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We aimed to determine: how many functional multiciliated airway cells are sufficient to maintain ciliary airway clearance?<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To answer this question we exploited the molecular defects of the X-linked recessive primary ciliary dyskinesia variant caused by pathogenic variants in<jats:italic>DNAAF6<\/jats:italic>(<jats:italic>PIH1D3<\/jats:italic>), characterised by immotile cilia in affected males. We carefully analysed the clinical phenotype and molecular defect (using immunofluorescence and transmission electron microscopy) and performed<jats:italic>in vitro<\/jats:italic>studies (particle tracking in air\u2013liquid interface cultures) and<jats:italic>in vivo<\/jats:italic>studies (radiolabelled tracer studies) to assess ciliary clearance of respiratory cells from female individuals with heterozygous and male individuals with hemizygous pathogenic<jats:italic>DNAAF6<\/jats:italic>variants.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Primary ciliary dyskinesia male individuals with hemizygous pathogenic<jats:italic>DNAAF6<\/jats:italic>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<jats:italic>DNAAF6<\/jats:italic>variants, 54.3\u00b110% (range 38\u201370%) of multiciliated cells were defective. Nevertheless,<jats:italic>in vitro<\/jats:italic>and<jats:italic>in vivo<\/jats:italic>assessment of the ciliary airway clearance was normal or slightly abnormal. Consistently, heterozygous female individuals showed no or only mild respiratory symptoms.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings indicate that having 30\u201362% 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.<\/jats:p><\/jats:sec>","DOI":"10.1183\/13993003.01441-2023","type":"journal-article","created":{"date-parts":[[2024,7,11]],"date-time":"2024-07-11T16:05:26Z","timestamp":1720713926000},"page":"2301441","update-policy":"https:\/\/doi.org\/10.1183\/ers-crossmark-policy","source":"Crossref","is-referenced-by-count":19,"title":["A range of 30\u201362% of functioning multiciliated airway cells is sufficient to maintain ciliary airway clearance"],"prefix":"10.1183","volume":"64","author":[{"given":"Niki T.","family":"Loges","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4420-3091","authenticated-orcid":false,"given":"June Kehlet","family":"Marthin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Raidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heike","family":"Olbrich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inga M.","family":"H\u00f6ben","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Cindric","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Bracht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4974-5540","authenticated-orcid":false,"given":"Julia","family":"K\u00f6nig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia","family":"Rieck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"George","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim Luis","family":"Kloth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Wohlgemuth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Pennekamp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernd","family":"Dworniczak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9944-6253","authenticated-orcid":false,"given":"Mathias G.","family":"Holgersen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1535-8852","authenticated-orcid":false,"given":"Jobst","family":"R\u00f6mel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Schmalstieg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella","family":"Aprea","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jann","family":"Mortensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim G.","family":"Nielsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0282-6765","authenticated-orcid":false,"given":"Heymut","family":"Omran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"81","published-online":{"date-parts":[[2024,7,11]]},"reference":[{"key":"2024112623043091000_64.4.2301441.1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2278"},{"key":"2024112623043091000_64.4.2301441.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-020-0209-6"},{"key":"2024112623043091000_64.4.2301441.3","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.31967"},{"key":"2024112623043091000_64.4.2301441.4","doi-asserted-by":"crossref","unstructured":"Desai PB , Dean AB , Mitchell DR . 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