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; Heymut Omran

doi:10.1038/ncomms5418

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

Bar-Ilan University - Azrieli Faculty of Medicine

Research output: Contribution to journal › Article › peer-review

215 Scopus citations

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 language	English
Article number	4418
Journal	Nature Communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms5418
State	Published - 22 Jul 2014

Bibliographical note

Publisher Copyright:
© 2014 Macmillan Publishers Limited. All rights reserved.

Funding

We thank all the affected patients, their families and their care givers for the participation in the study. We are grateful for the help of the German patient support group ‘Kartagener Syndrom und Primaere Ciliaere Dyskinesie’. We thank Cordula Wester-mann, Cordula Vorspohl, Laura Overkamp, Martina Herting, Simone Helms, Valerie Vlaeminck and Franz-Josef Seesing for their technical assistance. We kindly thank Mitali Patel and Alexandros Onoufriadis for their work. H.M. acknowledges funding from Action Medical Research (GN2101) and the Milena Carvajal Pro-Kartagener Foundation. Work in H. Omran’s lab was funded by the Deutsche Forschungsgemeinschaft (DFG Om 6/4, DFG Om 6/5), by the Interdisziplinaeres Zentrum für Klinische Forschung (IZKF Om2/009/12) Muenster (H. Omran), by the European Community’s Seventh Framework Programme FP7/2009, under grant agreement 241955, SYSCILIA (H. Omran), and BESTCILIA, under grant agreement 305404 (H. Omran), the Schroeder Stiftung (H. Omran) and Kindness for Kids (H. Omran). Work reported here was also supported by grants 2011-R10150-003 (Koning Boudewijnstichting, Fonds Alphonse en Jean Forton), IWT O&O 100500 to H.C., and a NIH grant, GM096021, to C.K.

Funders	Funder number
BESTCILIA	305404
Fonds Alphonse en Jean Forton
Interdisziplinaeres Zentrum für Klinische Forschung	IZKF Om2/009/12
Kindness for Kids	2011-R10150-003
Schroeder Stiftung
National Institutes of Health
National Institute of General Medical Sciences	R01GM096021
Action Medical Research	GN2101
Deutsche Forschungsgemeinschaft	Om 6/5, DFG Om 6/4
Agentschap voor Innovatie door Wetenschap en Technologie	O&O 100500
Fondation Milena Carvajal - Pro-Kartagener
Seventh Framework Programme	241955
Koning Boudewijnstichting

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Boon, M., Wallmeier, J., Ma, L., Loges, N. T., Jaspers, M., Olbrich, H., Dougherty, G. W., Raidt, J., Werner, C., Amirav, I., Hevroni, A., Abitbul, R., Avital, A., Soferman, R., Wessels, M., O'Callaghan, C., Chung, E. M. K., Rutman, A., Hirst, R. A., ... Omran, H. (2014). MCIDAS mutations result in a mucociliary clearance disorder with reduced generation of multiple motile cilia. Nature Communications, 5, Article 4418. https://doi.org/10.1038/ncomms5418

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title = "MCIDAS mutations result in a mucociliary clearance disorder with reduced generation of multiple motile cilia",

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.",

author = "Mieke Boon and Julia Wallmeier and Lina Ma and Loges, \{Niki Tomas\} and Martine Jaspers and Heike Olbrich and Dougherty, \{Gerard W.\} and Johanna Raidt and Claudius Werner and Israel Amirav and Avigdor Hevroni and Revital Abitbul and Avraham Avital and Ruth Soferman and Marja Wessels and Christopher O'Callaghan and Chung, \{Eddie M.K.\} and Andrew Rutman and Hirst, \{Robert A.\} and Eduardo Moya and Mitchison, \{Hannah M.\} and \{Van Daele\}, Sabine and \{De Boeck\}, Kris and Mark Jorissen and Chris Kintner and Harry Cuppens and Heymut Omran",

year = "2014",

month = jul,

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doi = "10.1038/ncomms5418",

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Boon, M, Wallmeier, J, Ma, L, Loges, NT, Jaspers, M, Olbrich, H, Dougherty, GW, Raidt, J, Werner, C, Amirav, I, Hevroni, A, Abitbul, R, Avital, A, Soferman, R, Wessels, M, O'Callaghan, C, Chung, EMK, Rutman, A, Hirst, RA, Moya, E, Mitchison, HM, Van Daele, S, De Boeck, K, Jorissen, M, Kintner, C, Cuppens, H & Omran, H 2014, 'MCIDAS mutations result in a mucociliary clearance disorder with reduced generation of multiple motile cilia', Nature Communications, vol. 5, 4418. https://doi.org/10.1038/ncomms5418

TY - JOUR

T1 - MCIDAS mutations result in a mucociliary clearance disorder with reduced generation of multiple motile cilia

AU - Boon, Mieke

AU - Wallmeier, Julia

AU - Ma, Lina

AU - Loges, Niki Tomas

AU - Jaspers, Martine

AU - Olbrich, Heike

AU - Dougherty, Gerard W.

AU - Raidt, Johanna

AU - Werner, Claudius

AU - Amirav, Israel

AU - Hevroni, Avigdor

AU - Abitbul, Revital

AU - Avital, Avraham

AU - Soferman, Ruth

AU - Wessels, Marja

AU - O'Callaghan, Christopher

AU - Chung, Eddie M.K.

AU - Rutman, Andrew

AU - Hirst, Robert A.

AU - Moya, Eduardo

AU - Mitchison, Hannah M.

AU - Van Daele, Sabine

AU - De Boeck, Kris

AU - Jorissen, Mark

AU - Kintner, Chris

AU - Cuppens, Harry

AU - Omran, Heymut

PY - 2014/7/22

Y1 - 2014/7/22

N2 - 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.

AB - 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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DO - 10.1038/ncomms5418

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C2 - 25048963

AN - SCOPUS:84906274398

SN - 2041-1723

VL - 5

JO - Nature Communications

JF - Nature Communications

M1 - 4418

ER -

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

Abstract

Bibliographical note

Funding

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