{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T18:46:53Z","timestamp":1793386013478,"version":"4.5.0"},"reference-count":38,"publisher":"BMJ","issue":"6","funder":[{"DOI":"10.13039\/501100010466","name":"Chancellerie des Universit\u00e9s de Paris","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100010466","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001677","name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001677","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002915","name":"Fondation pour la Recherche M\u00e9dicale","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002915","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2024,2,10]]},"published-print":{"date-parts":[[2024,6]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Primary ciliary dyskinesia (PCD) is a rare airway disorder caused by defective motile cilia. Only male patients have been reported with pathogenic mutations in X-linked <jats:italic>DNAAF6<\/jats:italic>, which result in the absence of ciliary dynein arms, whereas their heterozygous mothers are supposedly healthy. Our objective was to assess the possible clinical and ciliary consequences of X-chromosome inactivation (XCI) in these mothers.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>XCI patterns of six mothers of male patients with <jats:italic>DNAAF6<\/jats:italic>-related PCD were determined by DNA-methylation studies and compared with their clinical phenotype (6\/6 mothers), as well as their ciliary phenotype (4\/6 mothers), as assessed by immunofluorescence and high-speed videomicroscopy analyses. The mutated X chromosome was tracked to assess the percentage of cells with a normal inactivated <jats:italic>DNAAF6<\/jats:italic> allele.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>The mothers\u2019 phenotypes ranged from absence of symptoms to mild\/moderate or severe airway phenotypes, closely reflecting their XCI pattern. Analyses of the symptomatic mothers\u2019 airway ciliated cells revealed the coexistence of normal cells and cells with immotile cilia lacking dynein arms, whose ratio closely mirrored their XCI pattern.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>This study highlights the importance of searching for heterozygous pathogenic <jats:italic>DNAAF6<\/jats:italic> mutations in all female relatives of male PCD patients with a <jats:italic>DNAAF6<\/jats:italic> defect, as well as in females consulting for mild chronic respiratory symptoms. Our results also demonstrate that about one-third\u2014ranging from 20% to 50%\u2014normal ciliated airway cells sufficed to avoid severe PCD, a result paving the way for gene therapy.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmg-2023-109700","type":"journal-article","created":{"date-parts":[[2024,2,26]],"date-time":"2024-02-26T13:20:23Z","timestamp":1708953623000},"page":"595-604","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":7,"title":["Skewed X-chromosome inactivation drives the proportion of <i>DNAAF6<\/i>-defective airway motile cilia and variable expressivity in primary ciliary dyskinesia"],"prefix":"10.1136","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6998-590X","authenticated-orcid":false,"given":"Lucie","family":"Thomas","sequence":"first","affiliation":[{"name":"Childhood Genetic Diseases, Sorbonne Universit\u00e9, Inserm, H\u00f4pital Armand-Trousseau, Paris, F-75012, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurence","family":"Cuisset","sequence":"additional","affiliation":[{"name":"Service de M\u00e9decine G\u00e9nomique, Assistance Publique H\u00f4pitaux de Paris (AP-HP), Universit\u00e9 de Paris, H\u00f4pital Cochin, Paris, F-75014, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Francois","family":"Papon","sequence":"additional","affiliation":[{"name":"Service d\u2019Oto-Rhino-Laryngologie et de Chirurgie Cervico-Faciale, AP-HP, H\u00f4pital Bic\u00eatre, Le Kremlin-Bic\u00eatre, F-94270, France"},{"name":"Institut Mondor de Recherche Biom\u00e9dicale, Universit\u00e9 Paris-Est Cr\u00e9teil, Inserm U955, CNRS ERL7240, H\u00f4pital Henri-Mondor, Cr\u00e9teil, F-94010, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aline","family":"Tamalet","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Pneumologie P\u00e9diatrique, Centre National de R\u00e9f\u00e9rence des Maladies Respiratoires Rares RespiRare, AP-HP, Sorbonne Universit\u00e9, H\u00f4pital Armand-Trousseau Hospital, Paris, F-75012, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Pin","sequence":"additional","affiliation":[{"name":"P\u00e9diatrie, CHU Grenoble Alpes, Grenoble, F-38500, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rola","family":"Abou Taam","sequence":"additional","affiliation":[{"name":"Service de Pneumologie et Allergologie P\u00e9diatriques, AP-HP, H\u00f4pital Necker-Enfants Malades, Paris, F-75015, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Faucon","sequence":"additional","affiliation":[{"name":"Service d'Anatomopathologie, Laboratoire de Microscopie Electronique, Centre Hospitalier Intercommunal de Cr\u00e9teil, Cr\u00e9teil, F-94000, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guy","family":"Montantin","sequence":"additional","affiliation":[{"name":"G\u00e9n\u00e9tique mol\u00e9culaire, AP-HP, H\u00f4pital Armand-Trousseau, Paris, F-75012, Paris"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvie","family":"Tissier","sequence":"additional","affiliation":[{"name":"G\u00e9n\u00e9tique mol\u00e9culaire, AP-HP, H\u00f4pital Armand-Trousseau, Paris, F-75012, Paris"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Duquesnoy","sequence":"additional","affiliation":[{"name":"Childhood Genetic Diseases, Sorbonne Universit\u00e9, Inserm, H\u00f4pital Armand-Trousseau, Paris, F-75012, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florence","family":"Dastot - Le Moal","sequence":"additional","affiliation":[{"name":"G\u00e9n\u00e9tique mol\u00e9culaire, AP-HP, H\u00f4pital Armand-Trousseau, Paris, F-75012, Paris"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Copin","sequence":"additional","affiliation":[{"name":"Childhood Genetic Diseases, Sorbonne Universit\u00e9, Inserm, H\u00f4pital Armand-Trousseau, Paris, F-75012, France"},{"name":"G\u00e9n\u00e9tique mol\u00e9culaire, AP-HP, H\u00f4pital Armand-Trousseau, Paris, F-75012, Paris"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Carion","sequence":"additional","affiliation":[{"name":"Service de M\u00e9decine G\u00e9nomique, Assistance Publique H\u00f4pitaux de Paris (AP-HP), Universit\u00e9 de Paris, H\u00f4pital Cochin, Paris, F-75014, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Louis","sequence":"additional","affiliation":[{"name":"Institut Mondor de Recherche Biom\u00e9dicale, Universit\u00e9 Paris-Est Cr\u00e9teil, Inserm U955, CNRS ERL7240, H\u00f4pital Henri-Mondor, Cr\u00e9teil, F-94010, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Chantot-Bastaraud","sequence":"additional","affiliation":[{"name":"Childhood Genetic Diseases, Sorbonne Universit\u00e9, Inserm, H\u00f4pital Armand-Trousseau, Paris, F-75012, France"},{"name":"G\u00e9n\u00e9tique chromosomique, AP-HP, H\u00f4pital Trousseau, Paris, F-75012, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Pierre","family":"Siffroi","sequence":"additional","affiliation":[{"name":"Childhood Genetic Diseases, Sorbonne Universit\u00e9, Inserm, H\u00f4pital Armand-Trousseau, Paris, F-75012, France"},{"name":"G\u00e9n\u00e9tique chromosomique, AP-HP, H\u00f4pital Trousseau, Paris, F-75012, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rana","family":"Mitri","sequence":"additional","affiliation":[{"name":"Service d'Anatomopathologie, Laboratoire de Microscopie Electronique, Centre Hospitalier Intercommunal de Cr\u00e9teil, Cr\u00e9teil, F-94000, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9","family":"Coste","sequence":"additional","affiliation":[{"name":"Institut Mondor de Recherche Biom\u00e9dicale, Universit\u00e9 Paris-Est Cr\u00e9teil, Inserm U955, CNRS ERL7240, H\u00f4pital Henri-Mondor, Cr\u00e9teil, F-94010, France"},{"name":"Service d\u2019ORL et de Chirurgie Cervico-Faciale, AP-HP, H\u00f4pital Henri-Mondor, Centre Hospitalier Intercommunal de Cr\u00e9teil, Cr\u00e9teil, F-94000, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estelle","family":"Escudier","sequence":"additional","affiliation":[{"name":"Childhood Genetic Diseases, Sorbonne Universit\u00e9, Inserm, H\u00f4pital Armand-Trousseau, Paris, F-75012, France"},{"name":"G\u00e9n\u00e9tique mol\u00e9culaire, AP-HP, H\u00f4pital Armand-Trousseau, Paris, F-75012, Paris"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guillaume","family":"Thouvenin","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Pneumologie P\u00e9diatrique, Centre National de R\u00e9f\u00e9rence des Maladies Respiratoires Rares RespiRare, AP-HP, Sorbonne Universit\u00e9, H\u00f4pital Armand-Trousseau Hospital, Paris, F-75012, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serge","family":"Amselem","sequence":"additional","affiliation":[{"name":"Childhood Genetic Diseases, Sorbonne Universit\u00e9, Inserm, H\u00f4pital Armand-Trousseau, Paris, F-75012, France"},{"name":"G\u00e9n\u00e9tique mol\u00e9culaire, AP-HP, H\u00f4pital Armand-Trousseau, Paris, F-75012, Paris"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Legendre","sequence":"additional","affiliation":[{"name":"Childhood Genetic Diseases, Sorbonne Universit\u00e9, Inserm, H\u00f4pital Armand-Trousseau, Paris, F-75012, France"},{"name":"G\u00e9n\u00e9tique mol\u00e9culaire, AP-HP, H\u00f4pital Armand-Trousseau, Paris, F-75012, Paris"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2024,2,26]]},"reference":[{"key":"2025100521530101000_61.6.595.1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.02595"},{"key":"2025100521530101000_61.6.595.2","doi-asserted-by":"crossref","DOI":"10.1183\/13993003.01090-2016","article-title":"European respiratory society guidelines for the diagnosis of primary Ciliary dyskinesia","volume":"49","author":"Lucas","year":"2017","journal-title":"Eur Respir J"},{"key":"2025100521530101000_61.6.595.3","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-019-03389-7"},{"key":"2025100521530101000_61.6.595.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2020.11.007"},{"key":"2025100521530101000_61.6.595.5","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2005.034868"},{"key":"2025100521530101000_61.6.595.6","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2018-105918"},{"key":"2025100521530101000_61.6.595.7","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms14279","article-title":"X-linked primary Ciliary dyskinesia due to mutations in the cytoplasmic Axonemal Dynein assembly factor Pih1D3","volume":"8","author":"Olcese","year":"2017","journal-title":"Nat Commun"},{"key":"2025100521530101000_61.6.595.8","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-020-0779-4"},{"key":"2025100521530101000_61.6.595.9","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1016\/j.anl.2021.03.012","article-title":"A pediatric case of primary Ciliary dyskinesia caused by novel copy number variation in Pih1D3","volume":"49","author":"Xu","year":"2022","journal-title":"Auris Nasus Larynx"},{"key":"2025100521530101000_61.6.595.10","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-009-0670-5"},{"key":"2025100521530101000_61.6.595.11","doi-asserted-by":"publisher","DOI":"10.1038\/190372a0"},{"key":"2025100521530101000_61.6.595.12","doi-asserted-by":"publisher","DOI":"10.1101\/sqb.2010.75.032"},{"key":"2025100521530101000_61.6.595.13","doi-asserted-by":"crossref","DOI":"10.1186\/1750-1172-7-78","article-title":"Quantitative analysis of Ciliary beating in primary Ciliary dyskinesia: a pilot study","volume":"7","author":"Papon","year":"2012","journal-title":"Orphanet J Rare Dis"},{"key":"2025100521530101000_61.6.595.14","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm\/147.4.908"},{"key":"2025100521530101000_61.6.595.15","doi-asserted-by":"publisher","DOI":"10.1034\/j.1399-3003.2000.15b24.x"},{"key":"2025100521530101000_61.6.595.16","doi-asserted-by":"publisher","DOI":"10.1086\/301651"},{"key":"2025100521530101000_61.6.595.17","first-page":"135","article-title":"Sex Chromatin and gene action in the mammalian X-Chromosome","volume":"14","author":"LYON","year":"1962","journal-title":"Am J Hum Genet"},{"key":"2025100521530101000_61.6.595.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2017.09.005"},{"key":"2025100521530101000_61.6.595.19","doi-asserted-by":"publisher","DOI":"10.1080\/080352502762458030"},{"key":"2025100521530101000_61.6.595.20","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1016\/j.oret.2019.11.010","article-title":"X-Chromosome inactivation is a biomarker of clinical severity in female carriers of RPGR-associated X-linked Retinitis Pigmentosa","volume":"4","author":"Fahim","year":"2020","journal-title":"Ophthalmol Retina"},{"key":"2025100521530101000_61.6.595.21","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/S0002-9297(07)64075-0","article-title":"Nonrandom X-Chromosome inactivation in hemopoietic cells from carriers of Dyskeratosis Congenita","volume":"61","author":"Ferraris","year":"1997","journal-title":"Am J Hum Genet"},{"key":"2025100521530101000_61.6.595.22","first-page":"1136","article-title":"X-linked alpha-Thalassemia\/mental retardation (ATR-X) syndrome: localization to Xq12-Q21.31 by X inactivation and linkage analysis","volume":"51","author":"Gibbons","year":"1992","journal-title":"Am J Hum Genet"},{"key":"2025100521530101000_61.6.595.23","doi-asserted-by":"crossref","first-page":"1735","DOI":"10.1182\/blood.V72.5.1735.1735","article-title":"Carrier detection in the Wiskott Aldrich syndrome","volume":"72","author":"Fearon","year":"1988","journal-title":"Blood"},{"key":"2025100521530101000_61.6.595.24","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1046\/j.1440-1754.1998.00216.x","article-title":"Carrier identification in X-linked immunodeficiency diseases","volume":"34","author":"Li","year":"1998","journal-title":"J Paediatr Child Health"},{"key":"2025100521530101000_61.6.595.25","first-page":"4806","article-title":"Clonal analysis using recombinant DNA probes from the X-Chromosome","volume":"47","author":"Vogelstein","year":"1987","journal-title":"Cancer Res"},{"key":"2025100521530101000_61.6.595.26","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1055\/s-0037-1613833","article-title":"Absence of correlation between X Chromosome inactivation pattern and plasma concentration of factor VIII and factor IX in carriers of Haemophilia A and B","volume":"83","author":"Orstavik","year":"2000","journal-title":"Thromb Haemost"},{"key":"2025100521530101000_61.6.595.27","doi-asserted-by":"publisher","DOI":"10.1080\/08035320600618809"},{"key":"2025100521530101000_61.6.595.28","doi-asserted-by":"publisher","DOI":"10.1507\/endocrj.K07-083"},{"key":"2025100521530101000_61.6.595.29","unstructured":"Niermeijer MF . Mental status of females with an Fmr1 gene full Mutation B. B. A. de Vries,\u2019 A. M. Wiegers,3 A. P. T. Smits,4 S. Mohkamsing,1 H. J. Duivenvoorden,2 J.-P. Fryns,5 L. M. G. Curfs,3,* D. J. J. Halley,\u2019 B. A. Oostra,\u2019 A. M. W. Van den Ouweland. Am J Hum Genet 1996:8."},{"key":"2025100521530101000_61.6.595.30","doi-asserted-by":"crossref","DOI":"10.3389\/fgene.2020.00101","article-title":"Skewed X-Chromosome inactivation and compensatory upregulation of escape genes Precludes major clinical symptoms in a female with a large Xq deletion","volume":"11","author":"Santos-Rebou\u00e7as","year":"2020","journal-title":"Front Genet"},{"key":"2025100521530101000_61.6.595.31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/BF00281002","article-title":"Abnormal X Chromosomes in man: origin, behavior and effects","volume":"25","author":"Therman","year":"1974","journal-title":"Hum Genet"},{"key":"2025100521530101000_61.6.595.32","first-page":"69","article-title":"X -Chromosome activity in female Mouse embryos heterozygous for Pgk-1 and Searle\u2019s translocation","volume":"14","author":"McMahon","year":"1993","journal-title":"Genet Res"},{"key":"2025100521530101000_61.6.595.33","doi-asserted-by":"publisher","DOI":"10.1006\/geno.2001.6611"},{"key":"2025100521530101000_61.6.595.34","doi-asserted-by":"publisher","DOI":"10.1055\/s-2001-15395"},{"key":"2025100521530101000_61.6.595.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.11.019"},{"key":"2025100521530101000_61.6.595.36","doi-asserted-by":"crossref","first-page":"330","DOI":"10.4103\/aja.aja_43_20","article-title":"Novel deletion mutations of the Pih1D3 gene in an infertile young man with primary Ciliary dyskinesia and his cousin with Kartagener\u2019s syndrome","volume":"23","author":"Huang","year":"2021","journal-title":"Asian J Androl"},{"key":"2025100521530101000_61.6.595.37","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1007\/s10815-020-01735-4","article-title":"Novel Dnaaf6 variants identified by whole-Exome sequencing cause male infertility and primary Ciliary dyskinesia","volume":"37","author":"Wang","year":"2020","journal-title":"J Assist Reprod Genet"},{"key":"2025100521530101000_61.6.595.38","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1009306","article-title":"Defects in the cytoplasmic assembly of Axonemal Dynein arms cause morphological abnormalities and Dysmotility in Sperm cells leading to male infertility","volume":"17","author":"Aprea","year":"2021","journal-title":"PLoS Genet"}],"container-title":["Journal of Medical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jmg-2023-109700","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T04:53:11Z","timestamp":1759726391000},"score":1,"resource":{"primary":{"URL":"https:\/\/jmg.bmj.com\/lookup\/doi\/10.1136\/jmg-2023-109700"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,26]]},"references-count":38,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2024,5,21]]},"published-print":{"date-parts":[[2024,6]]}},"alternative-id":["10.1136\/jmg-2023-109700"],"URL":"https:\/\/doi.org\/10.1136\/jmg-2023-109700","relation":{},"ISSN":["0022-2593","1468-6244"],"issn-type":[{"value":"0022-2593","type":"print"},{"value":"1468-6244","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,26]]}}}