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Gametes
Original research
Biallelic mutations in ARMC12 cause asthenozoospermia and multiple midpiece defects in humans and mice
  1. Wensheng Liu1,
  2. Xiaoli Wei2,3,
  3. Xiaoyan Liu4,
  4. Gaowen Chen1,
  5. Xiaoya Zhang3,
  6. Xiaomei Liang1,
  7. Vladimir Isachenko5,
  8. Yanwei Sha6,
  9. Yifeng Wang1
  1. 1 Obstetrics and Gynecology Center, Department of Obstetrics and Gynecology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
  2. 2 School of Medicine, Yunnan University, Kunming, Yunnan, China
  3. 3 School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, Fujian, China
  4. 4 Reproductive Medicine Center, Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China
  5. 5 Research Group for Reproductive Medicine, Department of Obstetrics and Gynecology, Medical Faculty, University of Cologne, Cologne, North Rhine-Westphalia, Germany
  6. 6 Department of Andrology, United Diagnostic and Research Center for Clinical Genetics, Fujian Provincial Key Laboratory of Reproductive Health Research, Women and Children's Hospital & School of Medicine, Xiamen University, Xiamen, Fujian, China
  1. Correspondence to Dr Yifeng Wang, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China; wangyifeng{at}smu.edu.cn; Dr Yanwei Sha, Women and Children's Hospital & School of Medicine, Xiamen University, Xiamen, Fujian, China; shayanwei928{at}126.com; Dr Vladimir Isachenko, Department of Obstetrics and Gynecology, Medical Faculty, University of Cologne, Cologne, North Rhine-Westphalia, Germany; vladimir.isachenko{at}uk-koeln.de

Abstract

Background Asthenozoospermia is a major factor contributing to male infertility. The mitochondrial sheath (MS), an important organelle in the midpiece of spermatozoa, is crucial to sperm motility. ARMC12 is a mitochondrial peripheral membrane protein. Deletion of Armc12 impairs the arrangement of MS and causes infertility in mice. However, the role of ARMC12 in human asthenozoospermia remains unknown.

Objective To study the genetic defects in patients with asthenozoospermia.

Methods A total of 125 patients with asthenozoospermia and 120 men with proven fertility were recruited. Whole-exome sequencing and Sanger sequencing were performed for genetic analysis. Papanicolaou staining, HE staining, immunofluorescent staining, transmission electron microscopy and field emission scanning electron microscopy were employed to observe the morphological and structural defects of the spermatozoa and testes. Armc12-knockout mice were generated using the CRISPR-Cas9 system. Intracytoplasmic sperm injection was used to treat the patients.

Results Biallelic ARMC12 mutations were identified in three patients, including homozygous mutations in two siblings from a consanguineous family and compound heterozygous mutations in one sporadic patient. ARMC12 is mainly expressed in the midpiece of elongated and late spermatids in the human testis. The patients’ spermatozoa displayed multiple midpiece defects, including absent MS and central pair, scattered or forked axoneme and incomplete plasma membrane. Spermatozoa from Armc12-/- mice showed parallel defects in the midpiece. Moreover, two patients were treated with intracytoplasmic sperm injection and achieved good outcomes.

Conclusion Our findings prove for the first time that defects in ARMC12 cause asthenozoospermia and multiple midpiece defects in humans.

  • Genetics, Medical
  • Genetics
  • Genetic Variation
  • Human Genetics
  • Reproductive medicine

Data availability statement

Data are available on reasonable request.

https://doi.org/10.1136/jmedgenet-2021-108137

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    Data availability statement

    Data are available on reasonable request.

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    Footnotes

    • WL, XW and XL contributed equally.

    • Contributors YW, YS and VI conceived and designed the experiments. WL and XW performed the genetic analysis, performed the experiments and wrote the manuscript. GC and XL performed the bioinformatic analyses. YS, YW and XL contributed to sample processing and performed the clinical assessments. YS, YW, VI and WL contributed to the analysis and discussion of the data. All authors have read and agreed to the published version of the manuscript. YW is the guarantor of the research.

    • Funding This work was supported by grants from the National Natural Science Foundation of China (Grant Nos. 82001616, 82071697 and 81871200), the China Postdoctoral Science Foundation (2021M701621), the Medical Innovation Project of Fujian Province (Grant No. 2020CXB053), the Medical and Health Guidance Project of Xiamen (Grant No. 3502Z20199140) and the open project of NHC Key Laboratory of Male Reproduction and Genetics in Guangzhou (Grant Nos. KF201807 and KF202004).

    • 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.