Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.5.4.4 (adenosine deaminase)
5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Twenty-six patients with severe combined immunodeficiency (SCID) were examined. In 20 cases no defect of the biochemical pathways was found; 6 cases showed a deficiency in adenosine deaminase (ADA) activity. In 19 cases histological sections of the thymus were available. In 3 cases, in addition to the original thymuses, transplanted thymic allografts were microscopically examined. The thymus in SCID without abnormality of the ADA pathway showed a uniform dysplastic pattern with only moderate variations related to mode of inheritance and length of survival. The thymus in SCID with ADA deficiency displayed a heterogeneous pattern ranging from almost normal to a completely dysplastic structure, whereas the transplanted thymic allografts presented either a normal or a dysplastic appearance. The morphology of the thymus is not pathognomonic of any given biochemical defect, clinical course, or type of SCID. SCID with apparently normal biochemical pathways probably results from a variety of pathogenetic mechanisms.
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PMID:Morphology of original and transplanted thymuses in severe combined immunodeficiency. 378 59

We treated two children who had adenosine deaminase deficiency and severe combined immunodeficiency disease by injecting bovine adenosine deaminase modified by conjugation with polyethylene glycol. The modified enzyme was rapidly absorbed after intramuscular injection and had a half-life in plasma of 48 to 72 hours. Weekly doses of approximately 15 U per kilogram of body weight maintained plasma adenosine deaminase activity at two to three times the level of erythrocyte adenosine deaminase activity in normal subjects. The principal biochemical consequences of adenosine deaminase deficiency were almost completely reversed. In erythrocytes, adenosine nucleotides increased and deoxyadenosine nucleotides decreased to less than 0.5 percent of total adenine nucleotides. The activity of S-adenosylhomocysteine hydrolase, which is inactivated by deoxyadenosine, increased to normal in red cells and nucleated marrow cells. Neither toxic effects nor hypersensitivity reactions were observed. In vitro tests of the cellular immune function of each patient showed marked improvement, along with an increase in circulating T lymphocytes. Clinical improvement was indicated by absence of infection and resumption of weight gain. We conclude that from the standpoints of efficacy, convenience, and safety, polyethylene glycol-modified adenosine deaminase is preferable to red-cell transfusion as a treatment for adenosine deaminase deficiency. Patients with other inherited metabolic diseases in which accumulated metabolites equilibrate with plasma could benefit from treatment with the appropriate polyethylene glycol-modified enzyme.
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PMID:Treatment of adenosine deaminase deficiency with polyethylene glycol-modified adenosine deaminase. 380 53

A severe genetic deficiency of adenosine deaminase is causally associated with an autosomal recessive form of severe combined immunodeficiency disease, while subjects with absent erythrocyte but partial lymphocyte enzyme activity remain immunocompetent. The genetic expression of adenosine deaminase in B-lymphoblast cell lines derived from four unrelated subjects with the "partial" enzyme deficiency was examined. Enzymatic activity among these cell lines ranged from 5 to 50% of normal with the level of immunoreactive adenosine deaminase protein either proportional to enzyme activity or elevated in two of the cases. Northern blot analysis using a cDNA probe showed that adenosine deaminase mRNA in each of these cell lines was of normal expected size (1.6-1.8 kilobases) and was present in normal to above normal amounts. Rates of enzyme synthesis varied from 165 to 15% of normal. Adenosine deaminase protein degradation rates in these cell lines were 1.5 to almost 3 times faster than normal, consistent with the observed absence of the enzyme in erythrocytes. From these analyses apparent abnormalities in mRNA regulation, translation, and protein degradation can be identified among the partially adenosine deaminase-deficient cell lines studied. Ultimately, it will be essential to determine the nature of the protein mutation and the gene defect to define the structural alterations and functional abnormalities of enzyme variants isolated from subjects with partial adenosine deaminase deficiency.
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PMID:Genetic expression in partial adenosine deaminase deficiency. mRNA levels and protein turnover for the enzyme variants in human B-lymphoblast cell lines. 387 77

Inherited deficiency of the enzyme adenosine deaminase (ADA) has been found in a significant proportion of patients with severe combined immunodeficiency disease and inherited defect generally characterized by a deficiency of both B and T cells. Two questions are central to understanding the pathophysiology of this disease: (1) at what stage or stages in lymphocyte development are the effects of the enzyme deficiency manifested; (2) what are the biochemical mechanisms responsible for the selective pathogenicity of the lymphoid system. We have examined the stage or stages of rat T-cell development in vivo which are affected by an induced adenosine deaminase deficiency using the ADA inhibitors, erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) and 2'-deoxycoformycin (DCF). In normal rats given daily administration of an ADA inhibitor, cortical thymocytes were markedly depleted; peripheral lymphocytes and pluripotent hemopoietic stem cells (CFU-S) all were relatively unaffected. Since a deficiency of ADA affects lymphocyte development, the regeneration of cortical and medullary thymocytes and their precursors after sublethal irradiation was used as a model of lymphoid development. By Day 5 after irradiation the thymus was reduced to 0.10-0.5% of its normal size; whereas at Days 9 and 14 the thymus was 20-40% and 60-80% regenerated, respectively. When irradiated rats were given daily parenteral injections of the ADA inhibitor plus adenosine or deoxyadenosine, thymus regeneration at Days 9 and 14 was markedly inhibited, whereas the regeneration of thymocyte precursors was essentially unaffected. Thymus regeneration was at least 40-fold lower than in rats given adenosine or deoxyadenosine alone. Virtually identical results were obtained with both ADA inhibitors, EHNA and DCF. The majority of thymocytes present at Day 9 and at Day 14 in inhibitor-treated rats had the characteristics of subcapsular cortical thymocytes which are probably the most ancestral of the thymocytes. Thus, an induced ADA deficiency blocked the proliferation and differentiation of subcapsular cortical thymocytes which are the precursors of cortical and medullary thymocytes.
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PMID:The effects of an induced adenosine deaminase deficiency on T-cell differentiation in the rat. 387 60

Congenital deficiency of the enzyme adenosine deaminase (ADA) results in severe combined immunodeficiency. 2'deoxycoformycin (2'dcf) is a tightly binding inhibitor of ADA, and the drug makes it possible to mimic a state of ADA deficiency. In this study we tested the immunosuppressive effect of 2'dcf in a rat skin transplantation model. Rats treated with continuous infusion of 2'dcf at doses of 0.3 mg/kg, 0.5 mg/kg and 0.7 mg/kg body wt/day showed significant prolongation of graft survival. 2'dcf given by bolus injections did not prolong graft survival. In rats treated with continuous infusion of 2'dcf at a dose of 0.7 mg/kg body wt/day mean graft survival time (MST) after withdrawal of treatment was equal to MST in untreated animals, suggesting that during 2'dcf treatment allograft rejection was completely suppressed. In vitro, lymphocytes isolated from animals treated with continuous infusion of 2'dcf showed marked suppression of mitogen response. The 2'dcf preferentially effects lymphocytes, but neutrophils seem resistant to the effect of the drug. The lymphocytotoxic effect of the drug is extreme; during therapy splenic weight decreased by almost 50% and the differential lymphocyte count in blood decreased from 85% to 17%. Immunofluorescence studies showed that, within the spleen, the amount of T cells and B cells decreased markedly. Both T cell subsets were affected--OX8+ cells (suppressor/cytotoxic T cells) and W3/25+ (helper T cells). However OX8+ cells were more resistant to the drug than W3/25+ cells. Skin-grafted rats treated with 2'dcf showed a strong decrease in the W3/25: OX8 ratio. In contrast, untreated rats showed a slight increase in the ratio after skin transplantation. It is concluded that 2'dcf is a strong immunosuppressive drug in rats if given by continuous infusion.
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PMID:Complete suppression of skin allograft rejection in rats treated with continuous infusion of 2'deoxycoformycin. 389 17

A male infant X-linked, adenosine deaminase-positive severe combined immunodeficiency underwent partial immunological reconstitution by fetal liver transplantation at twenty months of age. Reconstitution of T lymphocytes was observed from sixteen weeks after transplantation, in the increase of T lymphocytes, positive delayed-type skin reaction and in vitro responsiveness to mitogens and allogeneic cells, sequentially. Chimerism was defined by chromosomal analysis and HLA typing, in which one haplotype seemed to be shared between the donor and the host by chance. However, defective immunoglobulin production has not yet been corrected. The assay on T-B lymphocyte interaction in vitro suggested that the failure might be attributed to an intrinsic defect of B lymphocytes, which were cells of donor origin after transplantation. Three years following transplantation, the patient is free of severe infections, although he requires regular injections of gamma globulin.
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PMID:Reconstitution of cell-mediated immunity in severe combined immunodeficiency following fetal liver transplantation. 391 46

Complete genetic deficiency of adenosine deaminase (ADA) results in a fatal syndrome of severe combined immunodeficiency (SCID). Genetic partial deficiency of ADA, with no detectable enzyme activity in erythrocytes but with variable amounts of enzyme activity detectable in other cells, is usually associated with normal immunologic function but can give rise to a late-onset, cellular immunodeficiency syndrome. We have previously described four different mutant alleles in four such partially ADA-deficient children. We have now examined ADA in lymphoid cells from five additional newly ascertained children with partial ADA deficiency with respect to electrophoretic mobility in starch gel, isoelectric point, heat-stability, and apparent Km and Vmax. These techniques identify at least five different abnormal alleles in these five additional unrelated subjects. Three of these abnormal alleles result in expression of abnormal allelic isozymes (allozymes) different from those previously described. These are: (1) an acidic allozyme that is less acidic than the acidic allozyme we have previously reported; (2) an allozyme that is even less acidic than (1); and (3) an allozyme with apparently normal charge but which is so heat sensitive that the lability to heat can easily be detected at physiologic to febrile temperatures. Two abnormal alleles detected in these five children could correspond with previously reported mutants. These are (4) a basic allozyme that could (but probably doesn't) correspond to the basic allozyme we have previously reported and (5) a "null" allele that cannot be differentiated by these methods from any other "null" allele seen in complete ADA- -SCIDs. Three of the five new patients are genetic compounds, identified either by the presence of two electrophoretically distinguishable allozymes or by family studies that demonstrate presence of a "null" allele in addition to an electrophoretically abnormal allozyme. In three patients, one or both allozymes are phenotypically indistinguishable from an abnormal allozyme also seen in a different individual. Determination of the nucleotide sequence will be required to determine whether or not the phenotypically indistinguishable mutations are indeed genotypically identical. The newly ascertained individuals appear to share a common ethnic West Indian background, out of proportion to the frequency of this ethnic background in the newborn population from which they were ascertained, suggesting that partial ADA deficiency may confer a selective advantage to the homozygous or heterozygous phenotype.
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PMID:Genetic heterogeneity in adenosine deaminase (ADA) deficiency: five different mutations in five new patients with partial ADA deficiency. 394 19

A large pedigree containing a child with severe combined immunodeficiency disease (CID) associated with adenosine deaminase (ADA) deficiency was investigated to ascertain if heterozygotes could be detected by measuring red cell ADA activity. 9 of 17 individuals in three generations who were at risk for being heterozygous had decreased red cell ADA activity. This genetic information establishes one form of CID as an autosomal recessive disorder. The identified heterozygote population had a mean ADA value of 19.2 U/g hemoglobin (0.95 confidence interval; 14.0 to 24.4 U/g hemoglobin), which was approximately one-half the mean, 36.1 U/g hemoglobin, of a randomly selected control population (0.95 confidence interval; 22.5-58.1 U/g hemoglobin). Statistical comparisons of the heterozygotes to the normal population indicates that within a high-risk family heterozygotes may be identified with 90% confidence.
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PMID:Detection of the carrier state in combined immunodeficiency disease associated with adenosine deaminase deficiency. 481 83

A previously cloned partial adenosine deaminase cDNA insert (0.8 kilobase) was used to clone additional nucleotide sequences from human HPB ALL cDNA libraries. cDNA encompassing the entire coding, and 3'-untranslated regions as well as nearly all of the 5'-untranslated region was obtained. The complete amino acid sequence of the enzyme deduced from the cDNA sequence and protein sequencing consists of 362 amino acids, excluding the initiator Met, and accounts for Mr = 40,638. Secondary structure predictions assign adenosine deaminase to the alpha/beta class of proteins. Northern blot analysis with a cDNA probe showed adenosine deaminase mRNA to be present in normal to above normal amounts in B-lymphoblasts derived from adenosine deaminase-deficient patients with severe combined immunodeficiency disease. Knowledge of the cDNA and primary amino acid sequence of adenosine deaminase will be pivotal in further defining the genetic abnormality and its functional consequences in adenosine deaminase expression defects.
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PMID:Human adenosine deaminase. cDNA and complete primary amino acid sequence. 609 Apr 54

Hereditary deficiency of adenosine deaminase (ADA) usually causes profound lymphopenia with severe combined immunodeficiency disease. Cells from patients with ADA deficiency contain less than normal, and sometimes undetectable, amounts of ADA catalytic activity and ADA protein. The molecular defects responsible for hereditary ADA deficiency are poorly understood. ADA messenger RNAs and their translation products have been characterized in seven human lymphoblast cell lines derived as follows: GM-130, GM-131, and GM-2184 from normal adults; GM-3043 from a partially ADA deficient, immunocompetent !Kung tribesman; GM-2606 from an ADA deficient, immunodeficient child; CCRF-CEM and HPB-ALL from leukemic children. ADA messenger (m)RNA was present in all lines and was polyadenylated. The ADA synthesized by in vitro translation of mRNA from each line reacted with antisera to normal human ADA and was of normal molecular size. There was no evidence that posttranslational processing of ADA occurred in normal, leukemic, or mutant lymphoblast lines. Relative levels of specific translatable mRNA paralleled levels of ADA protein in extracts of the three normal and two leukemic lines. However, unexpectedly high levels of ADA specific, translatable mRNA were found in the mutant GM-2606 and GM-3043 lines, amounting to three to four times those of the three normal lines. Differences in the amounts of ADA mRNA and rates of ADA synthesis appear to be of primary importance in maintaining the differences in ADA levels among lymphoblast lines with structurally normal ADA. ADA deficiency in at least two mutant cell lines is not caused by deficient levels of translatable mRNA, and unless there is some translational control of this mRNA, the characteristic cellular ADA deficiency is most likely secondary to synthesis and rapid degradation of a defective ADA protein.
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PMID:Adenosine deaminase messenger RNAs in lymphoblast cell lines derived from leukemic patients and patients with hereditary adenosine deaminase deficiency. 613 54


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