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Original research
Biallelic CFAP61 variants cause male infertility in humans and mice with severe oligoasthenoteratozoospermia
  1. Tongyao Hu1,
  2. Lanlan Meng1,2,3,4,
  3. Chen Tan1,
  4. Chen Luo1,
  5. Wen-Bin He1,2,3,4,
  6. Chaofeng Tu1,2,3,4,
  7. Huan Zhang1,2,3,4,
  8. Juan Du1,2,3,4,
  9. Hongchuan Nie2,3,
  10. Guang-Xiu Lu2,3,4,
  11. Ge Lin1,2,3,4,5,
  12. Yue-Qiu Tan1,2,3,4,5
  1. 1 Institute of Reproduction and Stem Cell Engineering, School of Basic Medical Science,Central South University, Changsha, People's Republic of China
  2. 2 Genetic Center, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, People's Republic of China
  3. 3 Clinical Research Center for Reproduction and Genetics in Hunan Province, Changsha, People's Republic of China
  4. 4 NHC key laboratory of human stem cell and reproductive engineering, Changsha, People's Republic of China
  5. 5 College of Life Science, Hunan Normal University, Changsha, People's Republic of China
  1. Correspondence to Dr Yue-Qiu Tan, School of Basic Medical Science, Central South University Xiangya School of Medicine, Changsha 410078, China; tanyueqiu{at}


Background The genetic causes for most male infertility due to severe oligoasthenoteratozoospermia (OAT) remain unclear.

Objective To identify the genetic cause of male infertility characterised by OAT.

Methods Variant screening was performed by whole-exome sequencing from 325 infertile patients with OAT and 392 fertile individuals. In silico and in vitro analyses were performed to evaluate the impacts of candidate disease-causing variants. A knockout mouse model was generated to confirm the candidate disease-causing gene, and intracytoplasmic sperm injection (ICSI) was used to evaluate the efficiency of clinical treatment.

Results We identified biallelic CFAP61 variants (NM_015585.4: c.1654C>T (p.R552C) and c.2911G>A (p.D971N), c.144–2A>G and c.1666G>A (p.G556R)) in two (0.62%) of the 325 OAT-affected men. In silico bioinformatics analysis predicted that all four variants were deleterious, and in vitro functional analysis confirmed the deleterious effects of the mutants. Notably, H&E staining and electron microscopy analyses of the spermatozoa revealed multiple morphological abnormalities of sperm flagella, the absence of central pair microtubules and mitochondrial sheath malformation in sperm flagella from man with CFAP61 variants. Further immunofluorescence assays revealed markedly reduced CFAP61 staining in the sperm flagella. In addition, Cfap61-deficient mice showed the OAT phenotype, suggesting that loss of function of CFAP61 was the cause of OAT. Two individuals accepted ICSI therapy using their own ejaculated sperm, and one of them succeeded in fathering a healthy baby.

Conclusions Our findings indicate that CFAP61 is essential for spermatogenesis and that biallelic CFAP61 variants lead to male infertility in humans and mice with OAT.

  • reproductive health
  • genetic research

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information. Not applicable.

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Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information. Not applicable.

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  • TH and LM contributed equally.

  • Correction notice This article has been corrected since it was published Online First. A statement about equal contributorship has been added.

  • Contributors Y-QT designed the research; TH, LM, CT and CL performed research; W-BH, CT, HN, HZ, JD and GL performed the bioinformatics analysis; JD, GL and G-XL analysed the data; Y-QT, TH and LM analysed the data and wrote the paper; Y-QT is the guarantor of the research.

  • Funding This work was supported by grants from the National Key Research & Developmental Program of China (2018YFC1004901), the National Natural Science Foundation of China (81771645 and 81971447), the Key Grant of Prevention and Treatment of Birth Defect from Hunan Province (2019SK1012), Hunan Provincial Grant for Innovative Province Construction (2019SK4012) and the Research Grant of CITIC-Xiangya (YNXM-202004, YNXM-202006).

  • 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.