# Combination of genetic studies and animal modeling proposes TMPRSS9 as a candidate gene for serum K+ variations

## TL;DR

This study suggests that the TMPRSS9 gene may influence potassium levels in women and shows sex-specific effects in mice.

## Contribution

The study proposes TMPRSS9 as a sex-specific modifier gene for serum potassium handling in humans and identifies sex differences in mice.

## Key findings

- Mouse Tmprss9 gene expression differs between sexes under potassium deprivation or loading.
- Male Tmprss9 knockout mice retained serum K+ on high K+ diet, unlike females.
- Protein abundances of sodium transporters were similar in knockout and wildtype mice.

## Abstract

A candidate gene association analysis identified TMPRSS9 as gene for potassium sensitivity in women. To validate this finding, constitutive and conditional Tmprss9 knockout mice were generated and subjected to dietary K+ deprivation and K+ loading. Interestingly, mouse renal Tmprss9 gene expression was similar in both sexes on standard diet but differed when challenged with K+-deprivation or -loading in wildtype (WT) mice. Constitutive deficiency of Tmprss9 was evidenced on a transcriptional level in knockout (KO) mice. Serum Na+ levels were lower in male and female KO mice on low K+ (LKD), while on high K+ (HKD) diet, serum K+ only increased in male KO mice. Upon all diet conditions namely standard diet (SD), LKD and HKD the protein abundances of sodium transporting proteins like the sodium-chloride symporter (NCC), alpha and gamma epithelial sodium channel (ENaC) subunits as well as their ratio of cleaved/full length protein and the sodium-hydrogen exchanger 3 (NHE3) were similar in WT and KO mice and/or showed only minor differences. We propose that in human, TMPRSS9 may function as a sex-specific modifier gene for serum K+ handling in women, whereas in mice, male rather than female Tmprss9 KO retained serum K+ on HKD.

The online version contains supplementary material available at 10.1038/s41598-025-11106-7.