Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q00604 (X-linked)
 16,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic stem cell disorder characterized by complement-mediated hemolysis. Abnormal hematopoietic cells from patients with PNH are deficient in glycosylphosphatidylinositol (GPI)-anchored proteins and clonally dominate various hematopoietic lineages in the bone marrow and the peripheral blood. Analysis of many patients with PNH has showed that somatic mutation in the X-linked gene PIG-A is responsible for the GPI-anchor deficiency in PNH. The PIG-A mutation must also be relevant to the clonal dominance of GPI-anchor deficient (GPI-) blood cells because two or more PIG-A mutant clones become dominant in many patients. However, whether the PIG-A mutation alone is sufficient for clonal dominance is not known. To address this question, we generated chimeric mice using Pig-a (the murine homologue of PIG-A) disrupted embryonic stem (ES) cells, in which the animals are chimeric with respect to the surface expression of GPI-anchored proteins. The chimerism of hematopoietic and nonhematopoietic tissues in such mice was always low, suggesting that the higher contribution of Pig-a disrupted GPI- cells had a lethal effect on the chimera. GPI- cells appeared in the peripheral blood of some of the chimeric mice. However, the percentage of GPI- erythrocytes did not increase for 10 months after birth, implying that the Pig-a mutation alone does not immediately cause the clonal dominance of GPI- blood cells; another pathologic or physiologic change(s) in the hematopoietic environments or in the clone itself may be necessary.
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PMID:Glycosylphosphatidylinositol-anchor-deficient mice: implications for clonal dominance of mutant cells in paroxysmal nocturnal hemoglobinuria. 861 83

Paroxysmal nocturnal hemoglobinuria is the first example of a non neoplastic human disease caused by the somatic mutation of an X-linked gene. The PIG-A gene maps to Xp22.1 and is required for the transfer of N-acetyl glucosamine to phosphoinositol, an early step in the production of the GPI anchor. A deficiency of GPI-linked proteins on the cell surface is responsible for the PNH cell defect, which can be detected by flow cytometry not only on red cells, but also on myeloid cells and in some patients even on lymphoid cells. Its location on the X-chromosome explains how a single recessive mutation can cause the appearance of the abnormal clone. A number of patients may have more than one PNH clone, suggesting that the expansion of GPI-deficient clones occurs under the pressure of a selection mechanism.
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PMID:The PIG-A gene somatic mutation responsible for paroxysmal nocturnal hemoglobinuria. 864 22

Analysis of the X-linked gene PIG-A from haemopoietic cells of a female PNH patient showed a homozygous C-55-T substitution that caused replacement of arginine with tryptophan at codon 19. Aval restriction analysis of PIG-A cDNA demonstrated that the patient was homozygous for this mutation, whereas her mother was heterozygous and her father was hemizygous. Flow cytometry, however, showed normal expression of glycosyl phosphatidylinositol anchored proteins on blood cells of the patient's mother and father. Therefore the C-55-T mutation is an inherited sequence variant that does not account for the PNH phenotype of this patient.
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PMID:Identification and characterization of an inherited mutation of PIG-A in a patient with paroxysmal nocturnal haemoglobinuria. 865 78

Patients with paroxysmal nocturnal hemoglobinuria have one or more mutant hematopoietic stem cell clones deficient in glycosylphosphatidylinositol (GPI)-anchor synthesis owing to somatic mutations in the X-linked gene PIG-A. The progeny of mutant stem cells dominates the peripheral blood. The presence of a large number of GPI-anchor deficient, complement-sensitive erythrocytes leads to hemolytic anemia. The somatic mutations in PIG-A are small, various, and widely distributed in the coding regions and splice sites, indicating they occur randomly. Profiles of the mutations vary geographically, suggesting the presence of mutagen-induced mutations. The clonal dominance by the mutants does not seem to be solely due to the PIG-A mutation but may be caused either by autonomous expansion of the mutants due to a combination of the PIG-A mutation and some other genetic change(s) or by selection that preferentially suppresses normal stem cells.
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PMID:Role of phosphatidylinositol-linked proteins in paroxysmal nocturnal hemoglobinuria pathogenesis. 871 63

The purpose of this review is to summarize recent studies that have led to a more complete understanding of the molecular basis of paroxysmal nocturnal hemoglobinuria (PNH). Somatic mutations of PIG-A arising in pluripotent hematopoietic stem cells are necessary for the development of PNH. PIG-A is an X-linked gene that is essential for synthesis of the glycosyl phosphatidylinositol (GPI) moiety that serves as a membrane anchor for a functionally diverse group of cell surface proteins. Consequently, the progeny of stem cells with mutant PIG-A are deficient in all GPI-anchored proteins (GPI-AP). Among the GPI-AP that are expressed on hematopoietic cells are two important regulators of the complement system, decay-accelerating factor, (CD55) and membrane inhibitor of reactive lysis, (CD59). It is the deficiency of erythrocyte CD55 and CD59 that accounts for the intravascular hemolysis and hemoglobinuria that are the clinical hallmarks of PNH. A remarkable feature of PNH is that the peripheral blood is a mosaic composed of variable proportions of GPI-AP+ and GPI-AP- cells and that, in an individual patient, the GPI-AP- cells can be derived from multiple mutant stem cells. Currently, however, there is no evidence that the PIG-A mutation per se provides a proliferative advantage. Thus, PNH is not a monoclonal disease with a malignant phenotype. Rather, the mutant stem cells appear to dominate hematopoiesis because under some pathological conditions, GPI-AP deficiency is advantageous. The close association of PNH with aplastic anemia suggests that the selection pressure arises as a consequence of a specific type of bone marrow injury.
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PMID:Molecular basis of paroxysmal nocturnal hemoglobinuria. 884 41

Many eukaryotic cell surface proteins are bound to the membrane via the glycosylphosphatidylinositol (GPI) anchor that is covalently linked to their carboxy-terminus. The GPI anchor precursor is synthesized in the endoplasmic reticulum (ER) and post-translationally linked to protein. We cloned a human gene termed PIG-B (phosphatidylinositol glycan of complementation class B) that is involved in transferring the third mannose. PIG-B encodes a 554 amino acid, ER transmembrane protein with an amino-terminal portion of approximately 60 amino acids on the cytoplasmic side and a large carboxy-terminal portion of 470 amino acids within the ER lumen. A mutant PIG-B lacking the cytoplasmic portion remains active, indicating that the functional site of PIG-B resides on the lumenal side of the ER membrane. The PIG-B gene was localized to chromosome 15 at q21-q22. This autosomal location would explain why PIG-B is not involved in the defective GPI anchor synthesis in paroxysmal nocturnal hemoglobinuria, which is always caused by a somatic mutation of the X-linked PIG-A gene.
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PMID:PIG-B, a membrane protein of the endoplasmic reticulum with a large lumenal domain, is involved in transferring the third mannose of the GPI anchor. 886 54

A large fraction of the hematopoietic cells of patients with paroxysmal nocturnal hemoglobinuria (PNH) are deficient in membrane expression of glycosylphosphatidylinositol-anchored proteins (GPI-APs). Current evidence suggests that this deficiency is sufficient to account for the hemolytic and thrombotic manifestations of this disease but not for its frequent association with aplastic anemia, an autoimmune disorder in which the patients' own hematopoietic progenitor cells are the target. Mutations in X-linked gene PIG-A, encoding one of several enzymes required for the biosynthesis of the glycophosphatidylinositol anchor, have been found in all PNH patients studied to date. Recent experiments with murine Pig-a knock-out embryonic stem cells show that although embryogenesis is critically dependent on normal GPI-AP expression, Pig-a-deficient cells can undergo apparently normal hematopoietic differentiation if they develop in a GPI-AP-replete environment. Thus, in an in vitro mouse model of PNH, Pig-a mutations confer no gross proliferative or differentiative advantage or disadvantage, suggesting an unidentified process selecting for these mutations in the bone marrow of patients with the PNH-aplastic anemia syndrome. The rescue of hematopoiesis observed in chimeric cultures of knock-out and normal cells was accompanied by intercellular transfer of GPI-AP, suggesting exciting new possibilities for future therapeutic manipulations in PNH patients.
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PMID:Paroxysmal nocturnal hemoglobinuria: new insights from murine Pig-a-deficient hematopoiesis. 906 78

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired, clonal disorder of hematopoietic cells caused by somatic mutation in the X-linked PIGA gene encoding a protein involved in the synthesis of the glycosylphosphatidylinositol (GPI) anchor by which many proteins are attached to the membrane of cells. About 15 proteins have been found to be lacking or markedly deficient on the abnormal blood cells. These defects result in a clinical syndrome that includes intravascular hemolysis mediated by complement, unusual venous thromboses, deficits of hematopoiesis, and other manifestations. Therapy is presently directed mainly at the consequences of the disorder rather than its basic causes and includes replacement of iron, folic acid, and whole blood; hormonal modulation (prednisone, androgens); anticoagulation; and bone marrow transplantation. PNH is a chronic disease with more than half of adult patients surviving 15 years or more; prognosis is less good in children.
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PMID:Paroxysmal nocturnal hemoglobinuria as a molecular disease. 910 Jul 36

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by clonal blood cells that are deficient in the surface expression of glycosylphosphatidylinositol-anchored proteins due to somatic mutation in the X-linked gene PIG-A. In some patients, more than one abnormal clone may be present. Analysis of bulk DNA/RNA from granulocytes has been useful in identifying the predominant PIG-A mutation in each patient. However, it is often not useful in determining the presence of minor clones. Many patients have cells with partial deficiency. Here, we analyzed the PIG-A gene in two B-cell lines bearing complete or partial deficiencies, cells of hematopoietic progenitor colonies and peripheral blood granulocytes from the same patient. We found that two B-cell lines had different mutations, the granulocytes contained at least two mutants, and the hematopoietic progenitors contained four mutants. Three of the four were shared by B cells and/or granulocytes whereas the other one was found only in the hematopoietic progenitors. The partial deficiency was caused by a point mutation near an alternative splice site within exon 2 that resulted in partial decreases of activity and quantity of the full-length transcript. These results further show the oligoclonal nature of PNH and differences in extent of expansion among mutant clones.
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PMID:A patient with paroxysmal nocturnal hemoglobinuria bearing four independent PIG-A mutant clones. 912 55

Paroxysmal nocturnal haemoglobinuria (PNH) is an acquired haemolytic disorder caused by deficient biosynthesis of the glycosyl phosphatidylinositol (GPI) anchor in haemopoietic stem cells. PIG-A, an X-linked gene that participates in the first step of GPI-anchor synthesis, is responsible for PNH. Various abnormalities of the PIG-A gene have been demonstrated in all patients with PNH so far examined. In this study we characterized the somatic mutations in PIG-A gene in four Taiwanese patients with PNH. We identified five novel mutations in the PIG-A gene, three single nucleotide substitution mutations (-342, C-->G, codon 335, GGT-->AGT and codon 405, GCT-->GTT) and two frameshift mutations (codon 22, GGA-->G-A and codon 356, TGT-->TGTT) in the PIG-A gene. The -342 mutation was judged to be a polymorphism. Furthermore, three patients had previous clinicopathologic evidence which suggested aplastic anaemia (AA), before the development of PNH. One of these was found to have thrombocytopenia during follow-up. We suggest that the somatic PIG-A gene mutations highlight a subgroup of AA having a pathogenetic link with PNH.
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PMID:PIG-A gene mutations in four Taiwanese patients with paroxysmal nocturnal haemoglobinuria following aplastic anaemia. 916 89


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