Biosynthesis of GPI anchored proteins, its deficiencies and treatment.

Glycosylphosphatidylinositol (GPI) anchoring is a widely conserved post-translational modification in eukaryotes, in which various proteins-such as receptors, cell adhesion molecules, and complement regulatory proteins-are modified with a GPI moiety and tethered to the cell membrane. GPI anchors are synthesized in the endoplasmic reticulum (ER), where they are attached to newly translated proteins. These GPI-anchored proteins (GPI-APs) then undergo structural remodeling and are transported to the cell surface. To date, approximately 30 gene products have been identified as essential for the GPI biosynthetic and remodeling pathways. In addition to paroxysmal nocturnal hemoglobinuria (PNH), a well-characterized acquired hematologic disorder caused by somatic mutations in GPI biosynthesis genes, an increasing number of inherited GPI deficiencies (IGDs) have recently been reported. These congenital disorders are typically caused by hypomorphic mutations in GPI biosynthetic genes and present with neurological abnormalities. In this review, we provide an overview of the biosynthetic pathway of GPI anchors in mammalian cells and the genetic disorders resulting from its dysfunction. We also discuss emerging therapeutic approaches currently under investigation, including gene therapy, which hold promise for improving clinical outcomes in patients with IGD.