Recent advances in research on paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is a hemolytic anemia caused by complement-mediated hemolysis. Blood cells from patients with PNH contain abnormal cells that lack complement regulatory proteins, DAF and CD59, both of which protect host cells from action of complement. DAF and CD59 are GPI-anchored and on the abnormal blood cells other GPI-anchored proteins are also deficient. A fundamental abnormality of PNH appeared to be deficient biosynthesis of the GPI-anchor at an early step. We cloned a cDNA of a gene termed PIG-A (for Phosphatidyl Inositol Glycan-class A) that encodes a 484 amino acid putative ER membrane protein which functions at that step and hence a responsible gene for PNH. Analysis of PIG-A transcripts in the abnormal cells from patients with PNH demonstrated various types of abnormalities such as decreased level of the transcript, splicing abnormality and mutations in the coding region. Thus, PNH is caused by a clonal expansion of abnormal blood cells derived from a hematopoietic stem cell bearing a somatic mutation occurred in PIG-A gene.