TTC25 Deficiency Results in Defects of the Outer Dynein Arm Docking Machinery and Primary Ciliary Dyskinesia with Left-Right Body Asymmetry Randomization

Am J Hum Genet. 2016 Aug 4;99(2):460-9. doi: 10.1016/j.ajhg.2016.06.014.

Julia Wallmeier ¹, Hidetaka Shiratori ², Gerard W Dougherty ¹, Christine Edelbusch ¹, Rim Hjeij ¹, Niki T Loges ¹, Tabea Menchen ¹, Heike Olbrich ¹, Petra Pennekamp ¹, Johanna Raidt ¹, Claudius Werner ¹, Katsura Minegishi ², Kyosuke Shinohara ², Yasuko Asai ², Katsuyoshi Takaoka ², Chanjae Lee ³, Matthias Griese ⁴, Yasin Memari ⁵, Richard Durbin ⁵, Anja Kolb-Kokocinski ⁵, Sascha Sauer ⁶, John B Wallingford ³, Hiroshi Hamada ², Heymut Omran ⁷

Affiliations

1 Department of Pediatrics, University Hospital Muenster, 48149 Muenster, Germany.
2 Developmental Genetics Group, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan.
3 Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA.
4 Department of Pediatric Pulmonology, Hauner Children's Hospital and Ludwig Maximilian University, The German Center for Lung Research (DZL), 80337 Munich, Germany.
5 Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
6 Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK; Berlin Institute for Medical Systems Biology and Berlin Institute of Health Genomics Platforms, Laboratory of Functional Genomics, Nutrigenomics, and Systems Biology, Max Delbrück Center for Molecular Medicine, Robert Rössle Straße 10, 13125 Berlin, Germany; Otto Warburg Laboratory, Max Planck Institute for Molecular Genetics, Ihnestraße 63-73, 14195 Berlin, Germany.
7 Department of Pediatrics, University Hospital Muenster, 48149 Muenster, Germany. Electronic address: heymut.omran@ukmuenster.de.

PMID: 27486780 DOI: 10.1016/j.ajhg.2016.06.014

Abstract

Multiprotein complexes referred to as outer dynein arms (ODAs) develop the main mechanical force to generate the ciliary and flagellar beat. ODA defects are the most common cause of primary ciliary dyskinesia (PCD), a congenital disorder of ciliary beating, characterized by recurrent infections of the upper and lower airways, as well as by progressive lung failure and randomization of left-right body asymmetry. Using a whole-exome Sequencing approach, we identified recessive loss-of-function mutations within TTC25 in three individuals from two unrelated families affected by PCD. Mice generated by CRISPR/Cas9 technology and carrying a deletion of exons 2 and 3 in Ttc25 presented with laterality defects. Consistently, we observed immotile nodal cilia and missing leftward flow via particle image velocimetry. Furthermore, transmission electron microscopy (TEM) analysis in TTC25-deficient mice revealed an absence of ODAs. Consistent with our findings in mice, we were able to show loss of the ciliary ODAs in humans via TEM and immunofluorescence (IF) analyses. Additionally, IF analyses revealed an absence of the ODA docking complex (ODA-DC), along with its known components CCDC114, CCDC151, and ARMC4. Co-immunoprecipitation revealed interaction between the ODA-DC component CCDC114 and TTC25. Thus, here we report TTC25 as a new member of the ODA-DC machinery in humans and mice.

Name
Email *

	Sorry, but the email address you supplied was invalid.