Mutations in CCNO result in congenital mucociliary clearance disorder with reduced generation of multiple motile cilia

Nat Genet. 2014 Jun;46(6):646-51. doi: 10.1038/ng.2961.

Julia Wallmeier ¹, Dalal A Al-Mutairi ², Chun-Ting Chen ³, Niki Tomas Loges ⁴, Petra Pennekamp ⁴, Tabea Menchen ⁴, Lina Ma ³, Hanan E Shamseldin ⁵, Heike Olbrich ⁴, Gerard W Dougherty ⁴, Claudius Werner ⁴, Basel H Alsabah ⁶, Gabriele Köhler ⁷, Martine Jaspers ⁸, Mieke Boon ⁹, Matthias Griese ¹⁰, Sabina Schmitt-Grohé ¹¹, Theodor Zimmermann ¹², Cordula Koerner-Rettberg ¹³, Elisabeth Horak ¹⁴, Chris Kintner ³, Fowzan S Alkuraya ¹⁵, Heymut Omran ⁴

Affiliations

1 1] Department of Pediatrics, University Hospital Muenster, Muenster, Germany. [2].
2 1] Department of Pathology, Faculty of Medicine, Health Sciences Center, Kuwait University, Safat, Kuwait. [2].
3 Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, San Diego, California, USA.
4 Department of Pediatrics, University Hospital Muenster, Muenster, Germany.
5 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
6 Zain Hospital for Ear, Nose and Throat, Shuwaikh, Kuwait City, Kuwait.
7 Department of Pathology, University Hospital Muenster, Muenster, Germany.
8 Department of Otorhinolaryngology, University Hospital Leuven, Leuven, Belgium.
9 Department of Pediatrics, Pediatric Pulmonology, University Hospital of Leuven, Leuven, Belgium.
10 Department of Pediatric Pulmonology, Hauner Children's Hospital, Ludwig Maximilians University, Member of the German Center for Lung Research (DZL), Munich, Germany.
11 Department of Pediatrics, Pediatric Pulmonology, University Hospital Bonn, Bonn, Germany.
12 Department of Pediatrics, Pediatric Pulmonology, University Hospital, Erlangen, Germany.
13 Department of Pediatrics and Adolescent Medicine, St. Josef Hospital, Ruhr-Universität Bochum, Bochum, Germany.
14 Department of Pediatrics and Adolescents, Division of Cardiology and Pulmonology, Innsbruck Medical University, Innsbruck, Austria.
15 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.

PMID: 24747639 DOI: 10.1038/ng.2961

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.

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