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Gametes
Original research
Homozygous mutations in CCDC34 cause male infertility with oligoasthenoteratozoospermia in humans and mice
  1. Jiangshan Cong1,2,
  2. Xiong Wang3,4,
  3. Amir Amiri-Yekta5,6,
  4. Lingbo Wang1,2,
  5. Zine-Eddine Kherraf6,7,
  6. Chunyu Liu1,2,
  7. Caroline Cazin6,7,8,
  8. Shuyan Tang1,2,
  9. Seyedeh Hanieh Hosseini9,
  10. Shixiong Tian1,2,
  11. Abbas Daneshipour5,
  12. Jiaxiong Wang10,11,
  13. Yiling Zhou1,2,
  14. Yuyan Zeng1,
  15. Shenmin Yang10,11,
  16. Xiaojin He12,13,14,
  17. Jinsong Li15,16,
  18. Yunxia Cao12,13,14,
  19. Li Jin1,
  20. Pierre F Ray6,7,
  21. Feng Zhang1,2
  1. 1Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical Technologies), State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai, China
  2. 2Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China
  3. 3Department of Surgery, Medical College of Shandong University, Jinan, Shandong, China
  4. 4Reproductive Medicine Center, Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China
  5. 5Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, Academic Center for Education, Culture, and Research, Tehran, Iran
  6. 6Université Grenoble Alpes, Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, INSERM U1209, CNRS UMR 5309, Grenoble, France
  7. 7Centre Hospitalier Universitaire de Grenoble, UM GI-DPI, Grenoble, France
  8. 8Laboratoire Eurofins Biomnis, Lyon, France
  9. 9Department of Andrology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, Academic Center for Education, Culture, and Research, Tehran, Iran
  10. 10State Key Laboratory of Reproductive Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, China
  11. 11Suzhou Municipal Hospital, Suzhou, Jiangsu, China
  12. 12Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
  13. 13NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, Anhui, China
  14. 14MOE Key Laboratory of Population Health Across Life Cycle, Anhui Medical University, Hefei, Anhui, China
  15. 15State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China
  16. 16University of the Chinese Academy of Sciences, Shangai, China
  1. Correspondence to Professor Feng Zhang, Fudan University, Shanghai, China; zhangfeng{at}fudan.edu.cn; Professor Pierre F Ray, Université Grenoble Alpes, Grenoble, France; pray{at}chu-grenoble.fr

Abstract

Background Oligoasthenoteratozoospermia is a typical feature of sperm malformations leading to male infertility. Only a few genes have been clearly identified as pathogenic genes of oligoasthenoteratozoospermia.

Methods and results Here, we identified a homozygous frameshift variant (c.731dup, p.Asn244Lysfs*3) in CCDC34, which is preferentially expressed in the human testis, using whole-exome sequencing in a cohort of 100 Chinese men with multiple morphological abnormalities of the sperm flagella (MMAF). In an additional cohort of 167 MMAF-affected men from North Africa, Iran and France, we identified a second subject harbouring a homozygous CCDC34 frameshift variant (c.799_817del, p.Glu267Lysfs*72). Both affected men presented a typical MMAF phenotype with an abnormally low sperm concentration (ie, oligoasthenoteratozoospermia). Transmission electron microscopy analysis of the sperm flagella affected by CCDC34 deficiency further revealed dramatic disorganisation of the axoneme. Immunofluorescence assays of the spermatozoa showed that CCDC34 deficiency resulted in almost absent staining of CCDC34 and intraflagellar transport-B complex-associated proteins (such as IFT20 and IFT52). Furthermore, we generated a mouse Ccdc34 frameshift mutant using CRISPR-Cas9 technology. Ccdc34-mutated (Ccdc34mut/mut) male mice were sterile and presented oligoasthenoteratozoospermia with typical MMAF anomalies. Intracytoplasmic sperm injection has good pregnancy outcomes in both humans and mice.

Conclusions Our findings support that CCDC34 is crucial to the formation of sperm flagella and that biallelic deleterious mutations in CCDC34/Ccdc34 cause male infertility with oligoasthenoteratozoospermia in humans and mice.

  • genetics
  • medical
  • genetic variation
  • reproductive medicine

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

https://doi.org/10.1136/jmedgenet-2021-107919

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    Data availability statement

    All data relevant to the study are included in the article or uploaded as supplementary information.

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    Footnotes

    • JC, XW, AA-Y and LW contributed equally.

    • Correction notice This article has been corrected since it was published Online First. The name of author Pierre F Ray has been amended.

    • Contributors JC, PR and FZ designed the study. XW, AA-Y, Z-EK, CC, SHH, AD, XH, YC and PR provided patients data and performed clinical assessments. JC, LW, CL, STa, STi, JW, YZh and YZe conducted the experiments. JC, XW, AA-Y, LW, SY, XH, JL, YC, LJ, PR and FZ analysed data. JC, PR and FZ wrote the manuscript. PR and FZ supervised the study.

    • Funding This work was supported by the National Natural Science Foundation of China (31625015, 31521003, 81971441 and 32000393), Shanghai Municipal Science and Technology Major Project (2017SHZDZX01), Scientific Research (TP202002) from Anhui Medical University, Innovative Research Team of High-level Local Universities in Shanghai (SSMU-ZLCX20180500), Science and Technology Major Project of Inner Mongolia Autonomous Region of China (zdzx2018065), 111 Project (B13016), State Key Laboratory of Reproductive Medicine (SKLRM-K202002), Scientific Research Project of Jiangsu Provincial Health and Family Planning Commission (H2018050) and Maternal and Child Health Research Project of Jiangsu Province (F201866). The work was also supported by the French Research Agency (ANR) project FLAGEL-OME (ANR-19-CE17-0014) to PR.

    • Competing interests None declared.

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

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.