The molecular basis for paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal disease characterized by chronic intravascular hemolysis, cytopenia due to bone marrow failure and increased tendency to thrombosis. All patients with PNH studied so far have a somatic mutation in an X-linked gene, called PIG-A (phosphatidyl inositol glycan complementation group A), which encodes for a protein involved in the biosynthesis of the glycosyl phosphatidylinositol (GPI) molecule, that serves as an anchor for many cell surface proteins. The mutation occurs in a hematopoietic stem cell and leads to a partial or total deficiency of the PIG-A protein with consequent impaired synthesis of the GPI anchor: as a result, a proportion of blood cells is deficient in all GPI-linked proteins. The mutations are spread all over the gene and in some patients more than one mutated clone have been identified. The absence of GPI-anchored proteins on PNH cells explains some of the clinical symptoms of the disease but not the mechanism that enables the PNH clone to expand in the bone marrow of patients. Both in vitro and in vivo experiments have shown that PIG-A inactivation per se does not confer a proliferative advantage to the mutated hematopoietic stem cell. Clinical observations have shown a close relationship between PNH and aplastic anemia. Taken together, these findings corroborate the hypothesis that one or more additional factors are needed for the expansion of the mutant clone. Selective damage to normal hematopoiesis could be the cause which enables the PNH clone(s) to proliferate.