A drug repurposing screen reveals dopamine signaling as a candidate therapeutic pathway for PIGA-CDG
Miriam C. Aziz, Jennie Wilson, Clement Y. Chow
Abstract
PIGA-CDG is a congenital disorder of glycosylation caused by pathogenic partial loss-of-function variants in the PIGA gene. PIGA encodes an enzyme responsible for the catalytic transfer of N-acetylglucosamine to phosphatidylinositol during the first step of glycosylphosphatidylinositol anchor biosynthesis.
Introduction
PIGA-CDG is an ultra-rare X-linked recessive neurodevelopmental disorder caused by partial loss-of-function variants in the Phosphatidylinositol glycan biosynthesis class A (PIGA) gene [1–4]. Fewer than 100 patients have been identified with PIGA-CDG. Of these patients, approximately 40 partial loss-of-function variants have been reported [3].
Methods
Fly stocks and maintenance
Fly stocks were maintained at room temperature. Flies for model development and genetic validation work were obtained from the Bloomington Drosophila Stock Center (BDSC). All flies were fed with Glucose medium (D2) (Archon Scientific). F1 progeny generated by crossing PIGA RNAi (BDSC 62696) to eya composite-GAL4 were used for the primary drug repurposing screen and subsequent drug validation experiments, with all drug repurposing and validation experiments conducted in a 27°C incubator. We received eya composite-GAL4 as a gift from Justin Kumar (Indiana University Bloomington).
Results
A drug repurposing screen reveals suppressors of a Drosophila PIGA-CDG eye model
To perform a drug repurposing screen, we developed an RNA interference (RNAi) based loss-of-function model of PIGA-CDG in Drosophila using the GAL4/UAS system. PIGA is knocked down only in eye tissue using the eya-GAL4 driver [16]. PIGA knockdown in the eye results in a smaller eye with a glassy appearance (Fig 1A). Previously, we demonstrated that this same RNAi results in a 60% reduction in PIGA expression [17].
Discussion
PIGA-CDG is a complex neurodevelopmental disorder with no disease-specific treatment. Because GPI-anchored proteins (GPI-APs) are broadly expressed and functionally diverse, it remains unknown how the loss of GPI-APs contributes to the neurological symptoms observed in patients. Although some symptoms of PIGA-CDG can be managed, the associated seizures are often severe and resistant to conventional treatments [3,4,36].
Acknowledgments
We dedicate this work to Emmett Nguyen, the first boy we met with PIGA-CDG. His life and parents, Ann and Steve, inspired us to begin work on this rare disorder. We thank Dr. Katherine Beebe, Emily Coelho, Delaney Baratka, and Caroline Massey for their technical advice regarding the drug repurposing screen. We thank Elsie Smith for her assistance in the lab. We thank Dr. Hugo Bellen and Dr. Oguz Kanka for generating and sharing the PIGA null allele. A special thank you to Dr. Holly Thorpe for advising on all things PIGA and her unwavering support throughout the course of this work and manuscript preparation.
Citation: Aziz MC, Wilson J, Chow CY (2026) A drug repurposing screen reveals dopamine signaling as a candidate therapeutic pathway for PIGA-CDG. PLoS Genet 22(8): e1012294
https://doi.org/10.1371/journal.pgen.1012294
Editor: David A. Buchner, Case Western Reserve University, UNITED STATES OF AMERICA
Received: May 3, 2026; Accepted: August 19, 2026; Published: August 31, 2026
Copyright: © 2026 Aziz et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All data generated is available in the supplement.
Funding: This research was funded by an NIH NIGMS award (R35GM124780), an NIH NINDS award (P01NS138003), and the University of Utah Mario R. Capecchi Endowed Chair in Genetics awarded to C.Y.C. M.C.A. was supported by an NIH NIGMS T32 fellowship from the University of Utah (T32GM141848). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012294#ack
