Biochemical background of paroxysmal nocturnal hemoglobinuria.
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired disorder characterized by paroxysms of intravascular hemolysis. A considerable part of erythrocytes in patient blood is susceptible to autologous complement activation because of the deficiency of CD59, which is a glycosylphosphatidylinositol (GPI)-anchored protein and inhibits the formation of the membrane attack complex (MAC) of complement. The deficiency of CD59 is derived from the inability of GPI-anchor synthesis. Although more than 10 proteins are involved in the GPI-anchor synthesis, the mutation of only one protein, PIG-A, causes the defect in about 200 patients with PNH who have been analyzed. The reason why only PIG-A causes the deficiency of GPI anchor is due to the location of its gene on X chromosome. The clonal stem cell mutated with PIG-A gene in the bone marrow loses the capability of the synthesis of GPI-anchor. The mutation of PIG-A gene alone, however, seems to be insufficient to account for the survival of the PIG-A-deficient cells in the bone marrow. Thus, a fraction of the mutant stem cells probably gain a survival advantage by some additional changes, either additional mutations or changes in immunological circumstances. The release of the surviving cells into blood stream results in a clinical syndrome with PNH.
Tomita
M
M
Department of Physiological Chemistry, Faculty of Pharmaceutical Science, Showa University, Tokyo, Japan. tomitam@pharm.showa-u.ac.jp
D000818:Animals; D018957:CD59 Antigens / Q000097:blood; D002240:Carbohydrate Sequence; D002940:Circadian Rhythm; D015938:Complement Membrane Attack Complex / Q000096:biosynthesis; D004910:Erythrocyte Membrane / Q000276:immunology; D017261:Glycosylphosphatidylinositols / Q000096:biosynthesis / Q000737:chemistry / Q000172:deficiency*; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006457:Hemoglobinuria, Paroxysmal / Q000097:blood / Q000378:metabolism* / Q000503:physiopathology; D006461:Hemolysis; D006801:Humans; D007962:Leukocytes / Q000276:immunology; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D011379:Prognosis
D018957:CD59 Antigens; D015938:Complement Membrane Attack Complex; D017261:Glycosylphosphatidylinositols; D008565:Membrane Proteins; C080086:phosphatidylinositol glycan-class A protein