Primary ciliary dyskinesia is a genetic disorder caused by aberrant motile cilia function that results in defective ciliary airway clearance and subsequently leads to recurrent airway infections and bronchiectasis. We aimed to determine: how many functional multiciliated airway cells are sufficient to maintain ciliary airway clearance?

To answer this question we exploited the molecular defects of the X-linked recessive primary ciliary dyskinesia variant caused by pathogenic variants in DNAAF6 (PIH1D3), characterised by immotile cilia in affected males. We carefully analysed the clinical phenotype and molecular defect (using immunofluorescence and transmission electron microscopy) and performed in vitro studies (particle tracking in air–liquid interface cultures) and in vivo studies (radiolabelled tracer studies) to assess ciliary clearance of respiratory cells from female individuals with heterozygous and male individuals with hemizygous pathogenic DNAAF6 variants.

Primary ciliary dyskinesia male individuals with hemizygous pathogenic DNAAF6 variants displayed exclusively immotile cilia, absence of ciliary clearance and severe primary ciliary dyskinesia symptoms. Owing to random or skewed X-chromosome inactivation in six female carriers with heterozygous pathogenic DNAAF6 variants, 54.3±10% (range 38–70%) of multiciliated cells were defective. Nevertheless, in vitro and in vivo assessment of the ciliary airway clearance was normal or slightly abnormal. Consistently, heterozygous female individuals showed no or only mild respiratory symptoms.

Our findings indicate that having 30–62% of multiciliated respiratory cells functioning can generate either normal or slightly reduced ciliary clearance. Because heterozygous female carriers displayed either no or subtle respiratory symptoms, complete correction of 30% of cells by precision medicine could improve ciliary airway clearance in individuals with primary ciliary dyskinesia, as well as clinical symptoms.

原发性纤毛运动障碍是一种由运动纤毛功能异常引起的遗传性疾病，可导致睫状气道清除缺陷，随后导致反复发作的气道感染和支气管扩张。我们旨在确定：多少功能性多纤毛气道细胞足以维持睫状气道清除？

为了回答这个问题，我们利用了由 DNAAF6 （PIH1D3） 致病性变异引起的 X 连锁隐性原发性纤毛运动障碍变异的分子缺陷，其特征是受影响男性的纤毛不动。我们仔细分析了临床表型和分子缺陷 （使用免疫荧光和透射电子显微镜） 并进行了体外研究 （气-液界面培养物中的颗粒追踪） 和体内研究 （放射性标记示踪剂研究） 以评估呼吸细胞的纤毛清除率 具有杂合子的女性个体和具有半合子致病性 DNAAF6 变体的男性个体。

具有半合致病性 DNAAF6 变体的原发性纤毛运动障碍男性个体表现出完全不动的纤毛，没有纤毛清除和严重的原发性纤毛运动障碍症状。由于具有杂合致病性 DNAAF6 变体的 6 名女性携带者随机或偏斜的 X 染色体失活，54.3±10%（范围 38-70%）的多纤毛细胞有缺陷。然而，睫状气道清除率的体外和体内评估是正常的或略微异常的。始终如一，杂合子女性个体没有或只有轻微的呼吸道症状。

我们的研究结果表明，拥有 30-62% 的多纤毛呼吸细胞功能可以产生正常或略微减少的纤毛清除。由于杂合子女性携带者表现出无或轻微的呼吸道症状，因此通过精准医学完全矫正 30% 的细胞可以改善原发性纤毛运动障碍个体的纤毛气道清除率以及临床症状。