The Cloning of PIG-A, a Component in the Early Step of GPI-Anchor Biosynthesis

Miyata, Toshio; Takeda, Junji; Iida, Yuichiro; Yamada, Norio; Inoue, Norimitsu; Takahashi, Minoru; Maeda, Kenji; Kitani, Teruo; Kinoshita, Taroh

doi:10.1126/science.7680492

Cited by 484 publications

(280 citation statements)

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“…Next, we asked whether a mutant of murine thymoma defective in PIG-A, that codes for the enzyme catalysing the early step of GP1 anchor biosynthesis and is functionally defective in the blood of paroxysmal nocturnal hemoglobinuria patients [23,27,28], would respond to HgC12 for protein tyrosine phosphorylation. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…T. Kinoshita and N. Inoue, Osaka University. This transfectant was prepared by transfecting BW5147 Thy-l-a with PIG-A cDNA plasmid into which a neomycin resistance gene had been introduced, followed by selection in medium with G418 [23]. PIPLC was obtained from the culture supernatant of Bacillus thuringiensis, and was purified to give a single band on SDS-PAGE [24].…”

Section: Cells Cell Lines and Reagentsmentioning

confidence: 99%

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Direct evidence of involvement of glycosylphosphatidylinositol‐anchored proteins in the heavy metal‐mediated signal delivery into T lymphocytes

Ohkusu

et al. 1995

FEBS Letters

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The biological significance of the action of glycosvlphosphatidylinositol (GPI)-anchored proteins in cell physiology and pathology when stimulated with their natural agonists is not known. Here we provide evidence that GPl-anchored proteins play a crucial role in the recently defined heavy metal (HgCI2)-triggered signal delivery to T lymphocytes. Thiol-reactive HgCI2, a multi-potent crosslinker of cell membrane proteins, induced heavy aggregation of Thy-l, a representative GPI-anchored prot ein, on murine thymocytes, and delivered a signal to induce heavy ! yrosine phosphorylation of cellular proteins. This rather unusual signal delivery by HgCI2 is diminished by the pre~treatment of cells with phosphatidylinositol-specific phospholipase C, which partially cleaved GPI-anchored proteins from the cell surface. Direct evidence for the involvement of GPI or GPI-anchored proteins in the HgCl2-mediated signaling is provided by the loss ~Df signaling in a mutant thymoma cell line defective in the phosphatidylinositol glycan-class A gene (PIG-A), and its restoration in a transfectant with PIG-A.

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Section: Resultsmentioning

confidence: 99%

Section: Cells Cell Lines and Reagentsmentioning

confidence: 99%

Direct evidence of involvement of glycosylphosphatidylinositol‐anchored proteins in the heavy metal‐mediated signal delivery into T lymphocytes

Ohkusu

et al. 1995

FEBS Letters

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“…2,[28][29][30] Genomic DNA was obtained from the sorted cells (1 Â 10 4 cells) using InstaGene Matrix (Bio-Rad Laboratories, Hercules, CA, USA). Genomic PIG-A DNA was amplified by PCR using AmpliTaq Gold polymerase (PE Applied Biosystems, Foster City, CA, USA).…”

Section: Polymerase Chain Reaction and Nucleotide Sequence Analysis Omentioning

confidence: 99%

“…1 The PIG-A gene consists of six exons and five introns and is involved in the first step of GPI-anchor biosynthesis; the transfer of N-acetylglucosamine to phosphatidylinositol. 2 All the PNH patients reported previously, in whom the PIG-A gene was examined, had abnormal PIG-A mRNA and/or genomic DNA in various cell lineages. 3 Therefore, PNH clones can be defined as GPIdeficient cell populations having PIG-A mutations.…”

Section: Introductionmentioning

confidence: 99%

High frequency of several PIG-A mutations in patients with aplastic anemia and myelodysplastic syndrome

et al. 2006

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To clarify some characteristics of phosphatidylinositol glycanclass A gene (PIG-A) mutations in aplastic anemia (AA) and myelodysplastic syndrome (MDS) patients compared with those in paroxysmal nocturnal hemoglobinuria (PNH) patients, we investigated PIG-A mutations in CD59 À granulocytes and CD48 À monocytes from seven AA, eight MDS, and 11 PNH Japanese patients. The most frequent base or type abnormalities of the PIG-A gene in AA and MDS patients were base substitutions or missense mutations, respectively, and deletions or frameshift mutations, respectively, in PNH patients. Several PIG-A mutations, most of which were statistically minor, were found in glycosylphosphatidylinositol-negative cells from all AA and MDS patients but not from all PNH patients. However, the common PIG-A mutations during the clinical course between CD59 À granulocytes and/or CD48 À monocytes from each AA or MDS patient, except for Case 5, were not found. PIG-A mutations were different between the granulocytes and monocytes from five AA and five MDS patients. Our results indicate that there were some characteristics of PIG-A mutations in AA and MDS patients compared with PNH patients and that several minor PNH clones in these patients occurred at random during the clinical course. This partly explains the transformation of AA or MDS to PNH at intervals.

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“…1 Progeny of affected stem cells are deficient in glycosyl phosphatidylinositol-anchored proteins (GPI-APs) which are important regulators of the complement system. Although more than 20 functionally diverse GPI-APs are expressed by hematopoietic stem cells, it is deficiency on red blood cells of the two GPIanchored complement regulatory proteins, CD55 and CD59, that is the leading cause of the intravascular hemolysis that represents the clinical hallmark of paroxysmal nocturnal hemoglobinuria.…”

Section: Introductionmentioning

confidence: 99%

Hematopoietic stem cell transplantation for paroxysmal nocturnal hemoglobinuria: long-term results of a retrospective study on behalf of the Gruppo Italiano Trapianto Midollo Osseo (GITMO)

Santarone¹,

Bacigalupo²,

Risitano³

et al. 2009

Haematologica

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BackgroundParoxysmal nocturnal hemoglobinuria is an acquired clonal disorder of the hemopoietic stem cells for which the only curative treatment is allogeneic hematopoietic stem cell transplantation. Design and MethodsThe aim of this retrospective study was to assess the long-term clinical and hematologic results in 26 paroxysmal nocturnal hemoglobinuria patients who received hematopoietic stem cell transplantation in Italy between 1988 and 2006. The patients were aged 22 to 60 years (median 32 years). Twenty-three donors were HLA-identical (22 siblings and one unrelated) and 3 were HLA-mismatched (2 related and one unrelated). ResultsFifteen patients received a myeloablative conditioning consisting of busulfan and cyclophosphamide (in all cases from identical donor) and 11 were given a reduced intensity conditioning (8 from identical donor and 3 from mismatched donor). The cumulative incidence of graft failure was 8% (4% primary and 4% secondary graft failure). Transplant-related mortality for all patients was 42% (26% and 63% for patients transplanted following myeloablative or reduced intensity conditioning, respectively). As of October 31, 2009, 15 patients (11 in the myeloablative conditioning group and 4 in the reduced intensity conditioning group) are alive with complete hematologic recovery and no evidence of paroxysmal nocturnal hemoglobinuria following a median follow-up of 131 months (range 30-240). The 10-year Kaplan-Meier probability of disease-free survival was 57% for all patients: 65% for 23 patients transplanted from identical donor and 73% for 15 patients transplanted with myeloablative conditioning. No thromboembolic event nor recurrence of the disease were reported following transplant. ConclusionsThe findings of this study confirm that most patients with paroxysmal nocturnal hemoglobinuria may be definitively cured with hematopoietic stem cell transplantation.Key words: paroxysmal nocturnal hemoglobinuria, hematopoietic stem cell transplantation, conditioning regimen. Haematologica 2010;95:983-988. doi:10.3324/haematol.2009 This is an open-access paper. Citation: Santarone S, Bacigalupo A, Risitano AM, Tagliaferri E, Di Bartolomeo E, Iori AP, Rambaldi A, Angelucci E, Spagnoli A, Papineschi F, Tamiazzo S, Di Nicola M, and Di Bartolomeo P. Hematopoietic stem cell transplantation for paroxysmal nocturnal hemoglobinuria: long-term results of a retrospective study on behalf of the Gruppo Italiano Trapianto Midollo Osseo (GITMO). Hematopoietic stem cell transplantation for paroxysmal nocturnal hemoglobinuria: long-term results of a retrospective study on behalf of the Gruppo Italiano Trapianto Midollo Osseo (GITMO)

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The Cloning of PIG-A, a Component in the Early Step of GPI-Anchor Biosynthesis

Cited by 484 publications

References 24 publications

Direct evidence of involvement of glycosylphosphatidylinositol‐anchored proteins in the heavy metal‐mediated signal delivery into T lymphocytes

Direct evidence of involvement of glycosylphosphatidylinositol‐anchored proteins in the heavy metal‐mediated signal delivery into T lymphocytes

High frequency of several PIG-A mutations in patients with aplastic anemia and myelodysplastic syndrome

Hematopoietic stem cell transplantation for paroxysmal nocturnal hemoglobinuria: long-term results of a retrospective study on behalf of the Gruppo Italiano Trapianto Midollo Osseo (GITMO)

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