Mandi Wild

Congenital Disorders of Glycosylation (CDGs) are a group of rare diseases known to impair glycosylation due to mutations in glycosylation-related genes. Glycosylation is an essential co- and post-translational modification that influences protein structure, function, and folding. This is a highly active biological process that occurs in over 50% of proteins. In CDG patients, disrupted glycosylation causes proteins to misfold, leading to cellular dysfunction and stress. Currently, 189 genes are associated with the 200 CDG phenotypes. My work focuses on DPAGT1-CDG, an ultra-rare subtype with fewer than 40 reported cases as of 2021. DPAGT1-CDG is a multi-systemic disease caused by loss-of-function mutations in DPAGT1 that impair N-glycosylation. Patients with DPAGT1-CDG have an array of debilitating symptoms, including neurodevelopmental delays, gastrointestinal issues, seizures, and more. DPAGT1 is an endoplasmic reticulum (ER) transmembrane enzyme that catalyzes the initial step in N-glycan biosynthesis. Since DPAGT1-CDG patients have reduced DPAGT1 function, N-glycan biosynthesis is impaired, and the pool of N-linked glycans available for protein glycosylation is reduced. When N-linked glycans are absent, proteins become hypoglycosylated, misfold, and are unable to be transported from the ER, which leads to protein accumulation. The accumulation of improperly folded proteins in the ER generates cellular stress signals that activate several ER quality-control systems (ERQC) to clear misfolded proteins, including the unfolded protein response (UPR), ER-associated degradation (ERAD), and autophagy. Ultimately, we aim to further elucidate ERQC mechanisms under glycosylation stress to identify modifier genes that can be targeted therapeutically in DPAGT1-CDG and related glycosylation disorders.