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Original research
Homozygous mutations in DZIP1 can induce asthenoteratospermia with severe MMAF
  1. Mingrong Lv1,2,3,
  2. Wangjie Liu4,5,6,
  3. Wangfei Chi7,
  4. Xiaoqing Ni1,2,3,
  5. Jiajia Wang1,2,3,
  6. Huiru Cheng1,8,9,
  7. Wei-Yu Li4,5,6,
  8. Shenmin Yang10,
  9. Huan Wu1,8,9,
  10. Junqiang Zhang1,8,9,
  11. Yang Gao1,2,3,
  12. Chunyu Liu4,5,6,
  13. Caihua Li11,
  14. Chenyu Yang12,
  15. Qing Tan1,8,9,
  16. Dongdong Tang1,8,9,
  17. Jingjing Zhang1,8,9,
  18. Bing Song1,8,9,
  19. Yu-Jie Chen1,8,9,
  20. Qiang Li1,8,9,
  21. Yading Zhong13,
  22. Zhihua Zhang14,
  23. Hexige Saiyin4,
  24. Li Jin4,
  25. Yuping Xu1,8,9,
  26. Ping Zhou1,8,9,
  27. Zhaolian Wei1,8,9,
  28. Chuanmao Zhang7,
  29. Xiaojin He1,2,3,
  30. Feng Zhang4,5,6,
  31. Yunxia Cao1,2,3
  1. 1 Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
  2. 2 NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, China
  3. 3 Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People’s Republic of China, Hefei, China
  4. 4 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, China
  5. 5 Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China
  6. 6 State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
  7. 7 Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, College of Life Sciences, Peking University, Beijing, China
  8. 8 Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, China
  9. 9 Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, Hefei, China
  10. 10 Center for Reproduction and Genetics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
  11. 11 Genesky Biotechnologies Inc, Shanghai, Shanghai, China
  12. 12 Center of Cryo-Electron Microscopy, Zhejiang University, Hangzhou, China
  13. 13 Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
  14. 14 Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China
  1. Correspondence to Associate Professor Xiaojin He; hxj0117{at}; Professor Feng Zhang; zhangfeng{at}; Professor Yunxia Cao; caoyunxia6{at}


Background Asthenoteratospermia, one of the most common causes for male infertility, often presents with defective sperm heads and/or flagella. Multiple morphological abnormalities of the sperm flagella (MMAF) is one of the common clinical manifestations of asthenoteratospermia. Variants in several genes including DNAH1, CEP135, CATSPER2 and SUN5 are involved in the genetic pathogenesis of asthenoteratospermia. However, more than half of the asthenoteratospermia cases cannot be explained by the known pathogenic genes.

Methods and results Two asthenoteratospermia-affected men with severe MMAF (absent flagella in >90% spermatozoa) from consanguineous families were subjected to whole-exome sequencing. The first proband had a homozygous missense mutation c.188G>A (p.Arg63Gln) of DZIP1 and the second proband had a homozygous stop-gain mutation c.690T>G (p.Tyr230*). Both of the mutations were neither detected in the human population genome data (1000 Genomes Project, Exome Aggregation Consortium) nor in our own data of a cohort of 875 Han Chinese control populations. DZIP1 encodes a DAZ (a protein deleted in azoospermia) interacting protein, which was associated with centrosomes in mammalian cells. Immunofluorescence staining of the centriolar protein Centrin1 indicated that the spermatozoa of the proband presented with abnormal centrosomes, including no concentrated centriolar dot or more than two centriolar dots. HEK293T cells transfected with two DZIP1-mutated constructs showed reduced DZIP1 level or truncated DZIP1. The Dzip1-knockout mice, generated by the CRSIPR-Cas9, revealed consistent phenotypes of severe MMAF.

Conclusion Our study strongly suggests that homozygous DZIP1 mutations can induce asthenoteratospermia with severe MMAF. The deficiency of DZIP1 induces sperm centrioles dysfunction and causes the absence of flagella.

  • asthenoteratospermia
  • centrosome
  • DZIP1
  • flagella

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  • ML, WaL, WC and XN contributed equally.

  • Contributors YC, FZ, CZ and XH designed the study. XH, SY, HW, JW, YG, QT, DT, JiZ, BS, YZ, YX, PZ, ZW and ZZ provided patients’ data and performed clinical assessments. XH, ML, WL, WC, HC,QL, XN, W-YL, JW, JuZ, YG, Y-JC, ChL, CaL, CY and HS conducted the experiments. HZ, XH, ML,WL, W-YL and FZ analysed the data. WL, RL, XH and FZ wrote the manuscript. YC and FZ were responsible for the study supervision. All authors read and approved the final manuscript.

  • Funding This study was supported by National Natural Science Foundation of China (81971441, 31625015, 81601340 and 31521003),Special Foundation for Development of Science and Technology of Anhui Province (2017070802D150), Natural Science Foundation of Anhui Province (1708085QC59 and 1908085QH313), Shanghai Medical Center of Key Programs for Female Reproductive Diseases (2017ZZ01016), the Shanghai Municipal Science and Technology Major Project (2017SHZDZX01) and Jiangsu Commission of Health (H2018050).

  • Competing interests None declared.

  • Patient consent for publication Obtained.

  • Ethics approval This study was approved by the Ethical Committees of Anhui Medical University and the School of Life Sciences at Fudan University.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available in a public, open access repository. Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. All data relevant to the study are available in public.

  • Author note YC, FZ, CZ and XH jointly direct this study.

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