阿米洛利通过抑制上皮钠通道减轻WFDC2缺陷引起的呼吸窘迫

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中文摘要

囊性纤维化（CF）和原发性纤毛运动障碍（PCD）等慢性气道疾病构成重大临床挑战。在此，我们探讨WAP四二硫键核心结构域蛋白2（WFDC2）中的p.C97W变异，该变异被提出是呼吸窘迫的一种新遗传起源，尤其在韩国人中。对来自62个家庭的64例表现为严重支气管扩张和慢性鼻窦炎的患者进行全外显子组和全基因组测序（WES/WGS）。在19.4%的家庭中发现致病性变异，包括五个无亲缘关系家庭中的一种新型纯合WFDC2错义变异（c.291 C > G，p.Cys97Trp）。WFDC2在肺上皮细胞中表达，p.C97W变异损害WFDC2蛋白折叠、分泌和功能。Wfdc2 p.C147W敲入小鼠因上皮钠通道（ENaC）过度活跃而表现出呼吸衰竭，这与PRSS8活性增加有关，并重现了人类疾病。用ENaC抑制剂阿米洛利治疗可改善这些小鼠的生存率和呼吸功能。总之，WFDC2中的p.C97W变异是严重慢性气道疾病的关键遗传因素，其临床特征与CF和PCD相似。鉴于其对诊断和治疗的意义，建议对具有CF或PCD样症状的个体进行WFDC2突变基因检测。

英文摘要

Chronic airway diseases such as cystic fibrosis (CF) and primary ciliary dyskinesia (PCD) pose substantial clinical challenges. Here, we explore the p.C97W variant in WAP four-disulfide core domain protein 2 (WFDC2), proposed as a new genetic origin of respiratory distress, especially among Koreans. Whole-exome and whole-genome sequencing (WES/WGS) are performed on 64 patients from 62 families presenting with severe bronchiectasis and chronic rhinosinusitis. Pathogenic variants are found in 19.4% of families, including a novel homozygous WFDC2 missense variant (c.291 C > G, p.Cys97Trp) in five unrelated families. WFDC2 is expressed in lung epithelial cells, and the p.C97W variant impairs WFDC2 protein folding, secretion, and function. Wfdc2 p.C147W knock-in mice exhibit respiratory failure due to the hyperactive epithelial sodium channel (ENaC) linked to increased PRSS8 activity and recapitulate human disease. Treatment with amiloride, an ENaC inhibitor, improves survival and respiratory function in these mice. In conclusion, the p.C97W variant in WFDC2 is a critical genetic factor in severe chronic airway disease that shares clinical features with CF and PCD. Given its implications for diagnosis and treatment, genetic testing for WFDC2 mutations in individuals with CF- or PCD-like symptoms is recommended.