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A novel homozygous nonsense mutation in zona pellucida 1 (ZP1) causes human female empty follicle syndrome

  • Genetics
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Abstract

Purpose

To identify a pathogenic gene mutation in a female infertility proband characterized by empty follicle syndrome (EFS) and explore the genetic cause of EFS.

Methods

Whole exome sequencing (WES) was performed to identify the candidate pathogenic mutation. Sanger sequencing was used to validate the mutation in family members. The pathogenicity of the identified variant and its possible effects on the protein were evaluated with in silico tools. Immunofluorescence staining was used to study the possible mechanism of the mutation on affected oocyte.

Results

We identified a family with a novel homozygous nonsense mutation in zona pellucida 1 (ZP1) (c.199G > T [p.Glu67Ter]). Based on bioinformatics analysis, the mutation was predicted to be pathogenic. This variant generates a premature stop codon in exon 2 at the 199th nucleotide, and was inferred to result in a truncated ZP1 protein of 67 amino acids at the ZP-N1 domain. An in vitro study showed that the oocyte of the EFS proband was degenerated and the zona pellucida was absent. Additionally, the mutant ZP1 proteins were localized in the cytoplasm of the degenerated oocyte but not at the surface.

Conclusions

The novel mutation in ZP1 is a genetic cause of female infertility characterized by EFS. Our finding expands the genetic spectrum for EFS and will help justify the EFS diagnosis in patients.

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Data availability

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

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Acknowledgements

We acknowledge Anthony Liu for his English edits. The authors thank the patients and their family members for participating in this study.

Funding

This work was supported by the National Key Research and Development Program of China (2017YFC1001004, 2016YFC1000603) and National Nature and Science Foundation of China (81571403, 81401267, 81971374).

Author information

Author notes

  1. Jing Wang and Xiaoyu Yang contributed equally to this work.

Authors and Affiliations

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

    Jing Wang, Xiaoyu Yang, Xueping Sun, Long Ma, Yaoxue Yin, Guoxiang He, Yuan Zhang, Jie Zhou, Lingbo Cai, Jiayin Liu & Xiang Ma

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  1. Jing Wang
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Corresponding author

Correspondence to Xiang Ma.

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Ethics approval

The ethics committee of the First Affiliated Hospital of Nanjing Medical University approved this study. This study was performed in line with the principles of the Declaration of Helsinki.

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Supplementary information

Supplementary Fig. 1

Clinical characterization of the proband. (a,b) Image of bilateral follicles under vaginal ultrasound on Human Chorionic Gonadotropin (HCG) day. (c,d) Empty cumulus oocyte complexes from the proband. (PNG 6295 kb).

High resolution image (TIF 35952 kb).

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Wang, J., Yang, X., Sun, X. et al. A novel homozygous nonsense mutation in zona pellucida 1 (ZP1) causes human female empty follicle syndrome. J Assist Reprod Genet 38, 1459–1468 (2021). https://doi.org/10.1007/s10815-021-02136-x

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  • DOI: https://doi.org/10.1007/s10815-021-02136-x

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