What causes paroxysmal nocturnal hemoglobinuria (PNH)?

By William Aird

Acquired mutation in the X-linked phosphatidylinositol glycan class A (PIGA) gene in an hematopoietic stem cell, leading to deficiency of GPI-anchored proteins on hematopoietic cells, including CD55 and CD59, which in turn leads to activation of the alternative complement pathway and complement-mediated hemolysis. Learn more here.

(A) In healthy subjects, GPI-anchored protein biosynthesis proceeds unperturbed in the endoplasmic reticulum. The full-length GPI anchor with attached protein (e.g., CD55 and CD59) resides in the membrane rafts of blood cells; thus red cells are protected from complement-mediated hemolysis. (B) In PIGA-PNH, a somatic mutation in PIGA  (required for the initial step in GPI-anchored biosynthesis) leads to failure to generate the GPI anchor in hematopoietic cells. After expansion of the PNH clone (often through immunologic escape) the PNH red cells are susceptible to complement-mediated hemolysis due to an absence of the GPI-anchored CD55 and CD59 from the cell surface. From RA Brodsky.