Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.5.4.4 (adenosine deaminase)
 5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cancer incidence and mortality were analyzed in 1,181 blood relatives and 558 spouse controls in 24 families of severe combined immune deficiency (SCID) patients, to test the hypothesis that heterozygous carriers of a gene for an autosomal recessive form of SCID are predisposed to cancer. Since at least 1 patient in each family was female and there were no cases outside the probands' sibships, the pattern of occurrence of SCID within the families was compatible with autosomal recessive inheritance. The observed numbers of cancer cases and deaths did not exceed the expected numbers derived from population-based rates; and there was no cancer excess when incidence rates in blood relatives were compared directly to those in spouse controls, since the rate ratios were 1.2 and 1.0 for males and females, respectively. In addition, cancer rate ratios were not significantly elevated when calculated separately for the 9 families of adenosine deaminase (ADA)-deficient SCID patients and for the 15 families without evidence of ADA deficiency.
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PMID:Cancer in families with severe combined immune deficiency. 346 59

Adenosine deaminase (ADA; adenosine aminohydrolase, EC 3.5.4.4) deficiency is one cause of the genetic disease severe combined immunodeficiency. To identify mutations responsible for ADA deficiency, we synthesized cDNAs to ADA mRNAs from two cell lines, GM2756 and GM2825A, derived from ADA-deficient immunodeficient patients. Sequence analysis of GM2756 cDNA clones revealed a different point mutation in each allele that causes amino acid changes of alanine to valine and arginine to histidine. One allele of GM2825A also has a point mutation that causes an alanine to valine substitution. The other allele of GM2825A was found to produce an mRNA in which exon 4 had been spliced out but had no other detrimental mutations. S1 nuclease mapping of GM2825A mRNAs showed equal abundance of the full-length ADA mRNA and the ADA mRNA that was missing exon 4. Several of the ADA cDNA clones extended 5' of the major initiation start site, indicating multiple start sites for ADA transcription. The point mutations in GM2756 and GM2825A and the absence of exon 4 in GM2825A appear to be directly responsible for the ADA deficiency. Comparison of a number of normal and mutant ADA cDNA sequences showed a number of changes in the third base of codons. These changes do not affect the amino acid sequence. Analyses of ADA cDNAs from different cell lines detected aberrant RNA species that either included intron 7 or excluded exon 7. Their presence is a result of aberrant splicing of pre-mRNAs and is not related to mutations that cause ADA deficiency.
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PMID:Mutations in the human adenosine deaminase gene that affect protein structure and RNA splicing. 347 10

A retroviral vector called SAX, containing the cloned human cDNA for adenosine deaminase (ADA), has been constructed and used to introduce the ADA gene into cultured T- and B-lymphocyte lines derived from patients with ADA deficiency. DNA analysis showed that the SAX vector was inserted intact into the T and B cells at approximately one copy per cell. The treated cells produced the characteristic isozymes of human ADA at a level similar to normal T and B lymphocytes. It is known that ADA-deficient lymphocytes are unusually sensitive to high levels of 2'-deoxyadenosine, and this is the mechanism thought to underlie the selective lymphocytotoxicity associated with ADA deficiency in vivo. Expression of the introduced ADA gene was sufficient to reverse the hypersensitivity of these genetically deficient lymphocytes to 2'-deoxyadenosine toxicity. These results support the suggestion that retroviral vector gene-delivery systems show promise for application to human gene therapy.
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PMID:Correction of adenosine deaminase deficiency in cultured human T and B cells by retrovirus-mediated gene transfer. 348 33

Skin fibroblasts might be considered suitable recipients for therapeutic genes to cure several human genetic diseases; however, these cells are resistant to gene transfer by most methods. We have studied the ability of retroviral vectors to transfer genes into normal human diploid skin fibroblasts. Retroviruses carrying genes for neomycin or hygromycin B resistance conferred drug resistance to greater than 50% of the human fibroblasts after a single exposure to virus-containing medium. This represents at least a 500-fold increase in efficiency over other methods. Transfer was achieved in the absence of helper virus by using amphotropic retrovirus-packaging cells. A retrovirus vector containing a human adenosine deaminase (ADA) cDNA was constructed and used to infect ADA-fibroblasts from a patient with ADA deficiency. The infected cells produced 12-fold more ADA enzyme than fibroblasts from normal individuals and were able to rapidly metabolize exogenous deoxyadenosine and adenosine, metabolites that accumulate in plasma in ADA-deficient patients and are responsible for the severe combined immunodeficiency in these patients. These experiments indicate the potential of retrovirus-mediated gene transfer into human fibroblasts for gene therapy.
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PMID:Efficient retrovirus-mediated transfer and expression of a human adenosine deaminase gene in diploid skin fibroblasts from an adenosine deaminase-deficient human. 349 85

Severe combined immunodeficiency (SCID) was originally thought to be one disease. Accumulating evidence indicates that SCID is a heterogeneous group of diseases that are clinically similar but are caused by quite different biochemical abnormalities. The best-studied form of SCID is that associated with an autosomal recessive inheritance pattern of adenosine deaminase (ADA) deficiency. Several biochemical mechanisms have been postulated to explain how a deficiency of ADA causes immune dysfunction. In forms of SCID not associated with ADA deficiency, other biochemical abnormalities have been detected. These abnormalities include deficiency in biotin-dependent carboxylases, alteration in lymphocyte surface membranes and irregularities in cytokine production. Two animal models for SCID now exist. Neither of these models is associated with ADA deficiency. Evidence for a possible defect in purine metabolism in one model has been demonstrated.
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PMID:Metabolic defects in severe combined immunodeficiency in man and animals. 351 64

A patient with adenosine deaminase-deficient severe combined immunodeficiency is described whose defect is secondary to deletion of a portion of the ADA structural gene. In Southern analyses, DNA from this patient does not hybridize to a genomic probe that includes the 3' end of exon 1. This implies that both his parents are heterozygous for deletions of exon 1 sequences. Consistent with this finding, the patient has no detectable adenosine deaminase mRNA by Northern analysis. This is the first report of a deletion mutation as the cause of adenosine deaminase deficiency.
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PMID:Identification of a deletion in the adenosine deaminase gene in a child with severe combined immunodeficiency. 357 74

We have investigated the structural gene for adenosine deaminase (ADA) in a female infant with ADA deficiency associated severe combined immune deficiency (ADA-SCID) disease and her family by DNA restriction-fragment-length analysis. In this family a new ADA-specific restriction-fragment-length variant was detected, which involves a 3.2-kb deletion spanning the ADA promoter as well as the first exon. It was found that the patient, who was born to a consanguineous couple, was homozygous and both her parents and her brother were heterozygous for the deletion. No ADA-specific mRNA could be detected by hybridization in fibroblasts derived from this patient. Thus the patient was established to be homozygous for a true null ADA allele. In the light of the apparently normal development of most tissues except the lymphoid tissue the above finding directly questions the classification of ADA as a 'housekeeping' enzyme.
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PMID:Severe combined immune deficiency due to a homozygous 3.2-kb deletion spanning the promoter and first exon of the adenosine deaminase gene. 368 97

The possibility that the mutant mouse wasted (wst/wst) may serve as an animal model for studies of severe combined immunodeficiency disease (SCID) and the role of adenosine deaminase (ADA, EC 3.5.4.4) in adenosine metabolism were investigated. The specific activity of ADA in wst/wst compared with control mice was significantly lower by 26% in thymus, but significantly higher by 18% in spleen and 32% in cerebellum. Vmax values of ADA in spleens were 43% higher in wst/wst mice and no changes were observed in Km values. In contrast, the Vmax of ADA was unchanged in erythrocytes from wst/wst mice, but the Km for adenosine was significantly elevated. Thus, based on ADA measurements alone, it may be premature to consider wst/wst mice as a model for ADA deficiency and SCID in humans.
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PMID:Lack of adenosine deaminase deficiency in the mutant mouse wasted. 378 Sep 80

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


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