Defective Glycosyl Phosphatidylinositol Anchor Synthesis and Paroxysmal Nocturnal Hemoglobinuria

Abstract

Publisher Summary The glycosyl phosphatidylinositol (GPI) anchor is synthesized in the endoplasmic reticulum (ER) and post-translationally linked to the nascent peptides in the ER. If the peptides are not GPI anchored, they are not expressed on the cell surface due to intracellular retention, degradation, and secretion. The human disease, paroxysmal nocturnal hemoglobinuria (PNH), is caused by this mechanism. PNH is a hematopoietic stem cell disorder characterized by the presence of abnormal cells of various hematopoietic cell lineages that are deficient in the surface expression of GPI-anchored proteins. The abnormal red blood cells of patients with PNH are sensitive to the hemolytic action of complement due to the deficient surface expression of decay accelerating factor and CD59, which are GPI-anchored complement inhibitors. The first step of GPI anchor biosynthesis is deficient in abnormal blood cells from patients with PNH. The X-linked gene PIG-A is cloned and somatically mutated in abnormal cells from patients with PNH. Due to its X-chromosomal location, a single inactivating mutation results in a loss of GPI anchor synthesis, even in a female hematopoietic stem cell, if it occurs in the active allele of the PIG-A gene. More than 60 patients with PNH from various countries were analyzed and the PIG-A gene was responsible for PNH in all of them. The X-chromosomal location of the PIG-A gene would also account for this uniformity of the responsible gene among the 10 or so genes involved in GPI anchor synthesis. Patients with PNH have one or more mutant hematopoietic stem cell clones that are deficient in GPI anchor synthesis due to somatic mutations in the X-linked gene, PIG-A. The somatic mutations of PIGA are widely distributed in the coding regions and splice sites, indicating that they occur at random sites.