Role of phosphatidylinositol-linked proteins in paroxysmal nocturnal hemoglobinuria pathogenesis.
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.
Kinoshita
T
T
Department of Immunoregulation, Osaka University, Japan.
Inoue
N
N
Takeda
J
J
D004912:Erythrocytes / Q000502:physiology; D008040:Genetic Linkage / Q000235:genetics; D017261:Glycosylphosphatidylinositols / Q000235:genetics / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000502:physiology; D006457:Hemoglobinuria, Paroxysmal / Q000235:genetics / Q000503:physiopathology*; D006461:Hemolysis / Q000235:genetics / Q000502:physiology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D009154:Mutation; D010716:Phosphatidylinositols / Q000235:genetics / Q000502:physiology*; D012729:Sex Chromosome Aberrations / Q000235:genetics; D014960:X Chromosome
D017261:Glycosylphosphatidylinositols; D008565:Membrane Proteins; D010716:Phosphatidylinositols; C080086:phosphatidylinositol glycan-class A protein