMID:Lymphoid malignancy as a presenting sign of ataxia-telangiectasia. 1103 63

Ataxia telangiectasia (A-T) is a human genetic disorder characterized by progressive cerebellar degeneration, hypersensitivity to ionizing radiation (IR), immunodeficiency, and high cancer risk. At the cellular level, IR sensitivity and increased frequency of spontaneous and IR-induced chromosomal breakage and rearrangements are the hallmarks of A-T. The ATM gene, mutated in this syndrome, has been cloned and codes for a protein sharing homology with DNA-PKcs, a protein kinase involved in DNA double-strand break (DSB) repair and DNA damage responses. The characteristics of the A-T cellular phenotypes and ATM gene suggest that ATM may play a role similar to that of DNA-PKcs in DSB repair and that there is a primary DNA repair defect in A-T cells. In the current study, the function of ATM in DNA DSB repair was evaluated in an in vitro system using two plasmids, carrying either an EcoRI-induced DSB within the lacZalpha gene or various endonuclease-induced DSB in the SupF suppressor tRNA gene. We found that the DSB repair efficiency in A-T nuclear extracts was comparable to, if not higher than, that in normal nuclear extracts. However, the repair fidelity in A-T nuclear extracts was decreased when repairing DSB with short 5' and 3' overhangs (<4 base pairs (bp)) or blunt ends, but not 5' 4-bp overhangs. Sequencing of the mutant plasmids revealed that deletions involving 1-6 nucleotide microhomologies were the major class of mutations in both A-T and normal extracts. However, the size of the deletions in plasmids from A-T nuclear extracts was larger than that from normal nuclear extracts. Expression of the ATM protein in A-T cells corrected the defect in DSB repair in A-T nuclear extracts. These results suggest that ATM plays a role in maintaining genomic stability by preventing the repair of DSB from an error-prone pathway.
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PMID:Expression of ATM in ataxia telangiectasia fibroblasts rescues defects in DNA double-strand break repair in nuclear extracts. 1124 19

Patients with the genetic disorder ataxia-telangiectasia (A-T) display a pleiotropic phenotype that includes neurodegeneration, immunodeficiency, cancer predisposition and hypersensitivity to ionizing radiation. The gene responsible is ATM, and ATM:-knockout mice recapitulate most features of A-T. In order to study the involvement of oxidative stress in the A-T phenotype, we examined mice deficient for Atm and overexpressing human Cu/Zn superoxide dismutase (SOD1). We report that elevated levels of SOD1 exacerbate specific features of the murine Atm- deficient phenotype, including abnormalities in hematopoiesis and radiosensitivity. The data are consistent with the possibility that oxidative stress contributes to some of the clinical features associated with the A-T phenotype.
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PMID:Elevated Cu/Zn-SOD exacerbates radiation sensitivity and hematopoietic abnormalities of Atm-deficient mice. 1128 18

Bloom syndrome (BS) is a recessive human genetic disorder characterized by short stature, immunodeficiency and an elevated risk of malignancy. The gene mutated in BS, BLM, encodes a RecQ-type DNA helicase. BS cells have mutator phenotypes such as hyper-recombination, chromosome instability and an increased frequency of sister chromatid exchange (SCE). To define the primary role of BLM, we generated BLM(-/-) mutants of the chicken B-cell line DT40. In addition to characteristics of BLM(-/-) cells reported previously by the other group, they are hypersensitive to genotoxic agents such as etoposide, bleomycin and 4-nitroquinoline-1-oxide and irradiation with the short wave length of UV (UVC) light, whereas they exhibit normal sensitivity to X-ray irradiation and hydroxyurea. UVC irradiation to BLM(-/-) cells during G(1) to early S phase caused chromosomal instability such as chromatid breaks and chromosomal quadriradials, leading to eventual cell death. These results suggest that BLM is involved in surveillance of base abnormalities in genomic DNA that may be encountered by replication forks in early S phase. Such surveillance would maintain genomic stability in vertebrate cells, resulting in the prevention of cellular tumorigenesis.
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PMID:Bloom helicase is involved in DNA surveillance in early S phase in vertebrate cells. 1131 58

Nijmegen breakage syndrome (NBS) is a genetic disorder characterized by immunodeficiency, microcephaly, and "bird-like" facies. NBS shares some clinical features with ataxia telangiectasia (AT), including increased sensitivity to ionizing radiation, increased spontaneous and induced chromosome fragility, and strong predisposition to lymphoid cancers. The mutated gene that results in NBS codes for a novel double-stranded DNA break repair protein, named nibrin. In the present work, a Spanish NBS patient was extensively characterized at the immunological and the molecular DNA levels. He showed low CD3(+)-cell numbers and an abnormal low CD4(+) naive cell/CD4(+) memory cell ratio, previously described in AT patients and also described in the present report in the NBS patient. The proliferative response of peripheral blood lymphocytes in vitro to mitogens is deficient in NBS patients, but the possible link among NBS mutations and the abnormal immune response is still unknown.
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PMID:Role of Nijmegen breakage syndrome protein in specific T-lymphocyte activation pathways. 1142 22

X-linked lymphoproliferative disease (XLP), a genetic disorder characterized by immunodeficiency to Epstein-Barr virus (EBV) infection, has been linked to mutations in the SH2D1A gene. To search for the occurrence of SH2D1A mutations in Japan, we performed genetic analysis of the SH2D1A gene in 40 males presenting with severe EBV-associated illnesses, including fulminant infectious mononucleosis, EBV-positive lymphoma, and severe chronic active EBV infection. SH2D1A mutations were detected in 10 of these 40 patients. Five of these 10 cases were sporadic. Patients with SH2D1A mutations displayed severe acute infectious mononucleosis with hyperimmunoglobulin M, hypogammaglobulinemia, and B-cell malignant lymphoma. By contrast, chronic active EBV infection was not associated with SH2D1A mutations. XLP survivors exhibited normal levels of circulating EBV-DNA during convalescence, suggesting that SH2D1A protein is not directly responsible for control of EBV replication. Thus, genetic analysis of the SH2D1A gene is particularly useful in the diagnosis of sporadic cases and carriers of XLP. (Blood. 2001;98:1268-1270)
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PMID:SH2D1A mutations in Japanese males with severe Epstein-Barr virus--associated illnesses. 1149 83

One of the cornerstones of the web of signaling pathways governing cellular life and differentiation is the DNA damage response. It spans a complex network of pathways, ranging from DNA repair to modulation of numerous processes in the cell. DNA double-strand breaks (DSBs), which are formed as a result of genotoxic stress or normal recombinational processes, are extremely lethal lesions that rapidly mobilize this intricate defense system. The master controller that pilots cellular responses to DSBs is the ATM protein kinase, which turns on this network by phosphorylating key players in its various branches. ATM is the protein product of the gene mutated in the human genetic disorder ataxia-telangiectasia (A-T), which is characterized by neuronal degeneration, immunodeficiency, sterility, genomic instability, cancer predisposition, and radiation sensitivity. The clinical and cellular phenotype of A-T attests to the numerous roles of ATM, on the one hand, and to the link between the DNA damage response and developmental processes on the other hand. Recent studies of this protein and its effectors, combined with a thorough investigation of animal models of A-T, have led to new insights into the mode of action of this master controller of the DNA damage response. The evidence that ATM is involved in signaling pathways other than those related to damage response, particularly ones relating to cellular growth and differentiation, reinforces the multifaceted nature of this protein, in which genome stability, developmental processes, and cancer cross paths.
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PMID:ATM: genome stability, neuronal development, and cancer cross paths. 1166 19

The rare human genetic disorder ataxia-telangiectasia (A-T) has multiple consequences including a variable degree of immunodeficiency. Khanna and co-workers (Khanna, K. K., Yan, J., Watters, D., Hobson, K., Beamish, H., Spring, K., Shiloh, Y., Gatti, R. A., and Lavin, M. F. (1997) J. Biol. Chem. 272, 9489-9495) evaluated signaling in Epstein-Barr virus (EBV) immortalized A-T lymphoblastoid cell lines (LCLs), derived from the B cells of A-T patients. They showed that A-T lymphoblastoid cells lack signaling through the B cell antigen receptor and concluded that the fault in A-T encompasses intracellular signaling in B cells. However, it is established that EBV latent membrane protein 2A (LMP2A) blocks signaling in EBV-bearing cells by interaction with cellular tyrosine kinases. To test whether the reported fault in A-T B cells was not inherent in A-T but the result of influence of wild-type EBV, we derived A-T LCLs with wild-type or LMP2A-deleted EBV and studied signaling in these cells in response to cross-linking the B cell antigen receptor. We report that intracellular calcium mobilization and tyrosine phosphorylation in LMP2A-depleted LCLs derived from A-T patients is indistinguishable from that in LMP2A-depleted LCLs derived from normal controls. Further, signaling is blocked similarly in A-T and normal lymphoblastoid cells bearing wild-type EBV. In conclusion there is no evidence of any defect in B cell receptor signal transduction in A-T B cells.
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PMID:Signal transduction through the B cell antigen receptor is normal in ataxia-telangiectasia B lymphocytes. 1173 29

Bloom syndrome (BS) is a rare autosomal recessive genetic disorder characterized by growth deficiency, unusual facies, sun-sensitive telangiectatic erythema, immunodeficiency and predisposition to cancer. The causative gene for BS is the BLM gene which encodes the BLM RecQ helicase protein. The BLM gene has 4437 bp and encodes 1417 amino acids. The detection of BLM gene mutations for laboratory diagnosis of BS is laborious and impractical, unless there are common mutations in a population. Here we describe the immunoblot and immunohistochemical analyses for the detection of the BLM protein using a polyclonal BLM antibody. The BLM gene and protein were consistently and clearly detected in Epstein-Barr virus (EBV)-transformed or phytohemagglutinin (PHA)-stimulated lymphoblasts from control and various human hematopoietic cell lines. In a 7-week old human fetal brain, the BLM gene expression was strongly detected in contrast to an adult human brain. The BLM protein was not detected in EBV-transformed lymphoblasts from three BS patients. By immunohistochemistry, nuclear dots of the BLM protein were detected in both EBV-transformed lymphoblasts and PHA-stimulated lymphoblasts from the control. However, in lymphoblasts from BS patients no nuclear dots of the BLM protein were detected. These results indicate that the combinational analysis of immunoblotting and immunohistochemistry is a useful approach to screening of BS, although a mutation analysis is necessary for a definitive diagnosis of BS.
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PMID:Expression of BLM (the causative gene for Bloom syndrome) and screening of Bloom syndrome. 1206 Aug 58


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