Mutations in CCNO result in congenital mucociliary clearance disorder with reduced generation of multiple motile cilia

Julia Wallmeier; Dalal A. Al-Mutairi; Chun Ting Chen; Niki Tomas Loges; Petra Pennekamp; Tabea Menchen; Lina Ma; Hanan E. Shamseldin; Heike Olbrich; Gerard W. Dougherty; Claudius Werner; Basel H. Alsabah; Gabriele Köhler; Martine Jaspers; Mieke Boon; Matthias Griese; Sabina Schmitt-Grohé; Theodor Zimmermann; Cordula Koerner-Rettberg; Elisabeth Horak; Chris Kintner; Fowzan S. Alkuraya; Heymut Omran

doi:10.1038/ng.2961

Mutations in CCNO result in congenital mucociliary clearance disorder with reduced generation of multiple motile cilia

Julia Wallmeier, Dalal A. Al-Mutairi, Chun Ting Chen, Niki Tomas Loges, Petra Pennekamp, Tabea Menchen, Lina Ma, Hanan E. Shamseldin, Heike Olbrich, Gerard W. Dougherty, Claudius Werner, Basel H. Alsabah, Gabriele Köhler, Martine Jaspers, Mieke Boon, Matthias Griese, Sabina Schmitt-Grohé, Theodor Zimmermann, Cordula Koerner-Rettberg, Elisabeth HorakChris Kintner, Fowzan S. Alkuraya, Heymut Omran

Kuwait University

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

217 Scopus citations

Abstract

Using a whole-exome sequencing strategy, we identified recessive CCNO (encoding cyclin O) mutations in 16 individuals suffering from chronic destructive lung disease due to insufficient airway clearance. Respiratory epithelial cells showed a marked reduction in the number of multiple motile cilia (MMC) covering the cell surface. The few residual cilia that correctly expressed axonemal motor proteins were motile and did not exhibit obvious beating defects. Careful subcellular analyses as well as in vitro ciliogenesis experiments in CCNO-mutant cells showed defective mother centriole generation and placement. Morpholino-based knockdown of the Xenopus ortholog of CCNO also resulted in reduced MMC and centriole numbers in embryonic epidermal cells. CCNO is expressed in the apical cytoplasm of multiciliated cells and acts downstream of multicilin, which governs the generation of multiciliated cells. To our knowledge, CCNO is the first reported gene linking an inherited human disease to reduced MMC generation due to a defect in centriole amplification and migration.

Original language	English
Pages (from-to)	646-651
Number of pages	6
Journal	Nature Genetics
Volume	46
Issue number	6
DOIs	https://doi.org/10.1038/ng.2961
State	Published - Jun 2014

Funding Agency

Kuwait Foundation for the Advancement of Sciences

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ng.2961

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Wallmeier, J., Al-Mutairi, D. A., Chen, C. T., Loges, N. T., Pennekamp, P., Menchen, T., Ma, L., Shamseldin, H. E., Olbrich, H., Dougherty, G. W., Werner, C., Alsabah, B. H., Köhler, G., Jaspers, M., Boon, M., Griese, M., Schmitt-Grohé, S., Zimmermann, T., Koerner-Rettberg, C., ... Omran, H. (2014). Mutations in CCNO result in congenital mucociliary clearance disorder with reduced generation of multiple motile cilia. Nature Genetics, 46(6), 646-651. https://doi.org/10.1038/ng.2961

@article{c4c9d930391747a5b921b0b72db990f9,

title = "Mutations in CCNO result in congenital mucociliary clearance disorder with reduced generation of multiple motile cilia",

abstract = "Using a whole-exome sequencing strategy, we identified recessive CCNO (encoding cyclin O) mutations in 16 individuals suffering from chronic destructive lung disease due to insufficient airway clearance. Respiratory epithelial cells showed a marked reduction in the number of multiple motile cilia (MMC) covering the cell surface. The few residual cilia that correctly expressed axonemal motor proteins were motile and did not exhibit obvious beating defects. Careful subcellular analyses as well as in vitro ciliogenesis experiments in CCNO-mutant cells showed defective mother centriole generation and placement. Morpholino-based knockdown of the Xenopus ortholog of CCNO also resulted in reduced MMC and centriole numbers in embryonic epidermal cells. CCNO is expressed in the apical cytoplasm of multiciliated cells and acts downstream of multicilin, which governs the generation of multiciliated cells. To our knowledge, CCNO is the first reported gene linking an inherited human disease to reduced MMC generation due to a defect in centriole amplification and migration.",

author = "Julia Wallmeier and Al-Mutairi, {Dalal A.} and Chen, {Chun Ting} and Loges, {Niki Tomas} and Petra Pennekamp and Tabea Menchen and Lina Ma and Shamseldin, {Hanan E.} and Heike Olbrich and Dougherty, {Gerard W.} and Claudius Werner and Alsabah, {Basel H.} and Gabriele K{\"o}hler and Martine Jaspers and Mieke Boon and Matthias Griese and Sabina Schmitt-Groh{\'e} and Theodor Zimmermann and Cordula Koerner-Rettberg and Elisabeth Horak and Chris Kintner and Alkuraya, {Fowzan S.} and Heymut Omran",

year = "2014",

month = jun,

doi = "10.1038/ng.2961",

language = "English",

volume = "46",

pages = "646--651",

journal = "Nature Genetics",

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Wallmeier, J, Al-Mutairi, DA, Chen, CT, Loges, NT, Pennekamp, P, Menchen, T, Ma, L, Shamseldin, HE, Olbrich, H, Dougherty, GW, Werner, C, Alsabah, BH, Köhler, G, Jaspers, M, Boon, M, Griese, M, Schmitt-Grohé, S, Zimmermann, T, Koerner-Rettberg, C, Horak, E, Kintner, C, Alkuraya, FS & Omran, H 2014, 'Mutations in CCNO result in congenital mucociliary clearance disorder with reduced generation of multiple motile cilia', Nature Genetics, vol. 46, no. 6, pp. 646-651. https://doi.org/10.1038/ng.2961

TY - JOUR

T1 - Mutations in CCNO result in congenital mucociliary clearance disorder with reduced generation of multiple motile cilia

AU - Wallmeier, Julia

AU - Al-Mutairi, Dalal A.

AU - Chen, Chun Ting

AU - Loges, Niki Tomas

AU - Pennekamp, Petra

AU - Menchen, Tabea

AU - Ma, Lina

AU - Shamseldin, Hanan E.

AU - Olbrich, Heike

AU - Dougherty, Gerard W.

AU - Werner, Claudius

AU - Alsabah, Basel H.

AU - Köhler, Gabriele

AU - Jaspers, Martine

AU - Boon, Mieke

AU - Griese, Matthias

AU - Schmitt-Grohé, Sabina

AU - Zimmermann, Theodor

AU - Koerner-Rettberg, Cordula

AU - Horak, Elisabeth

AU - Kintner, Chris

AU - Alkuraya, Fowzan S.

AU - Omran, Heymut

PY - 2014/6

Y1 - 2014/6

N2 - Using a whole-exome sequencing strategy, we identified recessive CCNO (encoding cyclin O) mutations in 16 individuals suffering from chronic destructive lung disease due to insufficient airway clearance. Respiratory epithelial cells showed a marked reduction in the number of multiple motile cilia (MMC) covering the cell surface. The few residual cilia that correctly expressed axonemal motor proteins were motile and did not exhibit obvious beating defects. Careful subcellular analyses as well as in vitro ciliogenesis experiments in CCNO-mutant cells showed defective mother centriole generation and placement. Morpholino-based knockdown of the Xenopus ortholog of CCNO also resulted in reduced MMC and centriole numbers in embryonic epidermal cells. CCNO is expressed in the apical cytoplasm of multiciliated cells and acts downstream of multicilin, which governs the generation of multiciliated cells. To our knowledge, CCNO is the first reported gene linking an inherited human disease to reduced MMC generation due to a defect in centriole amplification and migration.

AB - Using a whole-exome sequencing strategy, we identified recessive CCNO (encoding cyclin O) mutations in 16 individuals suffering from chronic destructive lung disease due to insufficient airway clearance. Respiratory epithelial cells showed a marked reduction in the number of multiple motile cilia (MMC) covering the cell surface. The few residual cilia that correctly expressed axonemal motor proteins were motile and did not exhibit obvious beating defects. Careful subcellular analyses as well as in vitro ciliogenesis experiments in CCNO-mutant cells showed defective mother centriole generation and placement. Morpholino-based knockdown of the Xenopus ortholog of CCNO also resulted in reduced MMC and centriole numbers in embryonic epidermal cells. CCNO is expressed in the apical cytoplasm of multiciliated cells and acts downstream of multicilin, which governs the generation of multiciliated cells. To our knowledge, CCNO is the first reported gene linking an inherited human disease to reduced MMC generation due to a defect in centriole amplification and migration.

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U2 - 10.1038/ng.2961

DO - 10.1038/ng.2961

M3 - Article

C2 - 24747639

AN - SCOPUS:84901651947

SN - 1061-4036

VL - 46

SP - 646

EP - 651

JO - Nature Genetics

JF - Nature Genetics

IS - 6

ER -

Mutations in CCNO result in congenital mucociliary clearance disorder with reduced generation of multiple motile cilia

Abstract

Funding Agency

UN SDGs

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