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Article

Primary Ciliary Dyskinesia Associated Disease-Causing Variants in CCDC39 and CCDC40 Cause Axonemal Absence of Inner Dynein Arm Heavy Chains DNAH1, DNAH6, and DNAH7

by
Alina Wilken
1,
Inga Marlena Höben
1,
Alexander Wolter
2,
Niki Tomas Loges
1,
Heike Olbrich
1,
Isabella Aprea
1,
Bernd Dworniczak
1,
Johanna Raidt
1 and
Heymut Omran
1,*
1
Department of General Pediatrics, University Hospital Muenster, 48149 Muenster, Germany
2
Department of Psychiatry, Ruhr University Bochum, LWL University Hospital, 44791 Bochum, Germany
*
Author to whom correspondence should be addressed.
Cells 2024, 13(14), 1200; https://doi.org/10.3390/cells13141200
Submission received: 30 April 2024 / Revised: 4 July 2024 / Accepted: 12 July 2024 / Published: 15 July 2024
(This article belongs to the Special Issue The Role of Cilia in Health and Diseases)
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Abstract

Disease-causing bi-allelic DNA variants in CCDC39 and CCDC40 are frequent causes of the hereditary disorder of primary ciliary dyskinesia (PCD). The encoded proteins form a molecular ruler complex, crucial for maintaining the 96 nm repeat units along the ciliary axonemes. Defects of those proteins cause a stiff, rapid, and flickery ciliary beating pattern, recurrent respiratory infections, axonemal disorganization, and abnormal assembly of GAS8, CCDC39, and DNALI1. We performed molecular characterization of the defects in the 96 nm axonemal ruler due to disease-causing variants in CCDC39 and CCDC40 and analyzed the effect on additional axonemal components. We identified a cohort of 51 individuals with disease-causing variants in CCDC39 and CCDC40 via next-generation sequencing techniques and demonstrated that the IDA heavy chains DNAH1, DNAH6, and DNAH7 are conspicuously absent within the respiratory ciliary axonemes by immunofluorescence analyses. Hence, we show for the first time that the centrin2 (CETN2) containing IDAs are also affected. These findings underscore the crucial role of CCDC39 and CCDC40 in the assembly and function of IDAs in human respiratory cilia. Thus, our data improve the diagnostics of axonemal ruler defects by further characterizing the associated molecular IDA defects.
Keywords: PCD; motile cilia; ruler; IDA; diagnostics; axonemal disorganization PCD; motile cilia; ruler; IDA; diagnostics; axonemal disorganization

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MDPI and ACS Style

Wilken, A.; Höben, I.M.; Wolter, A.; Loges, N.T.; Olbrich, H.; Aprea, I.; Dworniczak, B.; Raidt, J.; Omran, H. Primary Ciliary Dyskinesia Associated Disease-Causing Variants in CCDC39 and CCDC40 Cause Axonemal Absence of Inner Dynein Arm Heavy Chains DNAH1, DNAH6, and DNAH7. Cells 2024, 13, 1200. https://doi.org/10.3390/cells13141200

AMA Style

Wilken A, Höben IM, Wolter A, Loges NT, Olbrich H, Aprea I, Dworniczak B, Raidt J, Omran H. Primary Ciliary Dyskinesia Associated Disease-Causing Variants in CCDC39 and CCDC40 Cause Axonemal Absence of Inner Dynein Arm Heavy Chains DNAH1, DNAH6, and DNAH7. Cells. 2024; 13(14):1200. https://doi.org/10.3390/cells13141200

Chicago/Turabian Style

Wilken, Alina, Inga Marlena Höben, Alexander Wolter, Niki Tomas Loges, Heike Olbrich, Isabella Aprea, Bernd Dworniczak, Johanna Raidt, and Heymut Omran. 2024. "Primary Ciliary Dyskinesia Associated Disease-Causing Variants in CCDC39 and CCDC40 Cause Axonemal Absence of Inner Dynein Arm Heavy Chains DNAH1, DNAH6, and DNAH7" Cells 13, no. 14: 1200. https://doi.org/10.3390/cells13141200

APA Style

Wilken, A., Höben, I. M., Wolter, A., Loges, N. T., Olbrich, H., Aprea, I., Dworniczak, B., Raidt, J., & Omran, H. (2024). Primary Ciliary Dyskinesia Associated Disease-Causing Variants in CCDC39 and CCDC40 Cause Axonemal Absence of Inner Dynein Arm Heavy Chains DNAH1, DNAH6, and DNAH7. Cells, 13(14), 1200. https://doi.org/10.3390/cells13141200

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