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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The heuristic concept of "inborn errors of metabolism" was introduced more then 70 years ago and by analogy has prompted the more recent introduction of the term "inborn errors of immunity". It is now well recognized that many inborn errors of immunity can be considered inborn errors of metabolism. Typically, many forms of severe combined immunodeficiency result from adenosine deaminase deficiency, i.e., an inborn error of purine metabolism. On the other hand, errors of immunity are often associated with "errors of morphogenesis", resulting from an intrinsically abnormal developmental process (malformation), a secondary or extrinsic interference with originally normal development (disruption), or an abnormal organization of cells into tissues (dysplasia). Twenty years after the original description, the DiGeorge anomaly should be considered an inborn error of morphogenesis and immunity due either to disruption or less frequently to malformation. In other immunodeficiencies, such as ataxia telangiectasia, the morphologic and immunologic errors result from a dyshistogenesis, i.e., dysplasia. Also, true malformation syndromes, such as Down's syndrome, are consistently associated with immunodeficiency.
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PMID:Errors of morphogenesis and inborn errors of immunity 20 years after the discovery of DiGeorge anomaly. 401 10

Circulating levels of T-cell subsets and NK cells were determined in 78 patients with primary immunodeficiencies, 35 children with recurrent respiratory infections, and healthy age-matched controls. Normal T cell and natural killer (NK) cell values were observed in individuals with immunoglobulin A (IgA) deficiency and X-linked agammaglobulinemia, while reduced OKT4/OKT8 cell ratios and low levels of 5/9+ T helper cells were found in approximately 60% of patients with common variable immunodeficiency. Infants with severe combined immunodeficiency (SCID) and lymphopenia had virtually no cells expressing T-cell or NK-cell surface antigens, but had normal numbers of monocytes and other types of blood cells. Infants with DiGeorge syndrome, other primary T-cell defects, or SCID with B cells had few or no circulating cells of mature T helper-suppressor phenotypes, but had normal numbers of NK cells (HNK-1+) and NK function. These results support the idea of a common stem cell precursor for T, B, and NK cells, each of which follows a separate pathway of differentiation. Profound alterations were observed in the distribution and function of T-cell subsets in ataxia-telangiectasia patients who were previously shown to have thymic dysplasia. A significant reduction in the frequencies of OKT3+ and OKT4+ cells was observed in children with frequent respiratory infections during infancy.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Usefulness of monoclonal antibodies in the diagnosis and monitoring of patients with primary immunodeficiencies: combined experience in three clinical immunology centers. 638 70

Autopsy findings for two patients with the Nijmegen breakage syndrome (NBS) are presented. This syndrome has the same type of immunologic and cytogenetic abnormalities as ataxia telangiectasia (AT). In NBS, however, microcephaly is found and progressive cerebellar ataxia and oculocutaneous telangiectasia are lacking. We demonstrate a clear neuropathologic difference between these two syndromes, as the diffuse cortical cerebellar degeneration characteristic of AT was absent in NBS. In the thymus the histologic picture was suggestive of simple dysplasia. Lymphoid tissues were slightly atrophic but otherwise structurally normal. In one of the two presented cases an extranodal diffuse large cell malignant non-Hodgkin lymphoma of B cell immunoblastic type was found in Waldeyer's ring, in the small and large intestines, and in the brain, whose sequelae had caused death. Six of the 19 patients known with certainty to have this syndrome have developed lymphoid malignancy, which indicates that these patients are prone to develop malignancies.
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PMID:Postmortem findings in the Nijmegen breakage syndrome. 780 77

Yesterday's immunodeficiencies emphasized the clinical and familial associations of the syndromes and date from the 1920s (ataxia-telangiectasia, chronic mucocutaneous candidiasis), the 1930s (Wiskott-Aldrich syndrome), skipping the 1940s, but blossoming in the 15-y period from 1950 to 1965. In this period, primary immunodeficiencies affecting all the major limbs of the immune system were first described (1950: severe combined immunodeficiency; 1952: X-linked agammaglobulinemia; 1957: chronic granulomatous disease; 1965: C2 deficiency). Today's immunodeficiencies, as detailed in Stiehm's Immunologic Disorders in Infants and Children (Edition 1, 1973; Edition 2, 1980; and Edition 3, 1989) emphasize the immunologic and genetic aspects of immunodeficiency. These increased from 43 syndromes in the 1973 edition (34 primary, nine secondary) to 94 syndromes in the 1989 edition (66 primary, 28 secondary). This means that about two primary and one secondary immunodeficiencies have been uncovered annually. Tomorrow's immunodeficiencies, to be covered in Edition 4, will include new clinical and immunologic observations and molecular and biochemical studies that characterize some unique immunodeficiencies. These include the following six groups of defects: 1) neutropenic syndromes with hypogammaglobulinemia, including the WHIM syndrome; 2) phenotypic genetic syndromes with immunodeficiency including Bloom's syndrome and Schimke's immuno-osseous dysplasia; 3) natural killer cell defects associated with a) other primary immunodeficiencies, b) other nonimmunologic illness, and c) primary natural killer defects; 4) T-cell membrane defects; 5) IL defects; and 6) miscellaneous phagocytic illnesses including periodontitis and the asplenia syndrome.
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PMID:New and old immunodeficiencies. 843 70

Since the introduction of angiotensin converting enzyme-inhibitors (ACE-inhibitors) in the 1980's, more than 50 cases of foetotoxic effects ascribed to intrauterine exposure to inhibitors have been published. Among the most commonly reported effects are: Hypotension, renal dysplasia, anuria/oliguria, oligohydramios, intrauterine growth retardation, pulmonary hypoplasia, unclosed ductus arteriosus, incomplete ossification of the skull, intrauterine og neonatal death. Recent animal studies have confirmed that intrauterine or neonatal exposure to ACE-inhibitors or the AT1-receptor antagonist losartan can cause death and serious, irreversible organ damage. These effects are similar to the complications previously reported in humans. Animal studies suggest that the foetotoxic actions are most common after exposure during the last trimester. However, due to the severity of these complications, the use of ACE-inhibitors and AT1-receptor antagonists should be avoided throughout pregnancy and in women who are breast feeding.
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PMID:[Teratogenic effects of ACE-inhibitors and angiotensin II receptor antagonists]. 952 Jun 13

Ataxia-telangiectasia (AT) is a genetic syndrome resulting from the inheritance of two defective copies of the ATM gene that includes among its stigmata radiosensitivity and cancer susceptibility. Epidemiological studies have demonstrated that although women with a single defective copy of ATM (AT heterozygotes) appear clinically normal, they may never the less have an increased relative risk of developing breast cancer. Whether they are at increased risk for radiation-induced breast cancer from medical exposures to ionizing radiation is unknown. We have used a murine model of AT to investigate the effect of a single defective Atm allele, the murine homologue of ATM, on the susceptibility of mammary epithelial cells to radiation-induced transformation. Here we report that mammary epithelial cells from irradiated mice with one copy of Atm truncated in the PI-3 kinase domain were susceptible to radiation-induced genomic instability and generated a 10% incidence of dysplastic mammary ducts when transplanted into syngenic recipients, whereas cells from Atm(+/+) mice were stable and formed only normal ducts. Since radiation-induced ductal dysplasia is a precursor to mammary cancer, the results indicate that AT heterozygosity increases susceptibility to radiogenic breast cancer in this murine model system.
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PMID:Radiation induces genomic instability and mammary ductal dysplasia in Atm heterozygous mice. 1146 22

Gene promoter hypermethylation is increasingly recognized to play an important role in cancer development through silencing of gene transcription. This study determined the methylation profiles of primary colorectal cancers and adenomas to elucidate the role of epigenetic changes in different stages of colorectal carcinogenesis. We examined the methylation profiles of 47 sporadic colorectal cancers, 36 colonic adenomas from patients without cancer and 34 colonic biopsies from patients without colonic lesions. Paired adjacent dysplasia tissues obtained from 17 cancer patients were also examined. Promoter hypermethylation in 10 tumor-related genes (APC, ATM, GSTP1, HLTF, MGMT, hMLH1, p14, p15, SOCS-1 and TIMP-3) were studied by methylation-specific PCR. Promoter hypermethylation was frequently detected in more than 40% of colonic cancers and adenomas in APC, ATM, HLTF, MGMT and hMLH1 genes (p < 0.0001 vs. normal). While low level of methylation was detected in p14, p15 and TIMP-3, there was no methylation detected in GSTP1 and SOCS-1. The frequencies of methylation were comparable between tumors and adenomas, and advanced and nonadvanced adenoma. In contrast, K-ras mutation was only detected in advanced adenomas and cancers. Concurrent methylation in >/= 3 genes was found in 66.7% adenomas and 68.1% cancers but not in normal colonic tissues. Methylation was associated with reduced protein expressions in colorectal adenomas and cancers. Moreover, methylation in ATM was more common in older cancer patients (p = 0.002), but there was no significant association between promoter hypermethylation and other clinicopathologic characteristics of cancer. Our study demonstrated the early and specific involvement of promoter hypermethylation in the colorectal adenoma-carcinoma sequence.
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PMID:Promoter hypermethylation of tumor-related genes in the progression of colorectal neoplasia. 1538 72

Ataxia-telangiectasia (A-T), which is due to mutations in the ATM gene, is a rare autosomal recessive genomic instability syndrome characterized by radiosensitivity and predisposition to cancer. Epidemiological studies have suggested that relatives of A-T patients (A-T carriers) have increased risks of developing breast cancer. We propose that increased breast cancer risks in A-T carriers may be due to exposure to various environmental carcinogens and/or dietary consumption. To test this hypothesis, we treated a congenic strain of Atm+/- mice with DMBA (7,12-dimethylbenz(alpha)anthracene), a mammary carcinogen, and observed mammary tumor incidence. It was found that Atm+/- mice have a 2-fold increase, as well as early onset, in mammary tumor incidence relative to wild-type mice (P<0.005). The increased mammary tumor development is correlated with a 3-fold increase in the development of mammary dysplasia in Atm+/- compared with wild-type mice (P<0.05). We also found that Ras signaling pathway was not activated in DMBA-induced mammary tumors irrespective of the Atm status. At the cellular level, Atm-haploinsufficiency confers increased cellular stress manifested by an increased p53 expression and a slightly enhanced survival of mammary epithelial cells in response to radiation. Our results demonstrate that Atm heterozygotes are predisposed to mammary tumor development and support the hypothesis that exposure to environmental carcinogens contributes to the increased rate of breast cancer development in A-T carriers. Given that 1% of the general population are ATM heterozygotes (A-T carriers), this study has great implications in breast cancer development in this population.
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PMID:Atm-haploinsufficiency enhances susceptibility to carcinogen-induced mammary tumors. 1640 Jan 90

The telomere repeat-binding factor 1 (TERF1, referred to hereafter as TRF1) is a component of mammalian telomeres whose role in telomere biology and disease has remained elusive. Here, we report on cells and mice conditionally deleted for TRF1. TRF1-deleted mouse embryonic fibroblasts (MEFs) show rapid induction of senescence, which is concomitant with abundant telomeric gamma-H2AX foci and activation of the ATM/ATR downstream checkpoint kinases CHK1 and CHK2. DNA damage foci are rescued by both ATM and ATM/ATR inhibitors, further indicating that both signaling pathways are activated upon TRF1 deletion. Abrogation of the p53 and RB pathways bypasses senescence but leads to chromosomal instability including sister chromatid fusions, chromosome concatenation, and occurrence of multitelomeric signals (MTS). MTS are also elevated in ATR-deficient MEFs or upon treatment with aphidicolin, two conditions known to induce breakage at fragile sites, suggesting that TRF1-depleted telomeres are prone to breakage. To address the impact of these molecular defects in the organism, we deleted TRF1 in stratified epithelia of TRF1(Delta/Delta)K5-Cre mice. These mice die perinatally and show skin hyperpigmentation and epithelial dysplasia, which are associated with induction of telomere-instigated DNA damage, activation of the p53/p21 and p16 pathways, and cell cycle arrest in vivo. p53 deficiency rescues mouse survival but leads to development of squamous cell carcinomas, demonstrating that TRF1 suppresses tumorigenesis. Together, these results demonstrate that dysfunction of a telomere-binding protein is sufficient to produce severe telomeric damage in the absence of telomere shortening, resulting in premature tissue degeneration and development of neoplastic lesions.
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PMID:Increased telomere fragility and fusions resulting from TRF1 deficiency lead to degenerative pathologies and increased cancer in mice. 1967 47

Mutations in SMARCAL1 (HARP) cause Schimke immunoosseous dysplasia (SIOD). The mechanistic basis for this disease is unknown. Using functional genomic screens, we identified SMARCAL1 as a genome maintenance protein. Silencing and overexpression of SMARCAL1 leads to activation of the DNA damage response during S phase in the absence of any genotoxic agent. SMARCAL1 contains a Replication protein A (RPA)-binding motif similar to that found in the replication stress response protein TIPIN (Timeless-Interacting Protein), which is both necessary and sufficient to target SMARCAL1 to stalled replication forks. RPA binding is critical for the cellular function of SMARCAL1; however, it is not necessary for the annealing helicase activity of SMARCAL1 in vitro. An SIOD-associated SMARCAL1 mutant fails to prevent replication-associated DNA damage from accumulating in cells in which endogenous SMARCAL1 is silenced. Ataxia-telangiectasia mutated (ATM), ATM and Rad3-related (ATR), and DNA-dependent protein kinase (DNA-PK) phosphorylate SMARCAL1 in response to replication stress. Loss of SMARCAL1 activity causes increased RPA loading onto chromatin and persistent RPA phosphorylation after a transient exposure to replication stress. Furthermore, SMARCAL1-deficient cells are hypersensitive to replication stress agents. Thus, SMARCAL1 is a replication stress response protein, and the pleiotropic phenotypes of SIOD are at least partly due to defects in genome maintenance during DNA replication.
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PMID:The annealing helicase SMARCAL1 maintains genome integrity at stalled replication forks. 1983 62


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