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 MoyaHannah M. Mitchison, Sabine Van Daele, Kris De Boeck, Mark Jorissen, Chris Kintner, Harry Cuppens, Heymut Omran*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number4418
JournalNature Communications
Volume5
DOIs
StatePublished - 22 Jul 2014
Externally publishedYes

Funding

FundersFunder number
BESTCILIA305404
Fonds Alphonse en Jean Forton
Interdisziplinaeres Zentrum für Klinische ForschungIZKF Om2/009/12
Kindness for Kids2011-R10150-003
Schroeder Stiftung
National Institutes of Health
National Institute of General Medical SciencesR01GM096021
Action Medical ResearchGN2101
Deutsche ForschungsgemeinschaftOm 6/5, DFG Om 6/4
Agentschap voor Innovatie door Wetenschap en TechnologieO&O 100500
Fondation Milena Carvajal - Pro-Kartagener
Seventh Framework Programme241955
Koning Boudewijnstichting

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