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)

By a sensitive enzyme-linked immunosorbent assay, inactive variant nucleoside phosphorylase (NP) protein could be quantitated in red cells and cultured skin fibroblasts from the probands and parents in four families with enzyme-deficient members. Three different mutant alleles could be identified that, in the homozygous state, could lead to T-cell immunodeficiency. The mutant alleles formed proteins that differed from normal NP protein by their stability, catalytic activity, or isoelectric charge. Thus, sensitive biochemical techniques can demonstrate the presence of different mutations for purine NP. Any of the mutations can be responsible for a lack of purine NP and the development of the characteristic T-cell deficiency syndrome.
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PMID:Purine nucleoside phosphorylase deficiency. Measurement of variant protein in four families with enzyme-deficient members by an enzyme-linked immunosorbent assay. 677 6

We have localized a fraction of the enzyme, purine nucleoside phosphorylase (PNP), to the centrioles and basal bodies of mammalian, avian, and protozoan cells. Two completely independent methods were used, one based on the ultrastructural cytochemistry of the enzyme activity and one based on immunofluorescence microscopy using an antibody raised in rabbit against purified human PNP. PNP catalyzes the reversible conversion of purine nucleosides and inorganic phosphate to the corresponding purine bases and ribose-1-phosphate. Its partial localization to centrioles and basal bodies raises the possibility that purine compounds are involved in centriole replication and/or in the regulation of microtubule assembly in vivo. No centriolar PNP could be detected in primary skin fibroblast from two infants with severe immunodeficiency disease associated with the absence of soluble PNP. This raises the possibility that defects in centriole function may contribute to the impaired division and maturation of T lymphoid precursor in this inherited disorder. Initially, the immunofluorescence analyses were complicated by a residual centriole-binding antibody that persisted in immunoglobulins from immune animals after complete removal of anti-PNP by affinity chromatography. Binding was abolished by exposure of cells to sodium periodate, indicating that this (and possibly other) "spontaneous" anticentriole antibodies in rabbit serum may be directed against carbohydrates.
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PMID:Purine nucleoside phosphorylase is associated with centrioles and basal bodies. 679 22

GTP levels were low and NAD+ levels high in purine nucleoside phosphorylase (PNP) deficient erythrocytes, in addition to the raised deoxy-GTP (dGTP) levels previously noted by others. dGTP was also identified in the PNP deficient child's lymphocytes. A further novel finding was the conversion of hypoxanthine to inosine by the PNP deficient red cells, as compared to inosine monophosphate (IMP) in controls. This has been attributed to IMP formation with subsequent breakdown, and raises interesting questions regarding the controls which normally maintain erythrocyte nucleotide pools. These findings may also explain the gross purine overproduction seen in this defect; they may likewise be related to the associated immunodeficiency, anaemia, and other clinical manifestations. The results may also have important implications for the development and clinical use of PNP inhibitors.
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PMID:GTP depletion and other erythrocyte abnormalities in inherited PNP deficiency. 680 78

We have studied patients with various immunodeficiencies for the occurrence of blood lymphocytes bearing six different surface markers: the affinity to sheep erythrocytes (Es) to identify T cells, the presence of surface-bound immunoglobulins (sIg) to distinguish B cells, the affinity to mouse erythrocytes (Em) as a second B cell marker, and the receptors for the Fc part of IgM (IgM-FcR), the Fc part of IgG (IgG-FcR) and for complement (CR). IgG-FcR bearing lymphocytes were present in normal proportions and the same was found for CR-positive lymphocytes. None of the patients with congenital agammaglobulinaemia had sIg-bearing or Em-binding B lymphocytes. Four patients with ataxia teleangiectasia had low B cells and 3 out of 4 also had low proportions of IgM-FcR-bearing (T) cells. A child with partial DiGeorge syndrome did not have a grossly abnormal marker pattern although there appeared to be a shift in the T/B cell ratio in favour of the B cells. In a patient with selective cellular immunodeficiency associated with a purine nucleoside phosphorylase deficiency, who was followed during reconstitution therapy with plasma and red cells, a positive change in the marker pattern was seen. Similar observations were made in a child with combined immunodeficiency during treatment. The findings are being discussed in the light of the current knowledge of the functions and ontogeny of lymphocyte subsets.
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PMID:Lymphocyte subpopulations in patients with various immunodeficiencies. 696 17

Carbovir (CBV) [the (--)-enantiomer of the carbocyclic analog of 2',3'-dideoxy-2',3'-didehydroguanosine] is a potent inhibitor of human immunodeficiency virus type 1 (HIV) replication in vitro. We have characterized the metabolism of CBV and its effect on cellular metabolism in an effort to better understand its mechanism of action. CBV was primarily metabolized to the 5'-triphosphate of CBV (CBV-TP) to concentrations sufficient to inhibit HIV reverse transcriptase. Infection of CEM cells with HIV did not affect the metabolism of CBV. In CEM cells, there was no evidence of the degradation of CBV by purine nucleoside phosphorylase. The half-life of CBV-TP in CEM cells was 2.5 h, similar to that of the 5'-triphosphate of zidovudine (AZT). However, unlike the levels of the 5'-triphosphate of AZT, CBV-TP levels declined without evidence of a plateau. CBV did not affect the metabolism of AZT, and AZT did not affect the metabolism of CBV. A small amount of CBV was incorporated into DNA in intact CEM cells, and this incorporation was increased by incubation with mycophenolic acid, an inhibitor of IMP dehydrogenase. CBV specifically inhibited the incorporation of nucleic acid precursors into DNA but had no effect on the incorporation of radiolabeled precursors into RNA or protein. CBV did not decrease the level of TTP, dGTP, dCTP, or dATP. These results suggested that the cytotoxicity of CBV was due to the inhibition of DNA synthesis. Further studies are necessary to identify the target(s) responsible for growth inhibition.
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PMID:Metabolism of carbovir, a potent inhibitor of human immunodeficiency virus type 1, and its effects on cellular metabolism. 768 93

Purine nucleoside phosphorylase (PNP; EC 2.4.2.1) deficiency is associated with a fatal T cell immunodeficiency in children, a candidate condition for gene therapy by introduction of functional PNP sequences into either T lymphocytes or more primitive progenitor cells in the bone marrow. To test the effectiveness of PNP gene transfer in T lymphocytes, a retroviral vector (LmPSN-2) was designed and constructed to express the murine PNP cDNA under transcriptional regulation of the Moloney murine leukemia virus long terminal repeat. LmPSN-2 was first used to mediate gene transfer and expression of electrophoretically distinct murine PNP in normal (PNP-positive) human PBL. Peripheral blood leukocytes were then obtained from a PNP deficient patient and characterized phenotypically. Despite their paucity and general mitogenic unresponsiveness, T lymphocytes from this patient were successfully grown in culture by using anti-CD3 with rIL-2 and then transduced with LmPSN-2. Elevated PNP enzyme activity was observed in the transduced cell population. Mitogenic and allogeneic responses, normally depressed in PNP-deficient patients' cells, were partially corrected in the transduced cell population relative to nontransduced cells. These results suggest the possibility of effecting improved immunologic function in PNP-deficient T lymphoid cells by retroviral-mediated gene transfer as therapy for PNP deficiency.
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PMID:Correction of proliferative responses in purine nucleoside phosphorylase (PNP)-deficient T lymphocytes by retroviral-mediated PNP gene transfer and expression. 787 63

The T-cell immunodeficiency associated with purine nucleoside phosphorylase (PNP) deficiency in man is believed to be due to the accumulation of dGTP which may be preferentially formed from deoxyguanosine in T-lymphocytes or their precursor cells. We found no evidence for dGTP accumulation in thymocytes or spleen leucocytes, < 1 nmol/10(9) cells, nor in erythrocytes, < 0.05 nmol/10(9) cells, of the B6-NPE- or B6-NPF PNP-deficient mice strains. There were no changes in purine or pyrimidine ribonucleotide pools. As these mice had been previously shown to excrete PNP nucleoside substrates, we examined the metabolism of deoxyguanosine. Deoxyguanosine kinase activity as compared to control mice was 6 to 52% for the B6-NPE mutant, 2 to 22% for the B6-NPF mutant. Fractionation of erythrocyte and liver lysates from the F mutation and the background strain, C57BL/6J, by anion exchange chromatography confirmed the secondary deficiency of deoxyguanosine kinase and demonstrated that this activity was distinct from adenosine kinase and two major peaks of deoxycytidine kinase activity. Mouse PNP, expressed and purified as a fusion protein, did not show evidence of being bifunctional and having deoxyguanosine kinase activity. Metabolic modelling revealed that the ratio of deoxyguanosine phosphorylation versus phosphorolysis was < 0.06 in control mice, and < or = 0.3 in lymphocytes of PNP-deficient mice. Were deoxyguanosine kinase not reduced in the PNP-deficient mice, all tissues of the B6-NPF mutant would preferentially phosphorylate deoxyguanosine at low substrate concentrations.
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PMID:Secondary loss of deoxyguanosine kinase activity in purine nucleoside phosphorylase deficient mice. 791 81

2',3'dideoxyinosine (ddI) has potent activity against human immunodeficiency virus (HIV) but is rapidly metabolized by erythrocytic purine nucleoside phosphorylase (PNP), and therefore has a very short plasma half-life in rodents, monkeys and in patients with acquired immunodeficiency syndrome. It is now reported that 100 microM (2-[2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methyl]-phenyl]ethenyl) - phosphonic acid (MDL 74,428), a very potent inhibitor of PNP blocks the intracellular phosphorolysis of ddI in cultured human red blood cells, in T leukemic CEM lymphoblasts and prolongs ddI plasma effective concentration in mice at a dose of 250 mg/kg body weight given i.p. In MDL 74,428-treated CEM cells, despite marked reduction of ddI catabolism, neither further accumulation of ddATP, the active antiviral metabolite of ddI, nor potentiation of the activity of ddI against HIV cytopathogenicity is observed. MDL 74,428 does not also affect the inhibitory effect of ddI combined with ribavirin on the transformation in vitro of C3H/3T3 cells by Moloney murine sarcoma virus (MSV). In mice, on the contrary, MDL 74,428 (200 mg/kg body weight, i.p.) is effective at potentiating the effect of ribavirin used either alone, or combined with ddI on MSV-induced tumour formation and associated mortality. However, in the absence of ribavirin, co-administration of MDL 74,428 with ddI affords, no chemotherapeutic advantage.
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PMID:Potentiating effect of (2-[2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methyl]-phenyl]ethenyl) -phosphonic acid (MDL 74,428), a potent inhibitor of purine nucleoside phosphorylase, on the antiretroviral activities of 2',3'-dideoxyinosine combined with ribavirin in mice. 805 21

Approximately 20 years ago, Giblett and coworkers serendipitously discovered that in some patients with the syndrome of severe combined immunodeficiency, the disease is due to an inherited deficiency of the enzyme adenosine deaminase (ADA). This then led to the discovery that inherited deficiency of the next enzyme in the same pathway for purine salvage, purine nucleoside phosphorylase, results in a profound defect in cell-mediated immunity. These two disorders, sometimes termed "purinergic immunodeficiency disorders," were the first of the inherited immunodeficiency disorders in which the specific molecular basis was determined. Although both are rare diseases, they are of importance for several reasons. First, they are among the few inherited disorders of which some children can be cured by a single treatment; second, they are ideally suited for gene therapy; and third, the pathologic mechanisms can tell us more about the nature of the immune system and have already allowed development of chemotherapy for some malignancies of the immune system. Knowledge of the specific defects has also facilitated diagnosis, counseling of families, and development of new approaches to therapy. This article focuses on ADA deficiency, briefly reviews the clinical and biochemical findings to provide a background for the next two articles in this supplement issue, and details work in progress with respect to several aspects of the specific molecular defects in different patients.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Overview of biochemical abnormalities and molecular genetics of adenosine deaminase deficiency. 843 73

A 5-year-old boy with spastic quadriplegia, T cell immunodeficiency, hypouricemia and immune cytopenias from age 8 months, was found to have purine nucleoside phosphorylase (PNP) deficiency, and developed chronic lung disease. Successful matched sibling BMT for PNP deficiency has not previously been reported. BMT using marrow from an HLA-identical sibling donor was performed after conditioning with busulfan (16 mg/kg), cyclophosphamide (200 mg/kg), melphalan (90 mg/m2) and anti-thymocyte globulin (36 mg/kg). T lymphocyte numbers, PNP activity and uric acid levels rapidly improved and he remains well 12 months after transplant.
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PMID:Late diagnosis and correction of purine nucleoside phosphorylase deficiency with allogeneic bone marrow transplantation. 867 45


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