Volume 2 Supplement 1

Abstracts of the 51st Workshop for Pediatric Research

Open Access

Mutations in CCNO and MCIDAS lead to a mucociliary clearance disorder due to reduced generation of multiple motile cilia

  • J Wallmeier1,
  • M Boon2,
  • D Al Mutairi3,
  • NT Loges1,
  • L Ma4,
  • C-T Chen4,
  • H Olbrich1,
  • P Pennekamp1,
  • T Menchen1,
  • G Dougherty1,
  • C Werner1,
  • M Jaspers5,
  • M Griese6,
  • E Horak7,
  • C Körner-Rettberg8,
  • S Schmitt-Grohé9,
  • T Zimmermann10,
  • A Hevroni11,
  • R Abitbul12,
  • A Avital11,
  • R Soferman13,
  • I Amirav12,
  • H Mitchison14,
  • M Jorissen5,
  • F Alkuraya15, 16,
  • C Kintner4 and
  • H Omran1
Molecular and Cellular Pediatrics20152(Suppl 1):A15

https://doi.org/10.1186/2194-7791-2-S1-A15

Published: 1 July 2015

Meeting abstract

Since the 1980s, a few case reports described patients with oto-rhino-pulmonary symptoms and respiratory epithelia lacking cilia who were subsequently diagnosed to suffer from "ciliary aplasia" or "acilia syndrome". Via a whole exome sequencing approach, we analyzed "ciliary aplasia" candidates (including patients from previous reports) and identified recessive mutations in CCNO (encoding Cyclin O) and MCIDAS (encoding Multicilin) in 9 and 16 individuals, respectively [1, 2]. All individuals suffered from severe respiratory symptoms of the upper and lower airways and development of bronchiectasis at an early age. Thorough analysis of respiratory epithelial cells obtained by nasal brush biopsy by both transmission electron microscopy (TEM) and immunofluorescence analysis (IF) revealed that respiratory cilia were not completely absent; some cells still retained one or two cilia. These cells not only showed a reduction of cilia by TEM and IF, but also a reduction and mislocalization of basal bodies and rootlets throughout the cytoplasm. Detailed analyses by IF in both man and Xenopus revealed that this reduction of cilia number was due to a centriole amplification defect in the acentriolar pathway, which is specific for multiciliated cells [1, 2].

IF showed that MCIDAS functions upstream of CCNO and FOXJ1, which is important for transcriptional control of axonemal motor proteins such as DNAH5 and CCDC39. Whereas cilia in CCNO-mutant cells still contain motility-related proteins such as DNAH5 and CCDC39 and can display normal beating patterns, MCIDAS-mutant cells are immotile and lack those axonemal motor proteins [1, 2] .

MCIDAS and CCNO lie adjacently on chromosome 5q11 in a region related to multiciliogenesis, and act in the same pathway underlying multiciliogenesis. Based on these findings, we propose that this disease now should be referred to as "mucociliary clearance disorder with reduced generation of multiple motile cilia" (RGMC).

Authors’ Affiliations

(1)
General Pediatrics, University Hospital Münster
(2)
Department of Pediatrics, Pediatric Pulmonology, University Hospital of Leuven
(3)
Department of Pathology, Faculty of Medicine, Health Sciences Center, Kuwait University
(4)
Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies
(5)
Department of Otorhinolaryngology, Head & Neck Surgery, University Hospital Leuven
(6)
Department of Pediatric Pulmonology, Hauner Children's Hospital, Member of the German Center for Lung Research (DZL), Ludwig Maximilians University
(7)
Department of Pediatrics and Adolescents, Division of Cardiology and Pulmonology, Innsbruck Medical University
(8)
Department of Pediatrics and Adolescent Medicine, St. Josef Hospital, Ruhr-Universität Bochum
(9)
Department of Pediatrics, Pediatric Pulmonology, University Hospital Bonn
(10)
Department of Pediatrics, Pediatric Pulmonology, University Hospital
(11)
Institute of Pulmonology, Hadassah-Hebrew University Medical Centers
(12)
Department of Pediatric, Ziv Medical Center, Faculty of Medicine, Bar IIan University
(13)
Department of Pediatric Pulmonology, Critical Care and Sleep Medicine, Dana Children's Hospital, Tel Aviv Sourasky Medical Center
(14)
Molecular Medicine Unit, Birth Defects Research Centre, Institute of Child Health, University College London
(15)
Department of Genetics, King Faisal Specialist Hospital and Research Center
(16)
Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University

References

  1. Wallmeier J, Al-Mutairi DA, Chen C-T, Loges NT, Pennekamp P, Menchen T, et al.: Mutations in CCNO result in congenital mucociliary clearance disorder with reduced generation of multiple motile cilia. Nature Genetics 2014,46(6):646–51. 10.1038/ng.2961PubMedView ArticleGoogle Scholar
  2. Boon M, Wallmeier J, Ma L, Loges NT, Jaspers M, Olbrich H, et al.: MCIDAS mutations result in a mucociliary clearance disorder with reduced generation of multiple motile cilia. Nat Commun 2014, 5: 4418.PubMedView ArticleGoogle Scholar

Copyright

© Wallmeier et al. 2015

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.