title: MCIDAS mutations result in a mucociliary clearance disorder with reduced generation of multiple motile cilia.
abstract: Reduced generation of multiple motile cilia (RGMC) is a rare mucociliary clearance disorder. Affected persons suffer from recurrent infections of upper and lower airways because of highly reduced numbers of multiple motile respiratory cilia. Here we report recessive loss-of-function and missense mutations in MCIDAS-encoding Multicilin, which was shown to promote the early steps of multiciliated cell differentiation in Xenopus. MCIDAS mutant respiratory epithelial cells carry only one or two cilia per cell, which lack ciliary motility-related proteins (DNAH5; CCDC39) as seen in primary ciliary dyskinesia. Consistent with this finding, FOXJ1-regulating axonemal motor protein expression is absent in respiratory cells of MCIDAS mutant individuals. CCNO, when mutated known to cause RGMC, is also absent in MCIDAS mutant respiratory cells, consistent with its downstream activity. Thus, our findings identify Multicilin as a key regulator of CCNO/FOXJ1 for human multiciliated cell differentiation, and highlight the 5q11 region containing CCNO and MCIDAS as a locus underlying RGMC.
authors.affiliation: 1] Department of Pediatrics, Pediatric Pulmonology, University Hospital of Leuven, Leuven 3000, Belgium [2].
authors.forename: Mieke
authors.initials: M
authors.lastname: Boon
authors.affiliation: 1] Department of Pediatrics, University Hospital Muenster, 48149 Muenster, Germany [2].
authors.forename: Julia
authors.initials: J
authors.lastname: Wallmeier
authors.affiliation: Molecular Neurobiology Laboratory, Salk Institute for Biological Studies, San Diego, California 92186, USA.
authors.forename: Lina
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Pediatrics, University Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Niki Tomas
authors.initials: NT
authors.lastname: Loges
authors.affiliation: Department of Otorhinolaryngology, University Hospital Leuven, 3000 Leuven, Belgium.
authors.forename: Martine
authors.initials: M
authors.lastname: Jaspers
authors.affiliation: Department of Pediatrics, University Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Olbrich
authors.affiliation: Department of Pediatrics, University Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Gerard W
authors.initials: GW
authors.lastname: Dougherty
authors.affiliation: Department of Pediatrics, University Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Raidt
authors.affiliation: Department of Pediatrics, University Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Claudius
authors.initials: C
authors.lastname: Werner
authors.affiliation: Department of Pediatric, Ziv Medical Center, Faculty of Medicine, Bar IIan University, Safed 13100, Israel.
authors.forename: Israel
authors.initials: I
authors.lastname: Amirav
authors.affiliation: Institute of Pulmonology, Hadassah-Hebrew University Medical Centers, Jerusalem, Israel 91120.
authors.forename: Avigdor
authors.initials: A
authors.lastname: Hevroni
authors.affiliation: Department of Pediatric, Ziv Medical Center, Faculty of Medicine, Bar IIan University, Safed 13100, Israel.
authors.forename: Revital
authors.initials: R
authors.lastname: Abitbul
authors.affiliation: Institute of Pulmonology, Hadassah-Hebrew University Medical Centers, Jerusalem, Israel 91120.
authors.forename: Avraham
authors.initials: A
authors.lastname: Avital
authors.affiliation: Department of Pediatric Pulmonology, Critical Care and Sleep Medicine, Dana Children's Hospital, Tel Aviv Sourasky Medical Center, 6 Weizman Street, Tel Aviv 64239, Israel.
authors.forename: Ruth
authors.initials: R
authors.lastname: Soferman
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Center, 3000 CA Rotterdam, the Netherlands.
authors.forename: Marja
authors.initials: M
authors.lastname: Wessels
authors.affiliation: 1] Respiratory, Critical Care and Anaesthesia Unit, Institute of Child Health, University College London, Great Ormond Street Children's Hospital, 30 Guilford Street, London WC1N 1EH, UK [2] Centre for PCD Diagnosis and Research, Department of Infection, Immunity and Inflammation, RKCSB, University of Leicester, Leicester LE2 7LX, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: O'Callaghan
authors.affiliation: General and Adolescent Paediatric Unit, UCL Institute of Children Health, University College London, 30 Guilford Street, London WC1N 1EH, UK.
authors.forename: Eddie M K
authors.initials: EM
authors.lastname: Chung
authors.affiliation: Centre for PCD Diagnosis and Research, Department of Infection, Immunity and Inflammation, RKCSB, University of Leicester, Leicester LE2 7LX, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Rutman
authors.affiliation: Centre for PCD Diagnosis and Research, Department of Infection, Immunity and Inflammation, RKCSB, University of Leicester, Leicester LE2 7LX, UK.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hirst
authors.affiliation: Division of Services for Women and Children, Women's and Newborn Unit Bradford Royal Infirmary, University of Bradford, West Yorkshire BD9 6RJ, UK.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Moya
authors.affiliation: Molecular Medicine Unit, Birth Defects Research Centre, Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Mitchison
authors.affiliation: Department of Pediatrics, Pediatric Pulmonology, University Hospital Ghent, 9000 Ghent, Belgium.
authors.forename: Sabine
authors.initials: S
authors.lastname: Van Daele
authors.affiliation: Department of Pediatrics, Pediatric Pulmonology, University Hospital of Leuven, Leuven 3000, Belgium.
authors.forename: Kris
authors.initials: K
authors.lastname: De Boeck
authors.affiliation: Department of Otorhinolaryngology, University Hospital Leuven, 3000 Leuven, Belgium.
authors.forename: Mark
authors.initials: M
authors.lastname: Jorissen
authors.affiliation: Molecular Neurobiology Laboratory, Salk Institute for Biological Studies, San Diego, California 92186, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Kintner
authors.affiliation: Department of Pediatrics, Pediatric Pulmonology, University Hospital of Leuven, Leuven 3000, Belgium.
authors.forename: Harry
authors.initials: H
authors.lastname: Cuppens
authors.affiliation: Department of Pediatrics, University Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Heymut
authors.initials: H
authors.lastname: Omran
mesh_terms: D000328:Adult; D064199:Cdc20 Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002895:Chromosomes, Human, Pair 5; D002923:Cilia / Q000473:pathology / Q000648:ultrastructure; D002925:Ciliary Motility Disorders / Q000209:etiology / Q000235:genetics*; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007619:Kartagener Syndrome / Q000235:genetics; D008297:Male; D046529:Microscopy, Electron, Transmission; D009079:Mucociliary Clearance / Q000235:genetics; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D014157:Transcription Factors; D055815:Young Adult
chemical_list: D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins; C106349:FOXJ1 protein, human; D051858:Forkhead Transcription Factors; C560898:MCIDAS protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors; C492570:CCNO protein, human; D045647:DNA Glycosylases