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Mutations in PLCZ1 induce male infertility associated with polyspermy and fertilization failure

  • Genetics
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

To investigate the genetic causes of polyspermy and total fertilization failure (TFF) in two independent male patients suffering from male infertility.

Methods

Immunofluorescence (IF) staining was used to detect the localization of the PLCζ protein in sperm and the maternal pronucleus in the zygote. Genomic DNA samples were extracted from the peripheral blood of patients and their families. The ExAC database was used to identify the frequency of corresponding mutations. The PLCZ1 mutations were validated by Sanger sequencing. The pathogenicity of the identified mutations and their possible effects on the protein were assessed using in silico tools and molecular modeling.

Results

We identified a reported homozygous mutation c.588C > A (p.Cys196Ter) and a compound heterozygous mutation c.2 T > C(p.Met1Thr)/c.590G > A (p.Arg197His) with one novel mutation in PLCZ1. The IF results showed that these multipronuclear zygotes formed as a result of polyspermy. In silico analysis predicted that the mutations result in disease-causing proteins. IF staining revealed that PLCζ is abnormally localized in the sperm samples from the two affected patients. Assisted oocyte activation (AOA) successfully rescued polyspermy and TFF and achieved pregnancy in two patients with the PLCZ1 mutation.

Conclusion

We identified a homozygous mutation in PLCZ1 (c.588C > A [p.Cys196Ter]) in a male patient with polyspermy after in vitro fertilization (IVF) as well as a compound heterozygous mutation c.2 T > C(p.Met1Thr)/c.590G > A (p.Arg197His) with one novel mutation in a male patient with fertilization failure after intracytoplasmic sperm injection (ICSI), and we provide evidence that the homozygous mutation can cause polyspermy and the compound heterozygous mutation can cause fertilization failure.

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Availability of data and materials

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank all families for participating in this study.

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Authors and Affiliations

  1. State Key Laboratory of Reproductive Medicine, The Center for Clinical Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People’s Republic of China

    Yawen Peng, Yuting Lin, Kai Deng, Jiandong Shen, Yugui Cui, Jiayin Liu, Xiaoyu Yang & Feiyang Diao

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  1. Yawen Peng
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  2. Yuting Lin
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  3. Kai Deng
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  4. Jiandong Shen
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  5. Yugui Cui
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  6. Jiayin Liu
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  8. Feiyang Diao
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Correspondence to Xiaoyu Yang or Feiyang Diao.

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Peng, Y., Lin, Y., Deng, K. et al. Mutations in PLCZ1 induce male infertility associated with polyspermy and fertilization failure. J Assist Reprod Genet 40, 53–64 (2023). https://doi.org/10.1007/s10815-022-02670-2

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  • DOI: https://doi.org/10.1007/s10815-022-02670-2

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