Molecular genetics, biochemistry, and biology of PNH.

Paroxysmal nocturnal hemoglobinuria (PNH) manifests by clonal expansion of mutant hematopoietic stem cells (HSCs) bearing a somatic mutation in the X-linked PIGA gene. PIGA mutations cause defective biosynthesis of GPI and cell surface deficiency of GPI-anchored proteins such as DAF and CD59, leading to intravascular hemolysis and thrombosis. These two major symptoms of PNH can be controlled by eculizumab, an anti-C5 monoclonal antibody. Bone marrow failure, the third major symptom of PNH, is autoimmune-mediated and contributes to the clonal expansion of GPI-defective HSCs by selectively attacking GPI-positive wild-type HSCs. GPI-defective erythrocytes, being protected from intravascular hemolysis by eculizumab, accumulate C3-derived fragments, C3b, iC3b, and C3dg, because of DAF deficiency and in turn become susceptible to CR3-mediated phagocytosis by spleen macrophages. Approximately 3% of Japanese patients with PNH are refractory to eculizumab therapy. Approximately 3% of Japanese people are heterozygous for a single nucleotide polymorphism that changes an amino acid near the eculizumab binding site. New therapeutic measures are needed to solve these issues.