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Novel mutations in ZP2 and ZP3 cause female infertility in three patients

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

Abstract

Purpose

The aim of this study was to identify the disease-causing mutations found in three infertile female patients who were diagnosed with abnormal zona pellucida (ZP) and empty follicle syndrome (EFS).

Methods

We performed whole-exome sequencing and Sanger sequencing to identify and verify the disease-causing mutations. Additionally, we performed Western blotting and mini-gene splicing assay to assess the effects of the mutations.

Results

We identified two novel compound heterozygous mutations in the ZP2 gene, a patient with an abnormal ZP carrying a novel compound heterozygous mutation (c.1695-2A>G and c.1831G>T, p.V611F) and a patient with EFS carrying a novel compound heterozygous mutation (c.1695-2A>G and c.1924 C>T, p.R642*). Furthermore, we identified a patient with typical abnormal ZP carrying a novel heterozygous mutation (c.400G>T, p.A134S) in the ZP3 gene. The splice site mutation (c.1695-2A>G) can cause abnormal pre-mRNA splicing that inserts an extra sequence of 61 bp in the mRNA of ZP2, and the missense mutation (c.1831G>T) can cause a decrease of ZP2 protein in HEK293 cells.

Conclusion

We identified three novel mutations in the ZP2 gene and the ZP3 gene in three Chinese female patients with infertility. Our study expands the spectrum of ZP gene mutations and phenotypes and thus is beneficial in the genetic diagnosis of infertility in females.

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Acknowledgements

We would like to thank Sang Qing and Lei Wang from Fudan University for kindly providing the gift of ZP2 and ZP3 plasmids. And, we thank the family members for their enthusiastic participation in this study.

Funding

This work was supported by The National Natural Science Foundation of China (81000079, 81170165 and 81870959 to X.Z.), supported by The Program for HUST Academic Frontier Youth Team (2016QYTD02), and supported by The Fundamental Research Funds for the Central Universities (HUST: 2019JYCXJJ035).

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Author notes

  1. Weimin Jia and Qingsong Xi contributed equally to this work.

Authors and Affiliations

  1. College of Life Science and Technology, Huazhong University of Science and Technology, 1037 Luoyu Road, Wuhan, 430074, Hubei, China

    Weimin Jia, Yalin Luo, Meiqi Hou, Dazhi Zhang, Xue Yang & Xianqin Zhang

  2. Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    Qingsong Xi, Lixia Zhu, Zhou Li, Juan Hu & Lei Jin

Authors
  1. Weimin Jia
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  2. Qingsong Xi
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  3. Lixia Zhu
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  4. Yalin Luo
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  5. Zhou Li
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  9. Juan Hu
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  10. Lei Jin
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  11. Xianqin Zhang
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Corresponding authors

Correspondence to Juan Hu or Xianqin Zhang.

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Ethics approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the ethics committee on human subject research at Huazhong University of Science and Technology (2019S1160) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Written informed consent was obtained from the parents.

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The authors declare no competing interests.

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Supplementary information

Supplementary Fig. 1

Sanger sequencing of the PCR products from the cells transfected with mutant-type ZP2 mini gene (PNG 771 kb)

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Jia, W., Xi, Q., Zhu, L. et al. Novel mutations in ZP2 and ZP3 cause female infertility in three patients. J Assist Reprod Genet 39, 1205–1215 (2022). https://doi.org/10.1007/s10815-022-02466-4

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  • DOI: https://doi.org/10.1007/s10815-022-02466-4

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