Department of General Pediatrics, University Children's Hospital Muenster, Muenster, Germany.
Danish PCD Centre, Danish Paediatric Pulmonary Service, Department of Paediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Eur Respir J. 2024 Oct 10;64(4). doi: 10.1183/13993003.01441-2023. Print 2024 Oct.
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 (), characterised by immotile cilia in affected males. We carefully analysed the clinical phenotype and molecular defect (using immunofluorescence and transmission electron microscopy) and performed studies (particle tracking in air-liquid interface cultures) and studies (radiolabelled tracer studies) to assess ciliary clearance of respiratory cells from female individuals with heterozygous and male individuals with hemizygous pathogenic variants.
Primary ciliary dyskinesia male individuals with hemizygous pathogenic 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 variants, 54.3±10% (range 38-70%) of multiciliated cells were defective. Nevertheless, and 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异常的运动纤毛功能引起的遗传疾病，导致纤毛气道清除功能缺陷，随后导致反复的气道感染和支气管扩张。我们旨在确定：需要多少功能正常的多纤毛气道细胞才能维持纤毛气道清除功能？
为了回答这个问题，我们利用了 X 连锁隐性遗传的原发性纤毛运动障碍的分子缺陷，该缺陷由 （）中的致病变体引起，受影响的男性中存在不动纤毛。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 研究（空气-液体界面培养中的颗粒追踪）和 研究（放射性示踪剂研究），以评估具有杂合致病性 变体的女性个体和具有半合子致病性 变体的男性个体的呼吸细胞的纤毛清除功能。
具有半合子致病性 变体的原发性纤毛运动障碍男性个体表现出完全不动纤毛，缺乏纤毛清除功能和严重的原发性纤毛运动障碍症状。由于六位携带杂合致病性 变体的女性个体中存在随机或偏性 X 染色体失活，54.3±10%（范围 38-70%）的多纤毛细胞存在缺陷。然而， 和 评估的纤毛气道清除功能正常或略异常。一致地，杂合女性个体没有或只有轻微的呼吸道症状。
我们的发现表明，有 30-62%的多纤毛呼吸细胞功能正常可以产生正常或略降低的纤毛清除功能。由于杂合女性携带者没有或仅有轻微的呼吸道症状，通过精准医学完全纠正 30%的细胞可能会改善原发性纤毛运动障碍个体的纤毛气道清除功能以及临床症状。
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