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)

Activation-induced (cytidine) deaminase (AID) efficiently introduces multiple and diversified deaminations in immunoglobulin (Ig) variable and switch regions. Here, we review studies of AID, and the APOBEC family member, APOBEC3G, demonstrating that both enzymes introduce multiple deaminations by processive action on single-stranded DNA and that deaminations occur stochastically at hot- and cold-spot targets. In a more detailed analysis of AID, we examine phosphorylation-null mutants, particularly, S38A and S43P. S43P mutant AID has been identified in a patient with hyper-IgM immunodeficiency syndrome. The phosphorylation-null mutants have essentially the same specific activity, processivity and ability to undergo transcription-dependent deamination compared with wild-type (WT) AID. Although the phosphorylation-null mutants still deaminate 5'-WRC hot spots, the mutant deamination spectra differ from WT AID. The mutants strongly prefer two motifs, 5'AGC and 5'GGC, which are disfavoured by WT AID. Differences in deamination specificities can be attributed primarily to the replacement of Ser rather than to the absence of phosphorylation. The 5'GGC motif occurs with exceptionally high frequency on the non-transcribed strand of human switch regions, IgG4 and IgE. The potential for S43P to catalyse large numbers of aberrant deaminations in switch region sequences suggests a possible relationship between non-canonical AID deamination specificity and a loss of antibody diversification.
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PMID:Stochastic properties of processive cytidine DNA deaminases AID and APOBEC3G. 1902 38

Over 8.3 million people living in the Asia Pacific region are human immunodeficiency virus (HIV) positive and up to 40% of these individuals have had prior acquired immunodeficiency syndrome (AIDS) illnesses. Recently endeavors have been made to better characterize the burden of HIV-related neurological disease within the Asia Pacific region and, with this in mind, the NeuroAIDS in Asia and the Pacific Rim workshop was held in Sydney, Australia, as an affiliated event of the 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention. The workshop was supported by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of Mental Health (NIMH) of the United States National Institutes of Health and the Australian Government overseas AID program, AusAID. HIV neurologists, infectious disease physicians, pediatricians, psychiatrists, immunologists, virologists,and researchers from 12 countries of the Asia Pacific region (including Australia), the United States, and the United Kingdom attended the meeting. A broad range of topics were addressed, including common HIV neurological disorders, the lack of diagnostic, management, and research infrastructure, central nervous system (CNS) immune restoration disease, pediatric neuroAIDS, and current clinical and laboratory research projects being undertaken within the Asia Pacific region.
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PMID:NeuroAIDS in the Asia Pacific Region. 1903 Dec 89

Since 1996, AID FOR AIDS International (AFAI) has collected unused antiretroviral drugs (ART) and ;;recycled'' these medications to over 600 people living with human immunodeficiency virus/AIDS abroad under its AIDS Treatment Access Program. The investigators evaluated AIDS Treatment Access Program's efficacy using immunologic and virologic outcomes. Of the 404 eligible clients who had baseline and follow-up CD4 counts, mean baseline versus most recent measure was 230 + 222 cells/mm( 3) versus 372 + 256 cells/mm(3) (P < .01). Of the 216 eligible clients who had baseline (>400 copies/mL) and follow-up viral loads, 62% (134/ 216) had undetectable viral loads (<400 copies/mL) at their most recent measure. Median enrollment time in the recycling program was 3.1 years (range: 6 months to 9.5 years). AFAI's medication recycling program is efficacious in reaching and improving the clinical outcomes of people living with HIV/AIDS (PLWHA). Such programs should be considered a viable option among scale-up programs until governments provide universal access of ART to PLWHA.
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PMID:The efficacy of a US-based medicine recycling program delivering antiretroviral drugs worldwide. 1903 75

Human APOBEC3G (hA3G), a member of the AID/APOBEC family of deaminases, is a restriction factor for human immunodeficiency virus (HIV). In the absence of the viral Vif protein hA3G is packaged into virions and during reverse transcription in a recipient cell it deaminates cytosines, leading to G-->A hypermutation and inactivation of the viral DNA. Unlike humans, who carry seven APOBEC3 genes, mice only carry one, mA3. Thus the role of mA3 in restriction of retroviral infection could be studied in mA3 -/- knockout mice, where the gene is inactivated. M-MuLV-infected mA3 -/- mice showed substantially higher levels of infection at very early times compared to wild-type mice (ca. 2 logs at 0-10 days), particularly in the bone marrow and spleen. Restriction of M-MuLV infection was studied ex vivo in primary bone marrow-derived dendritic cells (BMDCs) that express or lack mA3, using an M-MuLV-based retroviral vector expressing enhanced jellyfish green fluorescent protein (EGFP). The results indicated that mA3 within the virions as well as mA3 in the recipient cell contribute to resistance to infection in BMDCs. Finally, M-MuLV-infected mA3 +/+ mice developed leukemia more slowly compared to animals lacking one or both copies of mA3 although the resulting disease was similar (T-lymphoma). These studies indicate that mA3 restricts replication and pathogenesis of M-MuLV in vivo.
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PMID:Enhanced replication and pathogenesis of Moloney murine leukemia virus in mice defective in the murine APOBEC3 gene. 1915 Jan 3

Sophisticated genetic tools have made possible the identification of the genes responsible for most well-described immunodeficiencies in the past 15 years. Mutations in Btk, components of the pre-B cell and B cell receptor (lambda5, Igalpha, Igbeta), or the scaffold protein BLNK account for approximately 90% of patients with defects in early B cell development. Hyper-IgM syndromes result from mutations in CD40 ligand, CD40, AID, or UNG in 70-80% of affected patients. Rare defects in ICOS or CD19 can result in a clinical picture that is consistent with common variable immunodeficiency, and as many as 10% of patients with this disorder have heterozygous amino acid substitutions in TACI. For all these disorders, there is considerable clinical heterogeneity in patients with the same mutation. Identifying the genetic and environmental factors that influence the clinical phenotype may enhance patient care and our understanding of normal B cell development.
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PMID:Primary B cell immunodeficiencies: comparisons and contrasts. 1930 39

Human APOBEC3G (A3G) belongs to a family of polynucleotide cytidine deaminases. This family includes APOBEC1 and AID, which edit APOB mRNA and antibody gene DNA, respectively. A3G deaminates cytidines to uridines in single-strand DNA and inhibits the replication of human immunodeficiency virus-1, other retroviruses, and retrotransposons. Although the mechanism of A3G-catalyzed DNA deamination has been investigated genetically and biochemically, atomic details are just starting to emerge. Here, we compare the DNA cytidine deaminase activities and NMR structures of two A3G catalytic domain constructs. The longer A3G191-384 protein is considerably more active than the shorter A3G198-384 variant. The longer structure has an alpha1-helix (residues 201-206) that was not apparent in the shorter protein, and it contributes to catalytic activity through interactions with hydrophobic core structures (beta1, beta3, alpha5, and alpha6). Both A3G catalytic domain solution structures have a discontinuous beta2 region that is clearly different from the continuous beta2 strand of another family member, APOBEC2. In addition, the longer A3G191-384 structure revealed part of the N-terminal pseudo-catalytic domain, including the interdomain linker and some of the last alpha-helix. These structured residues (residues 191-196) enabled a novel full-length A3G model by providing physical overlap between the N-terminal pseudo-catalytic domain and the new C-terminal catalytic domain structure. Contrary to predictions, this structurally constrained model suggested that the two domains are tethered by structured residues and that the N- and C-terminal beta2 regions are too distant from each other to participate in this interaction.
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PMID:An extended structure of the APOBEC3G catalytic domain suggests a unique holoenzyme model. 1938 8

Pathogenic common variable immunodeficiency diseases (CVID) are genetic, usually inherited diseases for which a limited number of genetic defects have been implicated. As CVID presents with a wide range of clinical characteristics, there are likely diverse and for the most part unidentified genetic causes. In some individuals, defects in somatic hypermutation (SHM) have been suggested as the underlying cause of CVID. To address the mechanisms of SHM defects in CVID, we conducted a comprehensive mutational analysis of immunoglobulin heavy chain sequences from CVID patients. We identified several remarkably specific alterations in the spectra of SHM in comparison to healthy individuals. We provide evidence that some CVID cases are associated with defective repair of AID-induced mutations by the DNA mismatch repair (MMR) machinery. Our findings together with reports of increased chromosomal radiosensitivity and associated lymphoproliferative disorders amongst CVID patients, suggest that altered DNA damage repair may be a cause of CVID.
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PMID:Altered spectrum of somatic hypermutation in common variable immunodeficiency disease characteristic of defective repair of mutations. 2093 59

The ability of mammalian cytidine deaminases encoded by the APOBEC3 (A3) genes to restrict a broad number of endogenous retroelements and exogenous retroviruses, including murine leukemia virus and human immunodeficiency virus (HIV)-1, is now well established. The RNA editing family member apolipoprotein B (apo B)-editing catalytic subunit 1 (APOBEC1; A1) from a variety of mammalian species, a protein involved in lipid transport and which mediates C-U deamination of mRNA for apo B, has also been shown to modify a range of exogenous retroviruses, but its activity against endogenous retroelements remains unclear. Here, we show in cell culture-based retrotransposition assays that A1 family proteins from multiple mammalian species can also reduce the mobility and infectivity potential of LINE-1 (long interspersed nucleotide sequence-1, L1) and long-terminal repeats (LTRs) retrotransposons (or endogenous retroviruses), such as murine intracisternal A-particle (IAP) and MusD sequences. The anti-L1 activity of A1 was mainly mediated by a deamination-independent mechanism, and was not affected by subcellular localization of the proteins. In contrast, the inhibition of LTR-retrotransposons appeared to require the deaminase activity of A1 proteins. Thus, the AID/APOBEC family proteins including A1s employ multiple mechanisms to regulate the mobility of autonomous retrotransposons in several mammalian species.
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PMID:Intrinsic restriction activity by apolipoprotein B mRNA editing enzyme APOBEC1 against the mobility of autonomous retrotransposons. 2139 38

V(D)J recombination and class switch recombination are achieved by the cooperative processes of recombination activation gene- or activation-induced cytidine deaminase-dependent DNA cleaving, DNA double-strand break (DSB) response signaling, and DNA repair. Primary immunodeficiency due to dysfunctional DNA recombination can be categorized as severe combined immunodeficiency or other conditions, based on the presence or absence of T cells. We can also classify these diseases as radiosensitive or non-radiosensitive immunodeficiencies. While diseases unable to trigger DNA cleavage do not exhibit radiosensitivity, dysfunction in DSB response signaling or repair does lead to radiosensitive immunodeficiency. Recent studies have begun to clarify the mechanisms underlying the molecular pathogenesis of such DNA DSB-related primary immunodeficiency.
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PMID:Abnormalities in DNA double-strand break response beyond primary immunodeficiency. 2147 81

The human immunodeficiency virus (HIV) and the acquired immunodeficiency syndrome (AIDS) have constituted a major challenge and concern worldwide. This is especially true among health workers who have to take care of such patients. This paper is aimed at studying the attitude to HIV/AID burn patients of nurses working in a burn unit. The work was carried out at the burns unit of the National Orthopaedics Hospital in Enugu, Nigeria. In a cross-sectional descriptive study, 125 questionnaires were distributed among nurses working in the burn unit. All the 120 nurses who responded were aware of HIV/AIDS: 80.8% of them believed that the prevalence was high, 93.3% that they could be infected while taking care of the patients, 91.5% that all burn patients should be screened for HIV, and 41.4% that their knowledge of the patients' HIV status would affect their professional duty to them; 31.1% would not want to dress the wounds of known HIV/AIDS burn patients. We conclude that there is a need to educate nurses and indeed all health care workers on adherence to universal precaution rather than routine screening for HIV of all burn patients as knowledge of the patients' HIV status may lead to discrimination against them.
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PMID:Attitude of nurses in a burn unit to hiv/aids burn patients. 2199 Sep 99


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