981B Poster - 15. Models of human disease
Friday April 08, 2:00 PM - 4:00 PM

Authors:
Shayna Scott; Emerald Lane ; Emily Coelho; Clement Chow

Affiliation: University of Utah, Salt Lake City, UT

Keywords:
w. genetic modifiers of disease; b. neural disorder

Phosphatidylinositol glycan class A (PIGA) deficiency is an X-linked condition classified as a congenital disorder of glycosylation (CDG). CDGs are rare genetic diseases that result from mutations in genes that affect the biosynthesis or addition of glycans to other macromolecules. PIGA deficiency shares many symptoms with other CDGs such as shortened lifespan, hypotonia, facial dysmorphism, and epileptic seizures. PIGA encodes an enzyme that catalyzes the first step of glycosylphosphatidylinositol (GPI) biosynthesis transferring a N-acetylglucosamine to phosphatidylinositol. GPI-anchored proteins (GPI-APs) are localized to the cell surface and involved in processes such as endocytosis, immunity, and signal transduction. Like many CDGs and rare diseases, variability in phenotypic severity is common in PIGA deficiency patients, though the reason behind this variability is unknown. Because these disorders are often congenital, background genetics likely plays a big role. It is necessary to study a large number of genetic backgrounds to fully understand what affects the phenotypic outcome of a disease. To do this, we performed a genetic screen that utilizes the genetic variation found in ~200 lines of the Drosophila Genetic Reference Panel (DGRP) to identify potential genetic modifiers that impact seizure susceptibility in our PIGA deficient Drosophila model. We found that seizure susceptibility associated with PIGA deficiency is highly dependent on genetic background, with seizure susceptibility between 0-60%. We also found that median seizure recovery time was also highly dependent on genetic background. There is a moderate correlation between seizure susceptibility and recovery time, suggesting only a partial overlap between the genetic architecture that underlies variability of either phenotype. We also found that there was a moderate correlation between the sexes for both phenotypes, suggesting some sex-specificity to the modifier genes. To identify modifiers of these phenotypes, we performed genome wide association analyses for each independently, and by sex. We will present functional characterization of the strongest genetic modifiers. Further investigation into genetic modifiers that impact the seizure susceptibility will provide insights into improved treatments and personalized therapies.