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Novel variants in DNAH9 are present in two infertile patients with severe asthenospermia

Journal of Human Genetics volume 70, pages 105–111 (2025)Cite this article

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Abstract

Asthenospermia is a type of sperm that has malformed sperm with movement disorders that lead to male infertility. DNAH9 is a member of the dynein family and a central part of the outer dynein arm of cilia and flagella. DNAH9 gene defects are associated with primary ciliary dyskinesia and ultrastructural abnormalities in ciliary axial ultrastructure. However, the role of DNAH9 in sperm motility remains unclear, prompting us to investigate its function in spermatozoa. Familial Sanger sequencing showed that sterile males carried homozygous DNAH9 variants (c. 12218A>C, p. N4073T) and compound heterozygous variants (c.8617G>A, p.V2873M; c.11742A>T, p.E3914D), respectively. Transmission electron microscopy revealed these variants resulted in a significant lack of outer dynein arms in the cross-sectional view of the axoneme in both patients. Immunofluorescence results showed that these variants can lead to decline in DNAH9 protein expression, which led to the dysfunction of flagellar ultrastructure-related proteins, including DNAI1, DNAH1 and DNAH10. In conclusion, we identified novel biallelic variants in DNAH9 that likely bring about sharply decreased motility of spermatozoa in the two patients with asthenospermia. Our findings will widen the variant spectrum of known DNAH9 variants involving asthenospermia and further offer more proofs for genetic counseling and diagnosis.

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Acknowledgements

We would like to thank all the researchers for their contributions.

Funding

This article was funded by National Natural Science Foundation of China (2301815); China Postdoctoral Science Foundation (2023M732468, GZC20231835); Sichuan Province Science and Technology Innovation Talent Project (24CXRC0056).

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Author notes

  1. These authors contributed equally: Fei Yan, Weiwei Zhi.

Authors and Affiliations

  1. Joint Laboratory of Reproductive Medicine, SCU-CUHK, Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, 610041, China

    Fei Yan, Wenming Xu & Rui Zheng

  2. Key Laboratory of Reproductive Medicine, Sichuan Provincial Maternity and Child Health Care Hospital, Chengdu, 610000, China

    Weiwei Zhi

  3. West China School of Pharmacy, Sichuan University, Chengdu, 610041, China

    Yazhen Wei

  4. National Office for Maternal and Child Health Surveillance of China, West China Second University Hospital, Sichuan University, Chengdu, 610066, China

    Li Dai

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  1. Fei Yan
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  2. Weiwei Zhi
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  3. Yazhen Wei
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  4. Li Dai
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  6. Rui Zheng
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Fei Yan, Weiwei Zhi, Yazhen Wei and Li Dai. The first draft of the manuscript was written by Rui Zheng and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Rui Zheng.

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Yan, F., Zhi, W., Wei, Y. et al. Novel variants in DNAH9 are present in two infertile patients with severe asthenospermia. J Hum Genet 70, 105–111 (2025). https://doi.org/10.1038/s10038-024-01304-y

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