The deficiency of glycosyl-phosphatidylinositol (GPI)-anchored proteins in plasma membranes of PIG-A gene mutated hematopoietic stem cells (HSCs) is so far insufficient to explain the domination of paroxysmal nocturnal hemoglobinuria (PNH) clone over the normal HSC.
Overexpression of high mobility group AT-hook 2 (HMGA2) is found in a number of benign and malignant tumors, including the clonal PIGA(-) cells in 2 cases of paroxysmal nocturnal hemoglobinuria (PNH) and some myeloproliferative neoplasms (MPNs), and recently in hematopoietic cell clones resulting from gene therapy procedures.
We produced an animal model of paroxysmal nocturnal hemoglobinuria by conditional Pig-a gene inactivation (Pig-a(-/-)) in hematopoietic cells; mice carrying two lox sites flanking exon 6 of the Pig-a gene were bred with mice carrying the transgene Cre-recombinase under the human c-fes promoter.
The author posits that the defining clinical pathology of PNH (ie, complementmediated intravascular hemolysis) is an epiphenomenon that is a consequence of an orchestrated response (ie, natural selection of PIGA-mutant stem cells) to a specific type of bone marrow injury (ie, immune mediated).Management of PNH is discussed also.
A scattergram profile of PNH-type cells unique to each patient persisted regardless of the response to immunosuppressive therapy and only single PIGA mutations were detected in PNH-type granulocytes sorted from four patients.
The molecular defect in PNH is mutation in the phosphotidylinositol glycan complementation class A (PIGA gene) causing defect in glycosylphosphatidylinositol anchored proteins (Cell, 73, 1993, 703).
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia caused by the expansion of a hematopoietic progenitor cell that has acquired a mutation in the X-linked PIGA gene.
Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by a deficient expression of glycosylphosphatidylinositol-anchored proteins (GPI-APs), due to somatic mutations of the phosphatidylinositolglycan complementation Class A (PIG-A) gene.
Chimerism and PIGA gene analyses showed the paroxysmal nocturnal hemoglobinuria (PNH)-type granulocytes to be of a donor-derived stem cell with a thymine insertion in PIGA exon 2.
Paroxysmal nocturnal haemoglobinuria (PNH) is a clonal disorder of haematopoietic stem cells caused by somatic PIGA mutations, resulting in a deficiency in glycosylphosphatidylinositol-anchored proteins (GPI-AP).
Multiple, discrete PIGA mutant clones are present in many patients, suggesting that a selection pressure that favors the PNH phenotype (i.e., GPI-AP deficiency) was applied to the bone marrow.
PNH is caused by a somatic mutation of the phosphatidylinositol glycan (GPI) complementation class A (PIGA) gene, followed by a survival advantage of the PNH clone, which results in a deficiency of GPI-anchored proteins on hematopoietic cells.
As a clinical entity, deficiency of GPI has been recognized as paroxysmal nocturnal hemoglobinuria, an acquired clonal disorder associated with somatic mutations of the X-linked PIGA gene in hematopoietic cells.
Somatic mutation in the PIG-A gene is the initial event in the pathogenesis of paroxysmal nocturnal hemoglobinuria (PNH), but the pathophysiologic mechanisms leading to clonal expansion remain unclear.
Paroxysmal nocturnal hemoglobinuria (PNH) is an uncommon intravascular hemolytic anemia that results from the clonal expansion of hematopoietic stem cells harboring somatic mutations in an X-linked gene, termed PIG-A.
These observations suggest that aberrant HMGA2 expression, in concert with mutant PIGA, accounts for clonal hematopoiesis in these 2 patients and suggest the concept of PNH as a benign tumor of the bone marrow.
Paroxysmal nocturnal haemoglobinuria (PNH) is a haematopoiesis disorder characterized by the expansion of a stem cell bearing a somatic mutation in the phosphatidylinositol glycan-A (PIG-A) gene, which is involved in the biosynthesis of the glycosylphosphatidylinositol (GPI) anchor.
Paroxysmal nocturnal haemoglobinuria (PNH) results from acquired mutations in the PIG-A gene of an haematopoietic stem cell, leading to defective biosynthesis of glycosylphosphatidylinositol (GPI) anchors and deficient expression of GPI-anchored proteins on the surface of the cell's progeny.
Increased resistance of PIG-A- bone marrow progenitors to tumor necrosis factor a and interferon gamma: possible implications for the in vivo dominance of paroxysmal nocturnal hemoglobinuria clones.