title: Mutations in CCNO result in congenital mucociliary clearance disorder with reduced generation of multiple motile cilia.
abstract: Using a whole-exome sequencing strategy, we identified recessive CCNO (encoding cyclin O) mutations in 16 individuals suffering from chronic destructive lung disease due to insufficient airway clearance. Respiratory epithelial cells showed a marked reduction in the number of multiple motile cilia (MMC) covering the cell surface. The few residual cilia that correctly expressed axonemal motor proteins were motile and did not exhibit obvious beating defects. Careful subcellular analyses as well as in vitro ciliogenesis experiments in CCNO-mutant cells showed defective mother centriole generation and placement. Morpholino-based knockdown of the Xenopus ortholog of CCNO also resulted in reduced MMC and centriole numbers in embryonic epidermal cells. CCNO is expressed in the apical cytoplasm of multiciliated cells and acts downstream of multicilin, which governs the generation of multiciliated cells. To our knowledge, CCNO is the first reported gene linking an inherited human disease to reduced MMC generation due to a defect in centriole amplification and migration.
authors.affiliation: 1] Department of Pediatrics, University Hospital Muenster, Muenster, Germany. [2].
authors.forename: Julia
authors.initials: J
authors.lastname: Wallmeier
authors.affiliation: 1] Department of Pathology, Faculty of Medicine, Health Sciences Center, Kuwait University, Safat, Kuwait. [2].
authors.forename: Dalal A
authors.initials: DA
authors.lastname: Al-Mutairi
authors.affiliation: Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, San Diego, California, USA.
authors.forename: Chun-Ting
authors.initials: CT
authors.lastname: Chen
authors.affiliation: Department of Pediatrics, University Hospital Muenster, Muenster, Germany.
authors.forename: Niki Tomas
authors.initials: NT
authors.lastname: Loges
authors.affiliation: Department of Pediatrics, University Hospital Muenster, Muenster, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Pennekamp
authors.affiliation: Department of Pediatrics, University Hospital Muenster, Muenster, Germany.
authors.forename: Tabea
authors.initials: T
authors.lastname: Menchen
authors.affiliation: Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, San Diego, California, USA.
authors.forename: Lina
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Hanan E
authors.initials: HE
authors.lastname: Shamseldin
authors.affiliation: Department of Pediatrics, University Hospital Muenster, Muenster, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Olbrich
authors.affiliation: Department of Pediatrics, University Hospital Muenster, Muenster, Germany.
authors.forename: Gerard W
authors.initials: GW
authors.lastname: Dougherty
authors.affiliation: Department of Pediatrics, University Hospital Muenster, Muenster, Germany.
authors.forename: Claudius
authors.initials: C
authors.lastname: Werner
authors.affiliation: Zain Hospital for Ear, Nose and Throat, Shuwaikh, Kuwait City, Kuwait.
authors.forename: Basel H
authors.initials: BH
authors.lastname: Alsabah
authors.affiliation: Department of Pathology, University Hospital Muenster, Muenster, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Köhler
authors.affiliation: Department of Otorhinolaryngology, University Hospital Leuven, Leuven, Belgium.
authors.forename: Martine
authors.initials: M
authors.lastname: Jaspers
authors.affiliation: Department of Pediatrics, Pediatric Pulmonology, University Hospital of Leuven, Leuven, Belgium.
authors.forename: Mieke
authors.initials: M
authors.lastname: Boon
authors.affiliation: Department of Pediatric Pulmonology, Hauner Children's Hospital, Ludwig Maximilians University, Member of the German Center for Lung Research (DZL), Munich, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Griese
authors.affiliation: Department of Pediatrics, Pediatric Pulmonology, University Hospital Bonn, Bonn, Germany.
authors.forename: Sabina
authors.initials: S
authors.lastname: Schmitt-Grohé
authors.affiliation: Department of Pediatrics, Pediatric Pulmonology, University Hospital, Erlangen, Germany.
authors.forename: Theodor
authors.initials: T
authors.lastname: Zimmermann
authors.affiliation: Department of Pediatrics and Adolescent Medicine, St. Josef Hospital, Ruhr-Universität Bochum, Bochum, Germany.
authors.forename: Cordula
authors.initials: C
authors.lastname: Koerner-Rettberg
authors.affiliation: Department of Pediatrics and Adolescents, Division of Cardiology and Pulmonology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Horak
authors.affiliation: Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, San Diego, California, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Kintner
authors.affiliation: 1] Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. [2] Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
authors.forename: Fowzan S
authors.initials: FS
authors.lastname: Alkuraya
authors.affiliation: Department of Pediatrics, University Hospital Muenster, Muenster, Germany.
authors.forename: Heymut
authors.initials: H
authors.lastname: Omran
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D002465:Cell Movement; D002502:Centrioles / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002923:Cilia / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D045647:DNA Glycosylases / Q000235:genetics*; D005260:Female; D006801:Humans; D007619:Kartagener Syndrome / Q000235:genetics*; D008297:Male; D051379:Mice; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009079:Mucociliary Clearance / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D014982:Xenopus laevis
chemical_list: C492570:CCNO protein, human; D045647:DNA Glycosylases
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