Katie Nguyen on Characterizing ROMK

Katie Nguyen, Brodsky Lab

Characterizing ROMK gain-of-function mutations and human variants and their roles in hypertension

Hypertension affects one billion people worldwide and is the most common risk factor for many cardiovascular diseases. Despite the high heritability of the condition, the relative contributions of genetic factors have yet to be fully defined. Major regulators of hypertension include the salt-handling transporters in the kidney, particularly the renal outer medullary K+ (ROMK) channel. While degradation-prone mutations in ROMK give rise to Bartter’s Syndrome Type II, heterozygous carriers of these same mutations are protected from hypertension. Therefore, we hypothesize that a mutation in ROMK that increases its potassium flux, a gain-of-function (GOF) mutation, could predispose people to hypertension. By utilizing an unbiased genetic screen in yeast, we have so far identified three potential GOF mutations. We found that these mutations lead to varying degrees of channel conductance and stability, and we plan to further characterize how they affect protein trafficking, endocytosis, and assembly. Furthermore, we will expand the GOF mutation list with a more directed approach by exploring a list of known pH-insensitive ROMK variants. Finally, in an attempt to systematically assess the functional impact of all human missense variants in ROMK, we experimentally tested a computational algorithm, Rhapsody, with yeast growth assays and showed that Rhapsody correctly predicted a majority of deleterious and disease-associated mutations in ROMK. Going forward, we plan to use Rhapsody as a guide to experimentally evaluate the functional impact of existing ROMK human missense variants and potentially uncover their connections to hypertension. 

Friday, May 22, 2020

12 PM

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22 May 2020

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