Drosophilamodels of PIGA-CDG mirror patient phenotypes

Abstract

AbstractMutations in the phosphatidylinositol glycan biosynthesis class A (PIGA) gene cause a rare, X-linked recessive congenital disorder of glycosylation (CDG). PIGA-CDG is characterized by seizures, intellectual and developmental delay, and congenital malformations. ThePIGAgene encodes an enzyme involved in the first step of GPI anchor biosynthesis. There are over 100 GPI anchored proteins that attach to the cell surface and are involved in cell signaling, immunity, and adhesion. Little is known about the pathophysiology of PIGA-CDG. Here we describe the firstDrosophilamodel of PIGA-CDG and demonstrate that loss ofPIG-Afunction inDrosophilaaccurately models the human disease. As expected, complete loss ofPIG-Afunction is larval lethal. Heterozygous null animals appear healthy, but when challenged, have a seizure phenotype similar to what is observed in patients. To identify the cell-type specific contributions to disease, we generated neuron- and glia-specific knockdown ofPIG-A. Neuron-specific knockdown resulted in reduced lifespan and a number of neurological phenotypes, but no seizure phenotype. Glia-knockdown also reduced lifespan and, notably, resulted in a very strong seizure phenotype. RNAseq analyses demonstrated that there are fundamentally different molecular processes that are disrupted whenPIG-Afunction is eliminated in different cell types. In particular, loss ofPIG-Ain neurons resulted in upregulation of glycolysis, but loss ofPIG-Ain glia resulted in upregulation of protein translation machinery. Here we demonstrate thatDrosophilais a good model of PIGA-CDG and provide new data resources for future study of PIGA-CDG and other GPI anchor disorders.Article SummaryPIGA-CDG is a rare genetic disorder. In order to study this rare disease, we generated and characterized several Drosophila models of PIGA-CDG. These models faithfully recapitulate different patient phenotypes, including movement disorder and seizures. Drosophila is a good model for PIGA-CDG and other GPI anchor disorders.