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MCIDAS mutations result in a mucociliary clearance disorder with reduced generation of multiple motile cilia

Author

Listed:
  • Mieke Boon

    (Pediatric Pulmonology, University Hospital of Leuven)

  • Julia Wallmeier

    (University Hospital Muenster)

  • Lina Ma

    (Molecular Neurobiology Laboratory, Salk Institute for Biological Studies)

  • Niki Tomas Loges

    (University Hospital Muenster)

  • Martine Jaspers

    (University Hospital Leuven)

  • Heike Olbrich

    (University Hospital Muenster)

  • Gerard W. Dougherty

    (University Hospital Muenster)

  • Johanna Raidt

    (University Hospital Muenster)

  • Claudius Werner

    (University Hospital Muenster)

  • Israel Amirav

    (Ziv Medical Center, Faculty of Medicine, Bar IIan University)

  • Avigdor Hevroni

    (Institute of Pulmonology, Hadassah-Hebrew University Medical Centers)

  • Revital Abitbul

    (Ziv Medical Center, Faculty of Medicine, Bar IIan University)

  • Avraham Avital

    (Institute of Pulmonology, Hadassah-Hebrew University Medical Centers)

  • Ruth Soferman

    (Critical Care and Sleep Medicine, Dana Children’s Hospital, Tel Aviv Sourasky Medical Center)

  • Marja Wessels

    (Erasmus Medical Center, 3000 CA Rotterdam, the Netherlands)

  • Christopher O’Callaghan

    (Respiratory, Critical Care and Anaesthesia Unit, Institute of Child Health, University College London, Great Ormond Street Children’s Hospital
    Centre for PCD Diagnosis and Research, Immunity and Inflammation, RKCSB, University of Leicester)

  • Eddie M. K. Chung

    (General and Adolescent Paediatric Unit, UCL Institute of Children Health, University College London)

  • Andrew Rutman

    (Centre for PCD Diagnosis and Research, Immunity and Inflammation, RKCSB, University of Leicester)

  • Robert A. Hirst

    (Centre for PCD Diagnosis and Research, Immunity and Inflammation, RKCSB, University of Leicester)

  • Eduardo Moya

    (Women's and Newborn Unit Bradford Royal Infirmary, University of Bradford)

  • Hannah M. Mitchison

    (Molecular Medicine Unit, Birth Defects Research Centre, Institute of Child Health, University College London)

  • Sabine Van Daele

    (Pediatric Pulmonology, University Hospital Ghent)

  • Kris De Boeck

    (Pediatric Pulmonology, University Hospital of Leuven)

  • Mark Jorissen

    (University Hospital Leuven)

  • Chris Kintner

    (Molecular Neurobiology Laboratory, Salk Institute for Biological Studies)

  • Harry Cuppens

    (Pediatric Pulmonology, University Hospital of Leuven)

  • Heymut Omran

    (University Hospital Muenster)

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.

Suggested Citation

  • Mieke Boon & Julia Wallmeier & Lina Ma & Niki Tomas Loges & Martine Jaspers & Heike Olbrich & Gerard W. Dougherty & Johanna Raidt & Claudius Werner & Israel Amirav & Avigdor Hevroni & Revital Abitbul , 2014. "MCIDAS mutations result in a mucociliary clearance disorder with reduced generation of multiple motile cilia," Nature Communications, Nature, vol. 5(1), pages 1-8, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5418
    DOI: 10.1038/ncomms5418
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