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Homozygous variant in DRC3 (LRRC48) gene causes asthenozoospermia and male infertility

Journal of Human Genetics volume 69, pages 401–409 (2024)Cite this article

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Abstract

Human infertility affects 10–15% of couples. Asthenozoospermia accounts for 18% of men with infertility and is a common male infertility phenotype. The nexin-dynein regulatory complex (N-DRC) is a large protein complex in the sperm flagellum that connects adjacent doublets of microtubules. Defects in the N-DRC can disrupt cilia/flagellum movement, resulting in primary ciliary dyskinesia and male infertility. Using whole-exome sequencing, we identified a pathological homozygous variant of the dynein regulatory complex subunit 3 (DRC3) gene, which expresses leucine-rich repeat-containing protein 48, a component of the N-DRC, in a patient with asthenozoospermia. The variant ENST00000313838.12: c.644dup (p. Glu216GlyfsTer36) causes premature translational arrest of DRC3, resulting in a dysfunctional DRC3 protein. The patient’s semen count, color, and pH were normal according to the reference values of the World Health Organization guidelines; however, sperm motility and progressive motility were reduced. DRC3 protein was not detected in the patient’s sperm and the ultrastructure of the patient’s sperm flagella was destroyed. More importantly, the DRC3 variant reduced its interaction with other components of the N-DRC, including dynein regulatory complex subunits 1, 2, 4, 5, 7, and 8. Our data not only revealed the essential biological functions of DRC3 in sperm flagellum movement and structure but also provided a new basis for the clinical genetic diagnosis of male infertility.

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Fig. 1: Identification of homozygous DRC3 mutation in a patient with asthenozoospermia.
Fig. 2: Morphology and ultrastructure of the patient’s sperm.
Fig. 3: Evaluation of DRC3.
Fig. 4: DRC3 variant reduced its interaction with DRC1, 2, 4, 5, 7, and 8.
Fig. 5: The structure models of DRC3 WT and MU.

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Acknowledgements

We wish to thank the patient and medical staff of Department of Andrology/Sichuan Human Sperm Bank, West China Second University Hospital.

Funding

This study was supported by the Clinical Discipline Development Fund, West China Second University Hospital of China (KL061).

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Authors and Affiliations

  1. Department of Andrology/Sichuan Human Sperm Bank, West China Second University Hospital, Sichuan University, Chengdu, China

    Jiao Qin, Jinyan Xu & Fuping Li

  2. Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China

    Jiao Qin, Jinyan Xu & Fuping Li

  3. Department of Medical Genetics, West China Second University Hospital of Sichuan University, Chengdu, 610041, China

    Jinyu Wang & Shanling Liu

  4. Department of Ecology and Evolution, Biological Sciences Division, The University of Chicago, 1101 E 57th Street, Chicago, IL, 60637, USA

    Jianhai Chen

  5. Department of Obstetrics, Key Laboratory of Birth Defects and Related Disease of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University, Chengdu, 610041, China

    Dong Deng

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  1. Jiao Qin
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Contributions

Jiao Qin designed the study and wrote the paper. Jinyu Wang performed the experiments and analyzed the data. Jianhai Chen analyzed the sequencing data and identified the variant gene. Jinyan Xu collected clinical samples and signed informed consent with human subjects, Fuping Li, Dong Deng and Shanling Liu directed this study.

Corresponding authors

Correspondence to Shanling Liu, Dong Deng or Fuping Li.

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The authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest.

Ethics

The study was reviewed and approved by Review Board of the West China Second University Hospital in China, Number 2020-102. All human subjects provided informed consent for this study.

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Qin, J., Wang, J., Chen, J. et al. Homozygous variant in DRC3 (LRRC48) gene causes asthenozoospermia and male infertility. J Hum Genet 69, 401–409 (2024). https://doi.org/10.1038/s10038-024-01253-6

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