Inherited glycosylphosphatidylinositol deficiency: a review from molecular and clinical perspectives

Abstract

Glycosylphosphatidylinositol (GPI) is a highly conserved post-translational modification in eukaryotes, which is essential for anchoring various proteins to the cell surface. Dysfunction of GPI biogenesis leads to human diseases, such as inherited GPI deficiency (IGD) caused by germline mutations in GPI-related genes. With accumulating reports on individuals with IGD, there has been increasing interest and studies on disease mechanism, diagnosis, and therapy. This review outlines the biosynthetic pathway of GPI-anchored proteins (GPI-APs) and summarizes clinical IGD cases from a molecular perspective. We also review current diagnostic and therapeutic approaches for IGD. Finally, we discuss future research directions to facilitate the understanding and treatment of GPI-related disorders.

1. Introduction

Cell-surface proteins play crucial roles in cellular function. In eukaryotes, proteins can be anchored to the plasma membrane through two primary mechanisms: transmembrane domain or glycosylphosphatidylinositol (GPI) modification. Forming an amide bond between the protein C-terminus and the phosphoethanolamine moiety in GPI, GPI-anchored proteins (GPI-APs) are anchored to the outer leaflet of the plasma membrane, in which the glycerophospholipid tail of GPI functions analogously to a single transmembrane domain of type-I transmembrane proteins. In humans, GPI modifies more than 150 protein substrates for their correct localization to the cell surface (Supplementary Table S1). These GPI-APs comprise various types of proteins, including enzymes, receptors, adhesion molecules, and complement regulators, which are functionally essential for a list of biological processes such as signal transduction and intercellular communication.

As a structurally complex molecule, GPI contains a phosphoethanolamine linker, a glycan core, and a glycerophospholipid tail. The biosynthetic pathway of GPI-APs is conserved across eukaryotes, consisting of two phases that involve over 20 enzymatic reaction steps and 33 proteins encoded by the phosphatidyl inositol glycan (PIG) and post-GPI attachment to proteins (PGAP) genes [1]. The first phase primarily occurs in the endoplasmic reticulum (ER), in which phosphatidylinositol (PI) undergoes stepwise modifications by glucosamine (GlcN), mannoses (Man), and ethanolamine phosphates (EtNP) to form free GPI. GPI-APs are generated by the transfer of intact GPI to protein substrates, followed by a remodeling phase involving further alterations of the lipid and glycan moieties in the ER and Golgi apparatus.

It has been known for a long time that the deficiency or dysfunction of GPI biosynthesis leads to human diseases. For example, somatic mutations of PIGA in hematopoietic cells result in paroxysmal nocturnal hemoglobinuria (PNH), a rare and acquired hematologic disorder characterized by hemolysis, thrombosis, and impaired bone marrow function [2]. Additionally, cases have been reported in recent years with GPI deficiency caused by germline mutations, referred to as inherited GPI deficiency (IGD). Currently, 24 out of 33 genes involved in the GPI biosynthetic pathway have been identified as causative factors in IGD [3,4]. Although IGD shares a common pathogenesis of defective GPI structure biosynthesis, the clinical manifestations vary widely, underscoring unknown mechanisms of pathogenicity across different IGDs.