Empty follicle syndrome (EFS) is the complete failure to retrieve oocytes after ovarian stimulation. Although LHCGR and ZP3 were identified as causative genes, it is still unclear what happens to these patients’ oocytes, and the pathogenesis of EFS remains obscure. Here, we identified six novel ZP1 mutations associated with EFS and female infertility that was inherited recessively in five unrelated families. Studies in CHO-K1 cells showed that these mutations resulted in either degradation or truncation of ZP1 protein. Immunohistochemistry using ovarian serial sections demonstrated that all preantral follicles had normal architecture, but with a thin ZP, lacking ZP1, surrounding the growing oocytes. The antral follicles were also defective in normal cumulus–oocyte complex organisation, leading us to speculate that the lack of ZP1 might lead to oocyte degeneration or increased fragility of the oocyte during follicular puncture, ultimately resulting in EFS. To our knowledge, this is the first study that presents morphological evidence showing normal preantral folliculogenesis with abnormal ZP assembly in EFS patients. Our data provides a better understanding of the biological functions of ZP1 in human ZP assembly and folliculogenesis and gives new insights into the pathogenesis of EFS and possible therapeutic developments.
Background: Empty follicle syndrome (EFS) is defined as the complete failure to retrieve oocytes after ovarian stimulation. Although several mutations in ZP1, ZP2, ZP3, and LHCGR have been identified as genetic causes of EFS, its pathogenesis is still not well-understood.Methods: Whole-exome sequencing (WES) was employed to identify the candidate pathogenic mutations, which were then verified by Sanger sequencing. A study in CHO-K1 cells was performed to analyze the effect of the mutation on protein expression. Additionally, immunohistochemistry (IHC) staining was used to examine follicular development and zona pellucida (ZP) assembly in the ovary of an EFS patient.Results: A novel heterozygous deletion in ZP3 (c.565_579del[p.Thr189_Gly193del]) was identified in the EFS patient. It was inherited dominantly and resulted in significant degradation of the ZP3 protein. Oocytes with degenerated cytoplasm and abnormal ZP assembly were observed in follicles up to the secondary stage, and many empty follicle-like structures were present.Conclusion: We identified a novel ZP3 mutation that expands the mutational spectrum associated with human EFS. We also showed the abnormal follicular development and ZP assembly of the EFS patient with the heterozygous ZP3 mutation, which provides new insights into the pathogenesis of EFS.
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