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Bi-allelic variants in human TCTE1/DRC5 cause asthenospermia and male infertility

European Journal of Human Genetics volume 30, pages 721–729 (2022)Cite this article

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Abstract

Asthenozoospermia (AZS) is a common male infertility phenotype, accounting for 18% of infertile patients. The N-DRC (Nexin-dynein Regulatory Complex) complex is the motor regulating device in the flagellum, which is found in most eukaryotic organisms with flagellum. The deletion of TCTE1 (T-Complex-Associated Testis-Expressed 1), a component of the N-DRC complex also known as DRC5 (Dynein regulatory complex subunit 5), has been shown to cause asthenospermia in mice. This study mainly introduces a clinical case of male infertility with normal sperm count, normal morphological structure, but low motility and weak forward movement. By whole-exome sequencing, we found that TCTE1 became a frameshift mutant, ENST00000371505.5: c.396_397insTC (p.Arg133Serfs*33), resulting in the rapid degradation of TCTE1 protein and male infertility. This phenotype is similar to the Tcte1−/− (Tcte1 knockout) mice, which showed structural integrity but reduced motility. Further, different from mice, in vitro Fertilization (IVF) could successfully solve the patient’s problem of infertility. Our data provides a better understanding of the biological functions of TCTE1 in human flagellum assembly and male fertility.

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Fig. 1: Schematic representation of the mutated TCTE1 variant and its expression profile.
Fig. 2: Morphological observations of the patient sperm using TEM and immunofluorescence.
Fig. 3: Expression and localization of N-DRC components in the human and mice sperm flagellum.
Fig. 4: Mice IVF experiment and movement analysis.
Fig. 5: Morphological observation of brain and tracheal cilia in mice.

Data availability

The data associated with this article can be shared upon reasonable request.

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Acknowledgements

We extend our appreciation to Fan Hu and Jinyang Cai for their support and provision of the microscope.

Funding

This work was supported by the Natural Science Foundation of China (31771654 and 32070842 to ML, 32000584 to RH, 82171607 to XH, 81901541 to HW); the Non-profit Central Research Institute Fund of the Chinese Academy of Medical Sciences (Grant no. 2019PT310002 to YC); the Natural Science Foundation of Jiangsu Province (Grants No. BK20190081 to ML); the Science and Technology Project of Anhui Province (Grant No.202003a07020012 to PZ); and Qing Lan Project (to ML).

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Author notes

  1. These authors contributed equally: Shushu Zhou, Huan Wu, Jintao Zhang.

Authors and Affiliations

  1. State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, 211166, China

    Shushu Zhou, Jintao Zhang, Siyu Liu & Mingxi Liu

  2. Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China

    Huan Wu, Xiaojin He, Ping Zhou, Rong Hua & Yunxia Cao

  3. NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, 230032, China

    Huan Wu, Xiaojin He, Ping Zhou, Rong Hua & Yunxia Cao

  4. Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People’s Republic of China, Hefei, 230032, China

    Rong Hua & Yunxia Cao

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  1. Shushu Zhou
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Correspondence to Rong Hua, Yunxia Cao or Mingxi Liu.

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Clinical exome sequencing was approved by the ethics committees of the First Affiliated Hospital of Anhui Medical University, Number P2020-12-36. All human subjects provided informed consent for this study.

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Zhou, S., Wu, H., Zhang, J. et al. Bi-allelic variants in human TCTE1/DRC5 cause asthenospermia and male infertility. Eur J Hum Genet 30, 721–729 (2022). https://doi.org/10.1038/s41431-022-01095-w

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