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Original research
Homozygous variants in AKAP3 induce asthenoteratozoospermia and male infertility
  1. Chunyu Liu1,2,
  2. Ying Shen3,
  3. Shuyan Tang1,2,
  4. Jiaxiong Wang4,
  5. Yiling Zhou1,2,
  6. Shixiong Tian1,2,
  7. Huan Wu5,6,7,
  8. Jiangshan Cong1,2,
  9. Xiaojin He5,6,7,
  10. Li Jin1,
  11. Yunxia Cao5,6,7,
  12. Yihong Yang8,
  13. Feng Zhang1,2
  1. 1Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering, Human Phenome Institute, Fudan University, Shanghai, China
  2. 2Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Institute of Reproduction and Development, Fudan University, Shanghai, China
  3. 3Department of Obstetrics/Gynecology, Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
  4. 4Center for Reproduction and Genetics, State Key Laboratory of Reproductive Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu, China
  5. 5Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
  6. 6NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, Anhui, China
  7. 7Key Laboratory of Population Health Across Life Cycle, Ministry of Education of the People’s Republic of China, Anhui Medical University, Hefei, Anhui, China
  8. 8Center of Reproductive Medicine, West China Second University Hospital, Key Laboratory of Obstetric and Gynecologic and Pediatric Diseases and Birth Defects, Ministry of Education, Sichuan University, Chengdu, Sichuan, China
  1. Correspondence to Professor Feng Zhang, Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering, Human Phenome Institute, Fudan University, Shanghai, China; zhangfeng{at}fudan.edu.cn; Dr Yihong Yang, West China Second University Hospital, Sichuan University, Chengdu, China; yyhpumc{at}foxmail.com

Abstract

Background As a common type of asthenoteratozoospermia, multiple morphological abnormalities of the sperm flagella (MMAF) can cause male infertility. Previous studies have revealed genetic factors as a major cause of MMAF. The known MMAF-associated genes are involved in the mitochondrial sheath, outer dense fibre or axoneme of the sperm flagella. These findings indicate the genetic heterogeneity of MMAF.

Methods and results Here, we conducted genetic analyses using whole-exome sequencing in a cohort of 150 Han Chinese men with asthenoteratozoospermia. Homozygous deleterious variants of AKAP3 (A-kinase anchoring protein 3) were identified in two MMAF-affected men from unrelated families. One AKAP3 variant was a frameshift (c.2286_2287del, p.His762Glnfs*22) and the other variant was a missense mutation (c.44G>A, p.Cys15Tyr), which was predicted to be damaging by multiple bioinformatics tools. Further western blotting and immunofluorescence assays revealed the absence of AKAP3 in the spermatozoa from the man harbouring the homozygous frameshift variant, whereas the expression of AKAP3 was markedly reduced in the spermatozoa of the man with the AKAP3 missense variant p.Cys15Tyr. Notably, the clinical outcomes after intracytoplasmic sperm injection (ICSI) were divergent between these two cases, suggesting a possibility of AKAP3 dosage-dependent prognosis of ICSI treatment.

Conclusions Our study revealed AKAP3 as a novel gene involved in human asthenoteratozoospermia.

  • genetics, medical
  • genetic variation
  • men's health
  • reproductive medicine

Data availability statement

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

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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

  • CL, YS, ST, JW and YZ contributed equally.

  • Contributors FZ, YY and CL conceived and designed the experiments. CL and YS performed the genetic analysis and wrote the manuscript. CL and YZ performed the immunofluorescence and western blotting analyses. STa performed the bioinformatic analyses. STi, YY and JW contributed to sample processing and performed the clinical assessments. HW, YC and XH analysed the data. CL, JC and LJ contributed to the discussion of the data. FZ and YY are responsible for the overall content as guarantors. All authors have read and agreed to the published version of the manuscript.

  • Funding This work was supported by the National Natural Science Foundation of China (31625015, 31521003 and 32100480), Shanghai Municipal Science and Technology Major Project (2017SHZDZX01), State Key Laboratory of Reproductive Medicine (SKLRM-K202002), Key Research Project of Science and Technology Department of Sichuan Province (2020YJ0291), China Postdoctoral Science Foundation (2020TQ0072), Scientific Research (TP202002) from Anhui Medical University, and the 111 Project (B13016).

  • 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.

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