Pathogenic variants in CLXN encoding the outer dynein arm docking–associated calcium-binding protein calaxin cause primary ciliary dyskinesia

Rim Hjeij, Isabella Aprea, Marco Poeta, Tabea Nöthe-Menchen, Diana Bracht, Johanna Raidt, Barbara I. Honecker, Gerard W. Dougherty, Heike Olbrich, Oliver Schwartz, Ulrike Keller, Harald Nüsse, Karin E.M. Diderich, Christian Vogelberg, Francesca Santamaria, Heymut Omran*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

5 Citations (Scopus)

Abstract

Purpose: Primary ciliary dyskinesia (PCD) is a heterogeneous disorder that includes respiratory symptoms, laterality defects, and infertility caused by dysfunction of motile cilia. Most PCD-causing variants result in abnormal outer dynein arms (ODAs), which provide the generative force for respiratory ciliary beating and proper mucociliary clearance. Methods: In addition to studies in mouse and planaria, clinical exome sequencing and functional analyses in human were performed. Results: In this study, we identified homozygous pathogenic variants in CLXN (EFCAB1/ODAD5) in 3 individuals with laterality defects and respiratory symptoms. Consistently, we found that Clxn is expressed in mice left-right organizer. Transmission electron microscopy depicted ODA defects in distal ciliary axonemes. Immunofluorescence microscopy revealed absence of CLXN from the ciliary axonemes, absence of the ODA components DNAH5, DNAI1, and DNAI2 from the distal axonemes, and mislocalization or absence of DNAH9. In addition, CLXN was undetectable in ciliary axonemes of individuals with defects in the ODA-docking machinery: ODAD1, ODAD2, ODAD3, and ODAD4. Furthermore, SMED-EFCAB1-deficient planaria displayed ciliary dysmotility. Conclusion: Our results revealed that pathogenic variants in CLXN cause PCD with defects in the assembly of distal ODAs in the respiratory cilia. CLXN should be referred to as ODA-docking complex–associated protein ODAD5.

Original languageEnglish
Article number100798
JournalGenetics in Medicine
Volume25
Issue number5
DOIs
Publication statusPublished - May 2023

Bibliographical note

Funding Information:
This work was supported by grants from the Deutsche Forschungsgemeinschaft HJ 7/1-1 and HJ 7/1-3 (R.H.), OM6/7, OM6/8, OM6/10, OM6/14, OM6/16, CRU 326 (subprojects OM6/11 [H.Om.] and RA3522/1-1 [J.R.]), OL 450/1 (H.O.), the Interdisziplinaeres Zentrum für Klinische Forschung (IZKF) Muenster (Om2/009/12, Om2/015/16, Om2/010/20), Registry Warehouse (Horizon2020 GA 777295), and Better Experimental Screening and Treatment for Primary Ciliary Dyskinesia (BESTCILIA) ( EU FP7-HEALTH GA 305404). This work is generated within the European Reference Network for rare respiratory diseases European Reference Network-LUNG.

Publisher Copyright:
© 2023 American College of Medical Genetics and Genomics

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