Katie Nguyen to speak

Katie Nguyen - Brodsky Lab

Friday, March 5, 2021

12:10 PM

Virtual Zoom seminar

Abstract:

Hypertension affects one billion people worldwide and is the most common risk factor for cardiovascular disease. Despite its high heritability, the relative contributions of genetic factors to hypertension have yet to be defined. I aim to identify and characterize missense variants in a renal potassium channel, ROMK, that is implicated in blood pressure regulation. While disease-causing ROMK mutations prematurely degrade the protein, heterozygous carriers of these same mutations are protected from hypertension. Therefore, I propose that hyperactive ROMK channels with a gain-of-function mutation predispose individuals to hypertension.

By utilizing an unbiased genetic yeast screen and a candidate-based approach, I identified six gain-of-function variants. Functional assays in three model systems revealed that one and possibly two variants enhanced channel conductance and stabilized the protein, leading to an increased level of tetrameric ROMK. I plan to further characterize how the variants affect protein trafficking, localization, endocytosis, and single channel conductance.

In parallel, to assess the functional impact of naturally-occurring ROMK missense variants in the population, I will computationally analyze and characterize select human ROMK variants using a genomic database of 155k participants, among whom ~50% have heart and blood problems. Notably, three out of the six isolated GOF variants are present in this database.

My study will provide a detailed characterization of ROMK variants implicated in blood pressure regulation and facilitate a deeper understanding of ROMK structure-function relationship. As ROMK has emerged as a new target for antihypertensives, my work may aid in the development of therapeutic strategies to reduce heart disease.

Date

05 Mar 2021

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