Diseases Associated With GPI Anchors☆

Abstract

Glycosylphosphatidylinositol (GPI) is a glycolipid that serves as a membrane anchor for many cell surface proteins. More than 150 mammalian proteins are anchored in the cell membrane via GPI. The core glycan structure of GPI-Anchored Proteins (GPI-Aps) is conserved among eukaryotes, however the side chain modification and lipid structure of inositol phospholipid vary among the species. Recently, whole exome sequencing to inherited diseases became feasible, many new diseases related to GPI pathway genes were found. Complete deficiency of GPI is embryonic lethal because all of the important GPI-APs fail to express on the cell surface. For this reason, GPI deficiency should be partial deficiency. There are two types of GPI deficiencies, the one is an acquired deficiency, paroxysmal nocturnal hemoglobinuria (PNH), and the other is an inherited GPI deficiency (IGD). PNH is often completely defective in GPI but only in hematopoietic cells and a major symptom is hemolytic anemia. IGD is caused by the hypomorphic mutations with recessive inheritance and shows neurological abnormalities. PNH is usually caused by the somatic mutation of X-linked gene, PIGA but recently, PNH caused by the PIGT mutations is found. IGD is reported with the mutations of 21 genes among the 27 GPI biosynthesis genes.