Adenosine-Deaminase Deficiency in Two Patients With Severely Impaired Cellular Immunity

Giblett, E. R.; Anderson, JeanneE.; Cohen, Flossie; Pollara, Bernard; Meuwissen, Hilaire J.

doi:10.1016/s0140-6736(72)92345-8

Cited by 1,518 publications

(467 citation statements)

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“…A severe combined immunodeficiency is associated with the lack of ADA activity (13), and a T-cell immunodeficiency is associated with the lack of PNP activity (12). Both conditions are recessive and autosomally inherited, and afflicted individuals suffer from opportunistic infections that lead to death early in childhood.…”

mentioning

confidence: 99%

Human purine nucleoside phosphorylase and adenosine deaminase: gene transfer into cultured cells and murine hematopoietic stem cells by using recombinant amphotropic retroviruses.

McIvor¹,

Johnson²,

Miller³

et al. 1987

Mol. Cell. Biol.

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Cell lines were established which produced high titers (_ 106 infectious units per ml) of amphotropic, replication-defective recombinant retroviruses which transduced sequences encoding either human purine nucleoside phosphorylase (PNP) or adenosine deaminase (ADA). These viruses also contained a human hypoxanthine phosphoribosyltransferase gene as a selectable marker and a mouse metallothionein promoter (MMP) sequence just upstream from the PNP or ADA genes. Virus structure was maintained through the replication cycle if a short (216-base pair) MMP sequence was used. However, the use of a longer (1,834-base pair) MMP sequence resulted in the deletion of a significant portion of the recombinant virus genome, including the transcriptional regulatory elements of the MMP sequence. Northern analysis indicated a predominance of genome length transcripts in cells infected with deleted virus. The demonstration of substantial human PNP or ADA activity in virus-infected mouse fibroblasts by isozyme analysis suggested that active gene product was translated from either spliced or bicistronic message. The deleted ADA and PNP viruses were introduced into mouse hematopoietic stem cells by cocultivating freshly explanted bone marrow with virus producer cells. The infected marrow cells were injected into irradiated, syngeneic recipient mice, and the presence of integrated ADA or PNP proviral sequences was demonstrated in the DNA of spleen colonies by Southern analysis. Failure of these integrated proviral sequences to express active, human isozyme in spleen colony tissue indicated the existence of some regulatory constraint not active in cultured mouse cells.Purine nucleoside phosphorylase (PNP) and adenosine deaminase (ADA) are enzymes of purine metabolism, the absence of which in humans results in immunodeficiency disease. A severe combined immunodeficiency is associated with the lack of ADA activity (13), and a T-cell immunodeficiency is associated with the lack of PNP activity (12). Both conditions are recessive and autosomally inherited, and afflicted individuals suffer from opportunistic infections that lead to death early in childhood. The metabolic basis of these diseases has been studied intensively (see references 22 and 27 for reviews). Although a number of hypotheses have been proposed to explain the specific toxicity of these conditions to immune cells, there is much evidence that in the absence of one of these enzyme activities, deoxynucleoside substrates accumulate, resulting in unbalanced deoxynucleoside triphosphate pools, feedback inhibition of ribonucleotide reductase, and limited DNA synthesis which does not support an immunoproliferative response (22,27,46).The availability of cloned ADA and PNP coding sequences (14, 48) and progress in gene transfer technology (3,52) have led to the suggestion that the ADA-and PNPassociated immunodeficiencies might be reasonable candidates for initial attempts at human gene therapy (1,33). To * Corresponding author.

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mentioning

confidence: 99%

Human purine nucleoside phosphorylase and adenosine deaminase: gene transfer into cultured cells and murine hematopoietic stem cells by using recombinant amphotropic retroviruses.

McIvor¹,

Johnson²,

Miller³

et al. 1987

Mol. Cell. Biol.

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“…This enzyme is important clinically because its hereditary deficiency in humans causes severe combined immunodeficiency disease (6,10,16). Although the metabolic consequences of ADA deficiency have been extensively investigated, not one of the variety of genetic defects that cause this deficiency is fully understood at the molecular level.…”

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confidence: 99%

Structure of adenosine deaminase mRNAs from normal and adenosine deaminase-deficient human cell lines.

Adrian¹,

Wiginton²,

Hutton³

1984

Mol. Cell. Biol.

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The structure of human adenosine deaminase mRNA from normal and mutant lymphoblasts was examined by sequence analysis of a cDNA for normal mRNA and electrophoretic analyses of DNA fragments generated by S1 endonuclease cleavage of mRNA-cDNA hybrids. The 1,533-base sequence of the cloned cDNA represents the complete mRNA sequence with the possible exception of some of the 5' untranslated region. S1 nuclease analyses of hybrids between cloned cDNA and normal adenosine deaminase mRNA confirmed that a 76-base sequence in a previously examined adenosine deaminase cDNA is an intron. S1 nuclease analyses of mRNAs from seven mutant cell lines demonstrated that four of the mutants, those in the GM-2471, GM-2756, GM-4258, and GM-2606 cells, contain small defects, such as single-base changes, that are not detectable by the S1 nuclease technique. Three of the mRNAs, those in GM-3043, GM-2294, and GM-2825A cells, do contain defects detectable with S1 nuclease. These defects differ from each other and have been mapped to specific regions of the mRNA. Some or all of these defective mRNAs are postulated to result from anomalous RNA processing.

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“…The original working hypothesis was that ADA might be low in adults with haematological neoplasms and acquired immunodeficiency, since decreased to absent activity of ADA in erythrocytes and lymphocytes is associated with an inherited, autosomal recessive form of immunodeficiency disease of childhood (Giblett et al, 1972;Parkman et al, 1975). Decreased levels of ADA have been reported in lymphoid cells from the peripheral blood of children with acute (Zimmer, Khalifa and Lightbody, 1975) and adults with chronic (Scholar and Calabresi, 1973;Tung et al, 1974) lymphocytic leukaemia, most of whom would be immunodeficient to some degree.…”

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Adenosine deaminase activity in peripheral blood cells of patients with haematological malignancies

Meier¹,

Colemán²,

Hutton³

1976

Br J Cancer

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Summary.-Adenosine deaminase (EC 3.5.4.4, ADA) has been assayed in lymphocytes, granulocytes and erythrocytes from 45 patients with haematological malignancies. Activities were uniformly low in lymphocytes from patients with chronic lymphocytic leukaemia. Variable, but abnormal activities were frequently found in multiple myeloma, untreated lymphoma and leukaemic reticuloendotheliosis. High values were observed in lymphocytes from patients with lymphoma during intensive combination chemotherapy. ADA levels in lymphocytes were not correlated with levels in granulocytes or erythrocytes. ADA was elevated in blasts of patients with acute lymphocytic and myelogenous leukaemias but the ranges of activities per cell were so similar that ADA assay is unlikely to be of major help in distinguishing the two diseases.

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Adenosine-Deaminase Deficiency in Two Patients With Severely Impaired Cellular Immunity

Cited by 1,518 publications

References 10 publications

Human purine nucleoside phosphorylase and adenosine deaminase: gene transfer into cultured cells and murine hematopoietic stem cells by using recombinant amphotropic retroviruses.

Human purine nucleoside phosphorylase and adenosine deaminase: gene transfer into cultured cells and murine hematopoietic stem cells by using recombinant amphotropic retroviruses.

Structure of adenosine deaminase mRNAs from normal and adenosine deaminase-deficient human cell lines.

Adenosine deaminase activity in peripheral blood cells of patients with haematological malignancies

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