Master of Science
Meredith Protas, PhD
Kristin Tracy, PhD
Kathryn Patton, PhD
Hernandez, Nicole, "An Investigation of The Dominant-Negative Effect of Multiple HAE Type I, SERPING1 Mutations Through In Vitro Model(s)" (2023). Natural Sciences and Mathematics | Biological Sciences Master's Theses. 44.
Hereditary Angioedema (HAE) is a rare, autosomal dominant disease that causes reoccurring edema attacks that include submucosal and cutaneous swelling, which are sporadic and can be deadly. HAE is caused by mutations in the SERPING1 gene, causing a deficiency in plasma C1 esterase inhibitor, also known as C1-inhibitor or C1-INH. C1-inhibitor protein regulates pathways within the inflammatory cascade, which includes the contact system, complement system, coagulation cascade, and fibrinolytic system. HAE type I (HAE-I) patients experience a decrease in C1-INH plasma levels, leading to edema attacks. The decrease of C1-INH in HAE-I patients has been linked to a dominant-negative effect of HAE-I mutations, which has been demonstrated in previous studies. However, further investigation is needed to better understand the dominant-negative effect of HAE-I mutations. In this study, transient transfections were used to characterize the dominant-negative effect of multiple HAE-I mutations. This work shows that the expression of mutant C1-INH proteins affects the secretion of C1-INH through different mechanisms; the 1417 G>A mutation is associated with intracellular C1-INH accumulation, while the 550 G>A and 449 C>T mutations are not. In addition, intracellular protein-protein interactions were observed between wild-type C1-INH and the 1417 G>A mutant, but not between wild-type C1-INH and either the 550 G>A or 449 C>T mutants. These findings demonstrate that the dominant-negative effect can differ across mutations and implies that the molecular mechanism of HAE-I may vary according to a patient’s mutation.
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