Dynein axonemal heavy chain 10 deficiency causes primary ciliary dyskinesia in humans and mice

Abstract

Primary ciliary dyskinesia (PCD) is a congenital, motile ciliopathy with pleiotropic symptoms. Although nearly 50 causative genes have been identified, they only account for approximately 70% of definitive PCD cases. Dynein axonemal heavy chain 10 (DNAH10) encodes a subunit of the inner arm dynein heavy chain in motile cilia and sperm flagella. Based on the common axoneme structure of motile cilia and sperm flagella, DNAH10 variants are likely to cause PCD. Using exome sequencing, we identified a novel DNAH10 homozygous variant (c.589C > T, p.R197W) in a patient with PCD from a consanguineous family. The patient manifested sinusitis, bronchiectasis, situs inversus, and asthenoteratozoospermia. Immunostaining analysis showed the absence of DNAH10 and DNALI1 in the respiratory cilia, and transmission electron microscopy revealed strikingly disordered axoneme 9+2 architecture and inner dynein arm defects in the respiratory cilia and sperm flagella. Subsequently, animal models of Dnah10-knockin mice harboring missense variants and Dnah10-knockout mice recapitulated the phenotypes of PCD, including chronic respiratory infection, male infertility, and hydrocephalus. To the best of our knowledge, this study is the first to report DNAH10 deficiency related to PCD in human and mouse models, which suggests that DNAH10 recessive mutation is causative of PCD.

Keywords

DNAH10 / mice / motile cilia / mutation / primary ciliary dyskinesia

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Acknowledgements

The authors would like to thank all individuals who participated in this study. We also thank the Center of Cryo-electron Microscopy at Central South University and Zhejiang University for technical support. We would like to thank Editage for English language editing. This study was supported by the National Natural Science Foundation of China (Nos. 82070003, 82100057, 81900002, 82101961, 31970504, and 31772548); Natural Science Foundation of Hunan Province, China (Nos. 2020JJ5805 and 2021JJ30943); Xiangya Clinical Big Data System Construction Project in Pulmonary Inflammatory Disease of Central South University; and the National Key Clinical Specialty Construction Projects of China.

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-023-0988-8 and is accessible for authorized users.

Compliance with ethics guidelines

Rongchun Wang, Danhui Yang, Chaofeng Tu, Cheng Lei, Shuizi Ding, Ting Guo, Lin Wang, Ying Liu, Chenyang Lu, Binyi Yang, Shi Ouyang, Ke Gong, Zhiping Tan, Yun Deng, YueqiuTan, Jie Qing, and Hong Luo declare that they have no conflict of interest. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study. All institutional and national guidelines for the care and use of laboratory animals were followed.

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