Paroxysmal nocturnal hemoglobinuria: insights from recent advances in molecular biology.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hemolytic anemia characterized by the increased sensitivity of red cells to complement, leading to intravascular hemolysis and hemoglobinuria. Other clinical features are cytopenias caused by bone marrow failure and an increased risk of thrombosis. If unrecognized and not treated appropriately, PNH is often associated with a substantial morbidity and mortality. PNH is caused by the expansion of a hematopoietic progenitor cell that caries a somatic mutation in the X-linked phosphatidylinositol glycan complementation group A (PIGA) gene. The PIGA gene encodes a protein essential in the biosynthesis of glycosylphosphatidylinositol (GPI)-anchor molecules. A proportion of blood cells from patients with PNH is therefore deficient in all GPI-linked surface proteins. Considerable progress in the field of PNH research in the last 7 years has resulted from the cloning of the PIGA gene. The purpose of the current article is to describe the structure and function of the PIGA gene, to summarize the lessons learned from the analysis of PIGA gene mutations, to review the impact of mouse models on our current understanding of the human disease, and to discuss the possible pathogenesis of PNH. In addition, we will outline novel approaches to PNH diagnosis, research, and therapy that became available thanks to the cloning of the PIGA gene.