Keely Weber
Pronouns: she/her
Research Mentor(s): Andrea Thompson
Research Mentor School/College/Department: Department of Internal Medicine/Cardiovascular Division / Medicine
Program: UROP
Session: Session 1 (9:00am – 9:50am)
Authors: Keely Weber, Jaime Yob, Ulla Lilenthal, Andrea Thompson
Abstract
Hypertrophic Cardiomyopathy (HCM) is a heart disease that causes thickening of the walls of the left ventricle of heart and can eventually lead to arrythmias, stroke, heart failure, and even sudden cardiac death. HCM is most commonly caused by loss of function variants in the MyBP-C, a sarcomere protein. Missense variants which replace one amino acid with another are difficult to characterize and as such a significant subset of these variants are classified as variants of uncertain significance. Our aim is to utilize immunofluorescence imaging techniques to study the effect of missense variants on MyBP-C protein localization within cardiomyocytes. We will express flagged tagged- MyBP-C missense variants within cardiomyocytes using adenovirus transduction. Cardiomyocytes will be patterned using a fibronectin microprinting technique to control sarcomere architecture and cell size. Immunofluorescence staining will be utilized to detect the location of flag-tagged MyBP-C missense variants in comparison to endogenous wild-type MyBP-C protein. We predict a subset of missense variants will fail to localize normally to the sarcomere, providing evidence for loss-of-function and pathogenicity. Prior studies have utilized this technique to understand the mechanism of action of known pathogenic missense variants. By generating experimental evidence of pathogenicity in a yet uncharacterized variant of uncertain significance, we will aid clinicians in identifying patients with pathogenic MyBP-C variants providing additional prognostic information and informing clinical monitoring and testing in at-risk family members.
