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

Nat Commun. 2014 Jul 22;5:4418. doi: 10.1038/ncomms5418.

Mieke Boon ¹, Julia Wallmeier ², Lina Ma ³, Niki Tomas Loges ⁴, Martine Jaspers ⁵, Heike Olbrich ⁴, Gerard W Dougherty ⁴, Johanna Raidt ⁴, Claudius Werner ⁴, Israel Amirav ⁶, Avigdor Hevroni ⁷, Revital Abitbul ⁶, Avraham Avital ⁷, Ruth Soferman ⁸, Marja Wessels ⁹, Christopher O'Callaghan ¹⁰, Eddie M K Chung ¹¹, Andrew Rutman ¹², Robert A Hirst ¹², Eduardo Moya ¹³, Hannah M Mitchison ¹⁴, Sabine Van Daele ¹⁵, Kris De Boeck ¹⁶, Mark Jorissen ⁵, Chris Kintner ³, Harry Cuppens ¹⁶, Heymut Omran ⁴

Affiliations

1 1] Department of Pediatrics, Pediatric Pulmonology, University Hospital of Leuven, Leuven 3000, Belgium [2].
2 1] Department of Pediatrics, University Hospital Muenster, 48149 Muenster, Germany [2].
3 Molecular Neurobiology Laboratory, Salk Institute for Biological Studies, San Diego, California 92186, USA.
4 Department of Pediatrics, University Hospital Muenster, 48149 Muenster, Germany.
5 Department of Otorhinolaryngology, University Hospital Leuven, 3000 Leuven, Belgium.
6 Department of Pediatric, Ziv Medical Center, Faculty of Medicine, Bar IIan University, Safed 13100, Israel.
7 Institute of Pulmonology, Hadassah-Hebrew University Medical Centers, Jerusalem, Israel 91120.
8 Department of Pediatric Pulmonology, Critical Care and Sleep Medicine, Dana Children's Hospital, Tel Aviv Sourasky Medical Center, 6 Weizman Street, Tel Aviv 64239, Israel.
9 Department of Clinical Genetics, Erasmus Medical Center, 3000 CA Rotterdam, the Netherlands.
10 1] Respiratory, Critical Care and Anaesthesia Unit, Institute of Child Health, University College London, Great Ormond Street Children's Hospital, 30 Guilford Street, London WC1N 1EH, UK [2] Centre for PCD Diagnosis and Research, Department of Infection, Immunity and Inflammation, RKCSB, University of Leicester, Leicester LE2 7LX, UK.
11 General and Adolescent Paediatric Unit, UCL Institute of Children Health, University College London, 30 Guilford Street, London WC1N 1EH, UK.
12 Centre for PCD Diagnosis and Research, Department of Infection, Immunity and Inflammation, RKCSB, University of Leicester, Leicester LE2 7LX, UK.
13 Division of Services for Women and Children, Women's and Newborn Unit Bradford Royal Infirmary, University of Bradford, West Yorkshire BD9 6RJ, UK.
14 Molecular Medicine Unit, Birth Defects Research Centre, Institute of Child Health, University College London, London WC1N 1EH, UK.
15 Department of Pediatrics, Pediatric Pulmonology, University Hospital Ghent, 9000 Ghent, Belgium.
16 Department of Pediatrics, Pediatric Pulmonology, University Hospital of Leuven, Leuven 3000, Belgium.

PMID: 25048963 DOI: 10.1038/ncomms5418

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.

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