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  • Bi-allelic variants in chromatoid body protein TDRD6 cause spermiogenesis defects and severe oligoasthenoteratozoospermia in humans

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Genotype-phenotype correlations
Original research
Bi-allelic variants in chromatoid body protein TDRD6 cause spermiogenesis defects and severe oligoasthenoteratozoospermia in humans
  1. Rui Guo1,2,3,
  2. Huan Wu1,2,3,
  3. Xiaoyu Zhu1,2,3,
  4. Guanxiong Wang1,2,3,
  5. Kaiqin Hu1,4,5,
  6. Kuokuo Li1,4,5,
  7. Hao Geng1,4,5,
  8. Chuan Xu1,4,5,
  9. Chenwan Zu1,4,5,
  10. Yang Gao1,4,5,
  11. Dongdong Tang1,2,3,
  12. Yunxia Cao1,2,3,
  13. Xiaojin He6
  1. 1 Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
  2. 2 NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, Anhui, 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, Anhui, China
  4. 4 Engineering Research Center of Biopreservation and Artifical Organs, Ministry of Education, Hefei, Anhui, China
  5. 5 Anhui Province Key Laboratory of Reproductive Health and Genetics, Hefei, Anhui, China
  6. 6 Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
  1. Correspondence to Professor Xiaojin He, Department of Obstetrics and Gynecology, Shanghai Jiao Tong University School of Medicine, Shanghai, China; xiaojinhe{at}sjtu.edu.cn; Professor Yunxia Cao; caoyunxia6{at}126.com; Dr Dongdong Tang; tangdongdong{at}ahmu.edu.cn

Abstract

Background The association between the TDRD6 variants and human infertility remains unclear, as only one homozygous missense variant of TDRD6 was found to be associated with oligoasthenoteratozoospermia (OAT).

Methods Whole-exome sequencing and Sanger sequencing were employed to identify potential pathogenic variants of TDRD6 in infertile men. Histology, immunofluorescence, immunoblotting and ultrastructural analyses were conducted to clarify the structural and functional abnormalities of sperm in mutated patients. Tdrd6-knockout mice were generated using the CRISPR–Cas9 system. Total RNA-seq and single-cell RNA-seq (scRNA-seq) analyses were used to elucidate the underlying molecular mechanisms, followed by validation through quantitative RT-PCR and immunostaining. Intracytoplasmic sperm injection (ICSI) was also used to assess the efficacy of clinical treatment.

Results Bi-allelic TDRD6 variants were identified in five unrelated Chinese individuals with OAT, including homozygous loss-of-function variants in two consanguineous families. Notably, besides reduced concentrations and impaired motility, a significant occurrence of acrosomal hypoplasia was detected in multiple spermatozoa among five patients. Using the Tdrd6-deficient mice, we further elucidate the pivotal role of TDRD6 in spermiogenesis and acrosome identified. In addition, the mislocalisation of crucial chromatoid body components DDX4 (MVH) and UPF1 was also observed in round spermatids from patients harbouring TDRD6 variants. ScRNA-seq analysis of germ cells from a patient with TDRD6 variants revealed that TDRD6 regulates mRNA metabolism processes involved in spermatid differentiation and cytoplasmic translation.

Conclusion Our findings strongly suggest that TDRD6 plays a conserved role in spermiogenesis and confirms the causal relationship between TDRD6 variants and human OAT. Additionally, this study highlights the unfavourable ICSI outcomes in individuals with bi-allelic TDRD6 variants, providing insights for potential clinical treatment strategies.

  • Genetics, Medical
  • Human Genetics
  • Mutation
  • RNA-Seq
  • Semen Analysis

Data availability statement

Data are available upon reasonable request. Not applicable.

https://doi.org/10.1136/jmg-2023-109766

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    Data availability statement

    Data are available upon reasonable request. Not applicable.

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    Footnotes

    • RG, HW, XZ and GW contributed equally.

    • Contributors RG, HW and XH conceived and designed the study. HG, CX, CZ and YG recruited the patients and control individuals, collected samples and performed routine semen analysis. KL, DT and HW performed the WES and further Sanger sequencing. XZ, GW and KH performed the experiments. RG, DT, YC and XH supervised the study, analysed the data and wrote the manuscript. XH is the guarantor of this study.

    • Funding This work was supported by the National Natural Science Foundation of China (Grant numbers: 82201834, 81971441 and 82171607), Natural Science Foundation of Anhui Province (Grant number: 2208085QH233), Basic and Clinical Cooperative Research promotion Program of Anhui Medical University (Grant number: 2021xkjT030), National Key R&D Program of China (2021YFC2700901), Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (Grant number 2019PT310002) and Research Fund of Anhui Institute of Translational Medicine (Grant number ZHYX2020A001).

    • 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.