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

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, Avraham Avital, Ruth Soferman, Marja Wessels, Christopher O’Callaghan, Eddie M. K. Chung, Andrew Rutman, Robert A. Hirst, Eduardo Moya, Hannah M. Mitchison, Sabine Van Daele, Kris De Boeck, Mark Jorissen, Chris Kintner, Harry Cuppens and Heymut Omran ()
Additional contact information
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
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

Nature Communications, 2014, vol. 5, issue 1, 1-8

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5418

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