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Novel biallelic loss-of-function variants in ZP1 identified in an infertile female with empty follicle syndrome

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

Abstract

Purpose

Empty follicle syndrome (EFS) refers to the inability to obtain mature oocytes after appropriate ovarian stimulation during the process of in vitro fertilization (IVF). However, the specific cause and mechanism of action underlying EFS remain to be further explored. Herein we aimed to investigate the clinical and genetic characteristics of EFS.

Methods

After data were collected in an infertile family, we performed whole-exome sequencing (WES) on the patient and confirmed the pathogenic mutations through Sanger sequencing. Western immunoblotting, immunofluorescence staining, and minigene assay were further used to investigate the negative effects of these mutations.

Results

Absence of oocytes was observed over 2 cycles of IVF in the patient, and we evaluated the novel compound heterozygous mutations c.2T>A (p. M1K) and c.1112+1G>T of the zona pellucida glycoprotein 1 gene (ZP1, MIM# 195000) by WES. For the family under study, EFS was classified as an autosomal recessive inheritance pattern. The results of western blotting and immunofluorescence staining analyses confirmed that the missense mutation of c.2T>A [p. M1K] resulted in almost missing protein production. Additionally, using a minigene assay, we demonstrated the deleterious effect on the ZP1 gene of the splice site mutation c.1112+1G>T, which caused truncation of ZP1 protein.

Conclusions

The compound heterozygous mutations of ZP1 gene identified in this study by genetic and functional experiments constituted a novel genetic cause of EFS, and further study will expand its use in the clinical and molecular diagnoses of EFS.

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Funding

This work was supported by General Program of China Post-doctoral Science Foundation (2018 M640920).

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Author notes

  1. Mohan Liu and Ying Shen contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, China

    Mohan Liu

  2. Department of Obstetrics/Gynecology, Joint Laboratory of Reproductive Medicine (SCU-CUHK), Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, 610041, China

    Mohan Liu, Ying Shen, Xueguang Zhang & Xiang Wang

  3. Clinical Laboratory, The Fourth People’s Hospital of Zigong, Zigong, 643000, China

    Dan Li

  4. Reproduction Medical Center of West China Second University Hospital, Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu, 610041, China

    Yan Wang

Authors
  1. Mohan Liu
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  2. Ying Shen
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  3. Xueguang Zhang
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  4. Xiang Wang
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  5. Dan Li
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  6. Yan Wang
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Correspondence to Yan Wang.

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Liu, M., Shen, Y., Zhang, X. et al. Novel biallelic loss-of-function variants in ZP1 identified in an infertile female with empty follicle syndrome. J Assist Reprod Genet 37, 2151–2157 (2020). https://doi.org/10.1007/s10815-020-01855-x

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  • DOI: https://doi.org/10.1007/s10815-020-01855-x

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