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.
Keywords
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Article info
Publication history
Published online: January 30, 2023
Accepted:
January 24,
2023
Received in revised form:
January 24,
2023
Received:
October 20,
2022
Footnotes
Rim Hjeij and Isabella Aprea contributed equally.
Identification
Copyright
© 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.
