Nucleoside-Phosphorylase Deficiency in a Child With Severely Defective T-Cell Immunity and Normal B-Cell Immunity

Giblett, E. R.; Ammann, ArthurJ.; Sandman, Robert; Wara, D W; Diamond, LouisK.

doi:10.1016/s0140-6736(75)91950-9

Cited by 819 publications

(329 citation statements)

References 13 publications

Supporting

Mentioning

326

Contrasting

Unclassified

Order By: Relevance

“…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.

View full text Add to dashboard Cite

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.

show abstract

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.

View full text Add to dashboard Cite

show abstract

“…The first case was presented in 1975, and up to the end of 2014, fewer than 80 cases have been reported. A total of 24 mutations causing PNP deficiency have been described (Giblett et al 1975;Markert 1991;Walker et al 2011). The two new mutations in our patient, c.729C>G (p.Asn243Lys) and c.746A>C (p.Tyr249Cys), both in exon 6, resulted in a near-complete absence of the PNP activity and caused both SCID and neurological defects such as developmental delay and muscular hypotonia, but no autoimmunity.…”

Section: Discussionmentioning

confidence: 73%

“…PNP deficiency is an autosomal recessive disorder and leads to a progressive form of severe combined immunodeficiency (SCID) with decreased numbers of T cells and lymphopenia (Giblett et al 1975). Some studies have shown that B cell function can be disrupted as well (Markert 1991).…”

Section: Introductionmentioning

confidence: 99%

Novel Genetic Mutations in the First Swedish Patient with Purine Nucleoside Phosphorylase Deficiency and Clinical Outcome After Hematopoietic Stem Cell Transplantation with HLA-Matched Unrelated Donor

et al. 2015

View full text Add to dashboard Cite

Purine nucleoside phosphorylase (PNP) is an enzyme active in the purine salvage pathway. PNP deficiency caused by autosomal recessive mutations in the PNP gene leads to severe combined immunodeficiency (SCID) and in two thirds of cases also to neurological effects such as developmental delay, ataxia, and motor impairment.PNP deficiency has a poor outcome, and the only curative treatment is allogenic hematopoietic stem cell transplantation (HSCT). We present the first Swedish patient with PNP deficiency with novel mutations in the PNP gene and the immunological results of the HSCT and evaluate the impact of HSCT on the neurological symptoms. The patient presented early in life with neurological symptoms and suffered later from repeated serious respiratory tract infections. Biochemical tests showed severe reduction in PNP activity (1% residual activity). Genetic testing revealed two new mutations in the PNP gene: c.729C>G (p.Asn243Lys) and c.746A>C (p.Tyr249Cys). HSCT was performed with an unrelated donor, resulting in prompt and sustained engraftment and complete donor chimerism. There was no further aggravation of the patient's neurological symptoms at 21 months post HSCT, and appropriate developmental milestones were achieved. HSCT is curative for the immunological defect caused by PNP deficiency, and our case strengthens earlier reports that HSCT is effective as a treatment even for neurological symptoms in PNP deficiency.

show abstract

“…These patients were judged to have normal T suppressor activity. In the other four patients (2,4,6,8), however, the quantities of IgM and IgG synthesized in co-cultures was suppressed by 74 to >95% as compared to that synthesized in individual cultures of patient and control PBM. Thus, these four patients were considered to have increased suppressor T cell activity.…”

Section: Resultsmentioning

confidence: 80%

“…INTRODUCTION Decreased activity of specific enzymes in the purine catabolic pathway leads to profound human immunodeficiency diseases. Deficiency of lymphocyte aden-osine deaminase (ADA)' activity causes severe combined immunodeficiency (1); deficiency of purine nucleoside phosphorylase (PNP) activity leads to an isolated T cell defect (2). Both enzyme deficiencies are the results of mutations in the structural genes coding for the missing enzymes, leading to losses of activity in all tissues (3)(4)(5)(6)(7).…”

mentioning

confidence: 99%

Ecto-5′-Nucleotidase Activity in Human T Cell Subsets. DECREASED NUMBERS OF ECTO-5′-NUCLEOTIDASE POSITIVE CELLS FROM BOTH OKT4+ AND OKT8+ CELLS IN PATIENTS WITH HYPOGAMMAGLOBULINEMIA

Thompson¹,

Saxon²,

O’Connor³

et al. 1983

J. Clin. Invest.

View full text Add to dashboard Cite

Nucleoside-Phosphorylase Deficiency in a Child With Severely Defective T-Cell Immunity and Normal B-Cell Immunity

Cited by 819 publications

References 13 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.

Novel Genetic Mutations in the First Swedish Patient with Purine Nucleoside Phosphorylase Deficiency and Clinical Outcome After Hematopoietic Stem Cell Transplantation with HLA-Matched Unrelated Donor

Ecto-5′-Nucleotidase Activity in Human T Cell Subsets. DECREASED NUMBERS OF ECTO-5′-NUCLEOTIDASE POSITIVE CELLS FROM BOTH OKT4+ AND OKT8+ CELLS IN PATIENTS WITH HYPOGAMMAGLOBULINEMIA

Contact Info

Product

Resources

About