Pathogenesis of PNH. (A) A schematic diagram depicting the normal biosynthesis of glycophosphatidylinositol (GPI)-anchored proteins. The first enzymatic step in GPI-anchor biosynthesis, the addition of N-acetylglucosamine (GIcNAc, tan circle) to phosphatidylinositol (PI, blue hexagon), is catalyzed on the cytoplasmic side of the endoplasmic reticulum (ER) by a multisubunit complex that requires PIGA. Subsequent enzymatic steps (denoted by multiple arrows) add sugar moieties (white hexagons) to form the GPI anchor, which is then added to the precursor proteins on the luminal side of the ER. (B) The clinical symptoms of PNH are characterized by complement-mediated intravascular hemolysis, which occurs due to the deficiency of 2 GPI-anchored complement-regulatory proteins, CD55 and CD59. Under normal conditions, CD55 and CD59 on the surface of the red blood cell (RBC) inhibit C3 convertase and the membrane attack complex (MAC), respectively, protecting RBCs from complement-mediated lysis. In PNH, the defect in the PIGA gene leads to the absence of all GPI-anchored proteins, including CD55 and CD59, making the PNH RBC susceptible to complement activation and lysis.