{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T02:26:07Z","timestamp":1791167167907,"version":"4.1.0"},"reference-count":87,"publisher":"Oxford University Press (OUP)","issue":"21","license":[{"start":{"date-parts":[[2023,8,9]],"date-time":"2023-08-09T00:00:00Z","timestamp":1691539200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Wellcome Trust Collaborative Award in Science","award":["210585\/Z\/18\/Z"],"award-info":[{"award-number":["210585\/Z\/18\/Z"]}]},{"name":"Kerstan Foundation"},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["210585\/B\/18\/Z"],"award-info":[{"award-number":["210585\/B\/18\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Community","award":["H-2020-MSCA-ITN-2019"],"award-info":[{"award-number":["H-2020-MSCA-ITN-2019"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,10,17]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Ciliopathies are inherited disorders caused by defective cilia. Mutations affecting motile cilia usually cause the chronic muco-obstructive sinopulmonary disease primary ciliary dyskinesia (PCD) and are associated with laterality defects, while a broad spectrum of early developmental as well as degenerative syndromes arise from mutations affecting signalling of primary (non-motile) cilia. Cilia assembly and functioning requires intraflagellar transport (IFT) of cargos assisted by IFT-B and IFT-A adaptor complexes. Within IFT-B, the N-termini of partner proteins IFT74 and IFT81 govern tubulin transport to build the ciliary microtubular cytoskeleton. We detected a homozygous 3-kb intragenic IFT74 deletion removing the exon 2 initiation codon and 40\u00a0N-terminal amino acids in two affected siblings. Both had clinical features of PCD with bronchiectasis, but no laterality defects. They also had retinal dysplasia and abnormal bone growth, with a narrowed thorax and short ribs, shortened long bones and digits, and abnormal skull shape. This resembles short-rib thoracic dysplasia, a skeletal ciliopathy previously linked to IFT defects in primary cilia, not motile cilia. Ciliated nasal epithelial cells collected from affected individuals had reduced numbers of shortened motile cilia with disarranged microtubules, some misorientation of the basal feet, and disrupted cilia structural and IFT protein distributions. No full-length IFT74 was expressed, only truncated forms that were consistent with N-terminal deletion and inframe translation from downstream initiation codons. In affinity purification mass spectrometry, exon 2-deleted IFT74 initiated from the nearest inframe downstream methionine 41 still interacts as part of the IFT-B complex, but only with reduced interaction levels and not with all its usual IFT-B partners. We propose that this is a hypomorphic mutation with some residual protein function retained, which gives rise to a primary skeletal ciliopathy combined with defective motile cilia and PCD.<\/jats:p>","DOI":"10.1093\/hmg\/ddad132","type":"journal-article","created":{"date-parts":[[2023,8,9]],"date-time":"2023-08-09T13:15:34Z","timestamp":1691586934000},"page":"3090-3104","source":"Crossref","is-referenced-by-count":12,"title":["Defective airway intraflagellar transport underlies a combined motile and primary ciliopathy syndrome caused by<i>IFT74<\/i>mutations"],"prefix":"10.1093","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2568-8326","authenticated-orcid":false,"given":"Mahmoud R","family":"Fassad","sequence":"first","affiliation":[{"name":"Genetics and Genomic Medicine Research and Teaching Department, University College London, UCL Great Ormond Street Institute of Child Health , 30 Guilford Street, London WC1N 1EH , United Kingdom"},{"name":"Department of Human Genetics, Medical Research Institute, Alexandria University , 22 El-Guish Road, El-Shatby, Alexandria 21526 , Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6493-1515","authenticated-orcid":false,"given":"Nisreen","family":"Rumman","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine, Makassed Hospital and Al-Quds University , East Jerusalem 91220 , Palestine"},{"name":"Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale University School of Medicine , 300 Cedar St #441, New Haven, CT 06520 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrin","family":"Junger","sequence":"additional","affiliation":[{"name":"Institute for Ophthalmic Research, Eberhard Karl University of T\u00fcbingen , Elfreide-Alhorn-Strasse 5-7, T\u00fcbingen 72076 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8098-2344","authenticated-orcid":false,"given":"Mitali P","family":"Patel","sequence":"additional","affiliation":[{"name":"Genetics and Genomic Medicine Research and Teaching Department, University College London, UCL Great Ormond Street Institute of Child Health , 30 Guilford Street, London WC1N 1EH , United Kingdom"},{"name":"MRC Prion Unit at UCL, Institute of Prion Diseases, University College London , 33 Cleveland Street, London W1W 7FF , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Thompson","sequence":"additional","affiliation":[{"name":"Primary Ciliary Dyskinesia Centre , NIHR Biomedical Research Centre, , Southampton SO16 6YD , United Kingdom"},{"name":"University Hospital Southampton NHS Foundation Trust , NIHR Biomedical Research Centre, , Southampton SO16 6YD , United Kingdom"},{"name":"School of Clinical and Experimental Sciences, University of Southampton Faculty of Medicine , University Road, Southampton SO17 1BJ , United Kingdom"},{"name":"Biomedical Imaging Unit, University of Southampton Faculty of Medicine , University Road, Southampton SO17 1BJ , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Goggin","sequence":"additional","affiliation":[{"name":"Primary Ciliary Dyskinesia Centre , NIHR Biomedical Research Centre, , Southampton SO16 6YD , United Kingdom"},{"name":"University Hospital Southampton NHS Foundation Trust , NIHR Biomedical Research Centre, , Southampton SO16 6YD , United Kingdom"},{"name":"Biomedical Imaging Unit, University of Southampton Faculty of Medicine , University Road, Southampton SO17 1BJ , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marius","family":"Ueffing","sequence":"additional","affiliation":[{"name":"Institute for Ophthalmic Research, Eberhard Karl University of T\u00fcbingen , Elfreide-Alhorn-Strasse 5-7, T\u00fcbingen 72076 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6302-8997","authenticated-orcid":false,"given":"Tina","family":"Beyer","sequence":"additional","affiliation":[{"name":"Institute for Ophthalmic Research, Eberhard Karl University of T\u00fcbingen , Elfreide-Alhorn-Strasse 5-7, T\u00fcbingen 72076 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karsten","family":"Boldt","sequence":"additional","affiliation":[{"name":"Institute for Ophthalmic Research, Eberhard Karl University of T\u00fcbingen , Elfreide-Alhorn-Strasse 5-7, T\u00fcbingen 72076 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8701-9975","authenticated-orcid":false,"given":"Jane S","family":"Lucas","sequence":"additional","affiliation":[{"name":"Primary Ciliary Dyskinesia Centre , NIHR Biomedical Research Centre, , Southampton SO16 6YD , United Kingdom"},{"name":"University Hospital Southampton NHS Foundation Trust , NIHR Biomedical Research Centre, , Southampton SO16 6YD , United Kingdom"},{"name":"School of Clinical and Experimental Sciences, University of Southampton Faculty of Medicine , University Road, Southampton SO17 1BJ , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3163-6293","authenticated-orcid":false,"given":"Hannah M","family":"Mitchison","sequence":"additional","affiliation":[{"name":"Genetics and Genomic Medicine Research and Teaching Department, University College London, UCL Great Ormond Street Institute of Child Health , 30 Guilford Street, London WC1N 1EH , United 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