Paroxysmal nocturnal hemoglobinemia: A molecular definition of the clinical biology of the disorder

Paroxysmal nocturnal hemoglobinemia (PNH), a hematopoietic stem cell disorder, arises from a somatic mutation of the phosphatidylinositol glycan-class A (PIG-A) gene. The gene product is required in the biosynthesis of a glycosylphosphatidylinositol (GPI) structure and serves as an anchor for a group of membrane proteins. The PNH cells are characterized by a total or partial lack of the GPI-anchored membrane proteins. Without this structure, intravascular hemolysis occurs due to the inability to regulate the lytic and cell-stimulatory activities of complement on the membrane surface of hematopoietic cells. Two proteins, CD55-decay accelerating factor and CD59-membrane inhibitor of reactive lysis, are known to be tethered to the cell membrane by the GPI-anchor Additionally, platelets lacking CD59 may cause venous thrombosis with possible Budd-Chiari syndrome, The development of PNH requires a hypoplastic bone marrow, somatic mutation restricted to the PIG-A gene in the stem cell, and clonal expansion of the hematopoietic stem cell pool.