Unveiling the "Guardian" of the Respiratory System: How a Single Gene Mutation Leads to Severe Lung Disease
Imagine what happens if our respiratory tract loses an important "guardian"? Bacteria may invade wantonly, inflammation recurs, and ultimately the lung structure is permanently damaged. Recently, a study published in Respiratory Medicine Case Reports, through three real cases, revealed how a mutation in a gene called WFDC2 can cause severe chronic rhinosinusitis and bronchiectasis, finding the cause for some patients who have long suffered from unexplained respiratory diseases.
Research Background: When the Respiratory Tract Loses its Defense
Our respiratory system, from the nose to the depths of the lungs, has a sophisticated defense mechanism. Among them, various proteins secreted by airway epithelial cells play a key role. They are like soldiers guarding the city walls, capable of resisting bacterial invasion and suppressing excessive inflammatory responses. The WFDC2 gene encodes precisely such a protein, which is mainly expressed in the epithelial cells and glands of the respiratory tract and has important antibacterial and "anti-protease" (i.e., inhibiting tissue-damaging enzymes) activity.
However, when the WFDC2 gene mutates, this "guardian" will be absent or dysfunctional. This leads to a decrease in the defense capability of the respiratory tract, making it prone to recurrent infections and chronic inflammation. Over time, this condition can cause "bronchiectasis"—that is, the bronchial walls become loose and permanently dilated due to repeated damage and inflammation—as well as "chronic rhinosinusitis."
This disease has symptomatic similarities with two other more well-known genetic lung diseases—cystic fibrosis (CF) and primary ciliary dyskinesia (PCD)—but its root cause is different, making it prone to misdiagnosis or long-term undiagnosed.
Key Findings: Three Cases from Japan
This study reported on three Japanese female patients who had suffered from chronic rhinosinusitis since childhood and were diagnosed with severe bronchiectasis in adolescence (aged 16, 18, and 24, respectively).
Despite long-term antibiotic (macrolide) treatment, their condition did not improve effectively, lung function continued to decline, and acute exacerbations recurred. Imaging examinations (CT scans) showed that their lung lesions were mainly concentrated in the upper lobes, which is very similar to the characteristics of cystic fibrosis (CF). More seriously, due to the severity of the disease, two of the three patients eventually had to undergo lung transplantation to survive.
After ruling out known causes such as CF and PCD, researchers performed gene sequencing and ultimately found a common "culprit" in all three patients: their WFDC2 gene all had the same homozygous mutation (NM_006103.4:c.291C>G). In layman's terms, "homozygous mutation" means that they inherited this defective gene version from both parents.
Interestingly, this specific gene mutation was also found in previous studies of Korean patients, strongly suggesting that it may be a "founder mutation" in East Asian populations (especially Japanese and Koreans). A founder mutation refers to a specific genetic variant that originated in an individual and spread among their descendants, leading to a higher frequency in a particular ethnic group.
Research Methods: The Diagnostic Process of Unraveling Clues
The diagnostic process of the researchers was exemplary. They first conducted a detailed clinical evaluation of the patients, including lung function tests, chest and sinus CT scans, and sputum cultures.
Next, they performed a series of exclusionary diagnoses. For example, they measured the patients' "nasal nitric oxide (nNO)" levels. This indicator is usually extremely low in PCD patients, and the nNO levels in these patients were also low, which once made doctors suspect PCD. However, electron microscopy examination revealed that the patients' airway ciliary structure was normal, thus ruling out PCD. At the same time, CFTR gene testing also ruled out the diagnosis of cystic fibrosis.
Finally, the research team focused on the WFDC2 gene, which has recently been found to be associated with such diseases. They used polymerase chain reaction (PCR) and Sanger sequencing techniques to analyze the coding region of this gene, and finally precisely located the key homozygous mutation site, providing the gold standard for disease diagnosis.
Limitations of the Study
Although this study is of great significance, it also has its limitations. First, this is a case series report with a very small sample size (only 3 cases), so the generalizability of its conclusions needs to be verified by larger-scale studies. Second, the study did not delve into the specific molecular mechanisms by which this gene mutation causes the disease, i.e., what specific pathophysiological changes occur downstream after WFDC2 protein function is lost. In addition, due to limited data, the study also failed to provide targeted treatment options, and current treatment still focuses on supportive therapies such as infection control and airway clearance.
Application Prospects and Implications
The most important implication of this study is that it provides clinicians with a new diagnostic direction. For East Asian patients who exhibit CF-like symptoms, suffer from severe chronic sinopulmonary disease, but have ruled out common causes, WFDC2 gene testing should be considered.
Early and accurate genetic diagnosis is crucial. It can not only help patients and their families understand the cause of the disease, avoid unnecessary examinations and incorrect treatments, but also guide doctors to take more proactive management measures, such as strengthening airway clearance techniques, actively controlling infections, and, if necessary, evaluating the feasibility of lung transplantation earlier. Including the WFDC2 gene in the diagnostic gene panel for "sinopulmonary disease" will be an important step towards future precision medicine.
Summary
This study with , although only a report of a few cases, clearly links homozygous WFDC2 gene mutations with a severe, cystic fibrosis-like respiratory disease and points out the possibility of a "founder mutation" in East Asian populations (especially Japanese and Koreans). This not only deepens our understanding of the genetic basis of bronchiectasis and chronic rhinosinusitis but also opens a new window for the diagnosis and management of such difficult diseases, with the potential to benefit more patients.
References: Ito, M., Morimoto, K., Hijikata, M., Hasegawa, H., Wakabayashi, K., Miyabayashi, A., & Keicho, N. (2025). Severe bronchiectasis and chronic rhinosinusitis due to homozygous WFDC2 variants. Respiratory Medicine Case Reports, 51, 102061. .
