Journal Article

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

Omran, Heymut, Olbrich, Heike, Schmitt-Grohé, Sabina, Chen, Chun-Ting, Menchen, Tabea, Alkuraya, Fowzan S, Ma, Lina, Werner, Claudius, Horak, Elisabeth, Griese, Matthias, Alsabah, Basel H, Dougherty, Gerard W, Boon, Mieke, Wallmeier, Julia, Zimmermann, Theodor, Pennekamp, Petra, Jaspers, Martine, Kintner, Chris, Köhler, Gabriele, Koerner-Rettberg, Cordula, Al-Mutairi, Dalal A, Loges, Niki Tomas, Shamseldin, Hanan E

2014

Overview

Heymut Omran and colleagues show that biallelic mutations in CCNO cause a chronic destructive lung disease resulting from loss of multiple motile cilia from the surface of respiratory epithelial cells. Subcellular analyses suggest that CCNO deficiency leads to defective centriole amplification and migration, leading to reduced ciliogenesis. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 101/28 / 38/1 / 45/23 / 64/114 / 692/308/2056 / 692/699/1785 / Adolescent / Adult / Agriculture / Amino Acid Sequence / Animal Genetics and Genomics / Animals / Biomedicine / Biopsy / Cancer Research / Cell Movement / Centrioles - metabolism / Child / Child, Preschool / Cilia - metabolism / Cystic fibrosis / Cytoplasm - metabolism / Defects / Development and progression / DNA Glycosylases - genetics / Experiments / Female / Gene Function / Gene mutations / Genetic aspects / Genomes / Human Genetics / Humans / Identification and classification / Kartagener Syndrome - genetics / letter / Lung diseases / Male / Mice / Microscopy / Models, Genetic / Molecular Sequence Data / Mucociliary Clearance - genetics / Mucociliary system / Mutation / Pedigree / Proteins / Sequence Analysis, DNA / Sequence Homology, Amino Acid / Studies / Xenopus / Xenopus laevis