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A novel homozygous variant in ZP2 causes abnormal zona pellucida formation and female infertility

  • Genetics
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Abstract

Purpose

We aimed to identify pathogenic variants in two infertile sisters in a family with a thin zona pellucida (ZP) phenotype.

Methods

Whole-exome sequencing was performed in the two affected sisters, and Sanger sequencing was used to confirm the identified variants. The effects of the identified variant were further investigated in mouse oocytes and Chinese hamster ovary (CHO) cells.

Results

We identified a novel homozygous frameshift variant in ZP2 (c.1235_1236del, p.Q412Rfs*17) in the two affected individuals. Immunoblotting demonstrated that the variant produced a truncated ZP2 protein that was expressed at low levels in CHO cells. Immunofluorescence in mouse oocytes confirmed the decreased protein level of mutant ZP2, although the subcellular localization was not affected. In addition, immunoprecipitation showed that the pathogenic variant reduced the interaction between ZP2 and ZP3.

Conclusion

This study identified a novel pathogenic variant in ZP2 that produces a truncated ZP2 protein. The variant might disrupt the assembly of ZP2-ZP3 dimers, thus resulting in a thin ZP and female infertility.

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References

  1. Vander Borght M, Wyns C. Fertility and infertility: Definition and epidemiology. Clin Biochem. 2018;62:2–10.

    Article  Google Scholar 

  2. Rudak E, Dor J, Kimchi M, Goldman B, Levran D, Mashiach S. Anomalies of human oocytes from infertile women undergoing treatment by in vitro fertilization. Fertil Steril. 1990;54(2):292–6.

    Article  CAS  Google Scholar 

  3. Feng R, Sang Q, Kuang Y, Sun X, Yan Z, Zhang S, et al. Mutations in TUBB8 and Human Oocyte Meiotic Arrest. N Engl J Med. 2016;374(3):223–32.

    Article  CAS  Google Scholar 

  4. Christou-Kent M, Kherraf ZE, Amiri-Yekta A, Le Blevec E, Karaouzene T, Conne B, et al. PATL2 is a key actor of oocyte maturation whose invalidation causes infertility in women and mice. EMBO Mol Med. 2018;10(5):e8515.

  5. Sang Q, Li B, Kuang Y, Wang X, Zhang Z, Chen B, et al. Homozygous mutations in WEE2 cause fertilization failure and female infertility. Am J Hum Genet. 2018;102(4):649–57.

    Article  CAS  Google Scholar 

  6. Gupta SK. The human egg’s zona pellucida. Curr Top Dev Biol. 2018;130:379–411.

    Article  CAS  Google Scholar 

  7. Rankin T, Talbot P, Lee E, Dean J. Abnormal zonae pellucidae in mice lacking ZP1 result in early embryonic loss. Development. 1999;126(17):3847–55.

    Article  CAS  Google Scholar 

  8. Bokhove M, Jovine L. Structure of Zona Pellucida Module Proteins. Curr Top Dev Biol. 2018;130:413–42.

    Article  CAS  Google Scholar 

  9. Rankin TL, O'Brien M, Lee E, Wigglesworth K, Eppig J, Dean J. Defective zonae pellucidae in Zp2-null mice disrupt folliculogenesis, fertility and development. Development. 2001;128(7):1119–26.

    Article  CAS  Google Scholar 

  10. Luo G, Zhu L, Liu Z, Yang X, Xi Q, Li Z, et al. Novel mutations in ZP1 and ZP2 cause primary infertility due to empty follicle syndrome and abnormal zona pellucida. J Assist Reprod Genet. 2020;37(11):2853–60.

    Article  Google Scholar 

  11. Huang H-L, Lv C, Zhao Y-C, Li W, He X-M, Li P, et al. Mutant ZP1 in Familial Infertility. N Engl J Med. 2014;370(13):1220–6.

    Article  CAS  Google Scholar 

  12. Xu Q, Zhu X, Maqsood M, Li W, Tong X, Kong S, et al. A novel homozygous nonsense ZP1 variant causes human female infertility associated with empty follicle syndrome (EFS). Mol Genet Genomic Med. 2020;8(7):e1269.

    Article  CAS  Google Scholar 

  13. Zhou Z, Ni C, Wu L, Chen B, Xu Y, Zhang Z, et al. Novel mutations in ZP1, ZP2, and ZP3 cause female infertility due to abnormal zona pellucida formation. Hum Genet. 2019;138(4):327–37.

    Article  CAS  Google Scholar 

  14. Liu W, Li K, Bai D, Yin J, Tang Y, Chi F, et al. Dosage effects of ZP2 and ZP3 heterozygous mutations cause human infertility. Hum Genet. 2017;136(8):975–85.

    Article  CAS  Google Scholar 

  15. Dai C, Hu L, Gong F, Tan Y, Cai S, Zhang S, et al. ZP2 pathogenic variants cause in vitro fertilization failure and female infertility. Genet Med. 2018;21(2):431–40.

    Article  Google Scholar 

  16. Chen T, Bian Y, Liu X, Zhao S, Wu K, Yan L, et al. A recurrent missense mutation in ZP3 causes empty follicle syndrome and female infertility. Am J Hum Genet. 2017;101(3):459–65.

    Article  CAS  Google Scholar 

  17. Burkart AD, Xiong B, Baibakov B. Jim¨¦nez-Movilla M, Dean J. Ovastacin, a cortical granule protease, cleaves ZP2 in the zona pellucida to prevent polyspermy. J Cell Biol. 2012;197(1):37–44.

    Article  CAS  Google Scholar 

  18. Cao Q, Zhao C, Zhang X, Zhang H, Lu Q, Wang C, et al. Heterozygous mutations in ZP1 and ZP3 cause formation disorder of ZP and female infertility in human. J Cell Mol Med. 2020;24(15):8557–66.

    Article  CAS  Google Scholar 

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Acknowledgements

We would like to sincerely thank the patients and their families for their support and participation.

Funding

This study was funded by the National Key Research and Development Program of China (2018YFC1003800, 2017YFC1001500, and 2016YFC1000600), the National Natural Science Foundation of China (81725006, 81822019, 81771581, 81971450, and 81971382), the project supported by the Shanghai Municipal Science and Technology Major Project (2017SHZDZX01), Project of the Shanghai Municipal Science and Technology Commission (19JC1411001), the Natural Science Foundation of Shanghai (19ZR1444500), the Shuguang Program of the Shanghai Education Development Foundation and the Shanghai Municipal Education Commission (18SG03), the Foundation of Shanghai Health and Family Planning Commission (20154Y0162), the Capacity Building Planning Program for Shanghai Women and Children’s Health Service, and the collaborative innovation center project construction for Shanghai Women and Children’s Health.

Author information

Author notes

  1. Biaobang Chen and Congjian Xu contributed equally as corresponding authors.

Authors and Affiliations

  1. Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, China

    Yiming Sun & Congjian Xu

  2. Institute of Pediatrics, Children’s Hospital of Fudan University, the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, the Ministry of Science and Technology, the Institutes of Biomedical Sciences, and the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China

    Yang Zeng, Zhou Zhou, Qing Sang & Lei Wang

  3. Shanghai Ji Ai Genetics and IVF Institute, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China

    Hua Chen, Jing Fu & Xiaoxi Sun

  4. NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Fudan University, Shanghai, 200032, China

    Biaobang Chen

Authors
  1. Yiming Sun
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  2. Yang Zeng
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  3. Hua Chen
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  4. Zhou Zhou
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  5. Jing Fu
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  6. Qing Sang
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  7. Lei Wang
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  8. Xiaoxi Sun
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  9. Biaobang Chen
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  10. Congjian Xu
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Corresponding authors

Correspondence to Biaobang Chen or Congjian Xu.

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Ethics approval

The study was approved by the Ethics Committee of the Medical College of Fudan University and the Reproductive Study Ethics Committee of Shanghai Ji Ai Genetics and IVF Institute.

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The authors declare that they have no conflict of interest.

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Sun, Y., Zeng, Y., Chen, H. et al. A novel homozygous variant in ZP2 causes abnormal zona pellucida formation and female infertility. J Assist Reprod Genet 38, 1239–1245 (2021). https://doi.org/10.1007/s10815-021-02107-2

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  • DOI: https://doi.org/10.1007/s10815-021-02107-2

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