Researchers discovered that amiloride improves survival and respiratory function in mouse models exhibiting respiratory distress caused by a deficiency in the WFDC2 gene, according to a study published in Nature Communications on August 12, 2026. The peer-reviewed study investigated the p.C97W variant in the WAP four-disulfide core domain protein 2 as a novel genetic origin of respiratory distress, particularly among Korean populations.
The research team performed whole-exome and whole-genome sequencing on 64 patients from 62 families presenting with severe bronchiectasis and chronic rhinosinusitis. Pathogenic variants were identified in 19.4 percent of families, including a novel homozygous WFDC2 missense variant, designated c.291 C > G or p.Cys97Trp, across five unrelated families.
WFDC2 is expressed in lung epithelial cells. The study found that the p.C97W variant impairs protein folding, secretion, and function. In Wfdc2 p.C147W knock-in mice, animals exhibited respiratory failure caused by hyperactive epithelial sodium channels linked to increased PRSS8 activity, effectively recapitulating the human disease.
Treatment with the epithelial sodium channel inhibitor amiloride improved both survival and respiratory function in the affected mice. Because the p.C97W variant represents a critical genetic factor in severe chronic airway disease sharing features with cystic fibrosis and primary ciliary dyskinesia, researchers recommended genetic testing for WFDC2 mutations in patients showing similar symptoms.
The research was conducted by scientists at Yonsei University College of Medicine and Severance Hospital in Seoul, Republic of Korea, with Jae Won Roh, Soo Kyung Seo, Jiyoung Oh, and Se Jin Kim contributing equally. The study was supported by National Research Foundation grants funded by the Korean government, submitted on January 6, 2025, and published under DOI 10.1038/s41467-026-76582-5.
