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Patients with severe asthenoteratospermia carrying SPAG6 or RSPH3 mutations have a positive pregnancy outcome following intracytoplasmic sperm injection

  • Genetics
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Abstract

Purpose

To investigate the relation between mutations in ciliopathy-related SPAG6 and RSPH3 and male infertility with severe asthenoteratospermia characterized by multiple flagellar malformations and reveal the intracytoplasmic sperm injection (ICSI) outcomes of those primary ciliary dyskinesia (PCD) patients.

Methods

Whole-exome sequencing was applied to identify the pathogenic genes for the five PCD patients. The ICSI outcomes of those patients were compared with eight DNAH1-mutated patients and 215 oligo-asthenospermia (OAT) patients.

Results

We identified, for the first time, the compound heterozygous SPAG6 mutations (c.143_145del: p.48_49del, c.585delA: p.Lys196Serfs*6) in a sporadic PCD patient. Further, a novel homozygous nonsynonymous RSPH3 mutation (c.C799T: p.Arg267Cys) was identified in another PCD patient with consanguineous parents. The pathogenicity of these mutations in the assembly of sperm flagella was confirmed by flagellar ultrastructure analysis, immunofluorescence, and quantitative real-time PCR. All five patients underwent six ICSI cycles. The fertilization rate, blastocyst development rate, and clinical pregnancy rate were 69.3%, 50.0%, and 66.7%, respectively. Four of the five couples, including the subjects carrying mutations in SPAG6 or RSPH3, got healthy children born after ICSI. Additionally, the ICSI outcomes of the five PCD couples were statistically comparable with those of the eight DNAH1-mutated couples and the 215 OAT couples.

Conclusions

Mutations in ciliopathy-related SPAG6 and RSPH3 cause severe asthenoteratospermia characterized by multiple flagellar malformations, resulting in sterility. ICSI is an optimal management with a positive pregnancy outcome.

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Funding

This study was supported by the Natural Science Foundation of Anhui Province (1908085QH313), Special Foundation for Development of Science and Technology of Anhui Province (2017070802D150 and YDZX20183400004194), National Natural Science Foundation of China (81901541 and 81971441), Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2019PT310002) and Shanghai Municipal Science and Technology Major Project (2017SHZDZX01).

Author information

Author notes

  1. Huan Wu, Jiajia Wang and Huiru Cheng contributed equally to this work.

Authors and Affiliations

  1. Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Hefei, 230022, Anhui, China

    Huan Wu, Jiajia Wang, Huiru Cheng, Yang Gao, Zhiguo Zhang, Huanhuan Jiang, Fuxi Zhu, Mingrong Lv, Chao Wang, Xiaoqing Ni, Yujie Chen, Bing Song, Ping Zhou, Zhaolian Wei, Xiaojin He & Yunxia Cao

  2. NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, No 81 Meishan Road, Hefei, 230032, Anhui, China

    Huan Wu, Jiajia Wang, Huiru Cheng, Xiaojin He & Yunxia Cao

  3. Key Laboratory of Population Health Across Life Cycle, Anhui Medical University, Ministry of Education of the People’s Republic of China, No 81 Meishan Road, Hefei, 230032, Anhui, China

    Huan Wu, Jiajia Wang, Huiru Cheng, Xiaojin He & Yunxia Cao

  4. Anhui Province Key Laboratory of Reproductive Health and Genetics, No 81 Meishan Road, Hefei, 230032, Anhui, China

    Zhiguo Zhang, Huanhuan Jiang, Fuxi Zhu, Mingrong Lv, Chao Wang, Bing Song, Ping Zhou & Zhaolian Wei

  5. Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, No 81 Meishan Road, Hefei, 230032, Anhui, China

    Zhiguo Zhang, Huanhuan Jiang, Fuxi Zhu, Mingrong Lv, Chao Wang, Bing Song, Ping Zhou & Zhaolian Wei

  6. Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, China

    Wangjie Liu, Weiyu Li, Chunyu Liu & Feng Zhang

  7. Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai, 200011, China

    Wangjie Liu, Weiyu Li, Chunyu Liu & Feng Zhang

  8. Department of Pulmonary and Critical Care Medicine, The Third Affiliated Hospital of Anhui Medical University, Hefei, 230061, China

    Chunyu Liu & Xiaofeng Zhang

  9. State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211116, China

    Wangjie Liu, Weiyu Li, Chunyu Liu & Feng Zhang

  10. Anhui Provincial Human Sperm Bank, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China

    Qing Tan

Authors
  1. Huan Wu
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  2. Jiajia Wang
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  3. Huiru Cheng
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  4. Yang Gao
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  5. Wangjie Liu
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  7. Huanhuan Jiang
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  11. Chunyu Liu
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  12. Qing Tan
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  13. Xiaofeng Zhang
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  14. Chao Wang
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  15. Xiaoqing Ni
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  17. Bing Song
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  18. Ping Zhou
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  19. Zhaolian Wei
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  20. Feng Zhang
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  21. Xiaojin He
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  22. Yunxia Cao
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Corresponding authors

Correspondence to Xiaojin He or Yunxia Cao.

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This research was approved by the ethical committee of The First Affiliated Hospital of Anhui Medical University. All participants in this study signed informed consent.

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Wu, H., Wang, J., Cheng, H. et al. Patients with severe asthenoteratospermia carrying SPAG6 or RSPH3 mutations have a positive pregnancy outcome following intracytoplasmic sperm injection. J Assist Reprod Genet 37, 829–840 (2020). https://doi.org/10.1007/s10815-020-01721-w

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