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Case Reports
. 2025 May;32(5):1557-1565.
doi: 10.1007/s43032-024-01729-y. Epub 2024 Oct 23.

A Compound Heterozygous Pathogenic Variant in ZP2 Gene Causes Female Infertility

Shulin Yang  1 , Zongzhe Li  2 , Xinling Ren  3 , Jing Yue  4
Affiliations
Case Reports

A Compound Heterozygous Pathogenic Variant in ZP2 Gene Causes Female Infertility

Shulin Yang et al. Reprod Sci. 2025 May.

Abstract

The oocyte maturation defect 6 is an autosomal recessive hereditary disease caused by a homozygous variant in ZP2 gene. It is characterized by female primary infertility due to an abnormally thin zona pellucida (ZP) and defective sperm binding. Here we identified a compound heterozygous variant (c.1924C > T and c.1695-2A > G) in ZP2 gene in a Chinese Han family. Quantitative real-time PCR showed that the variant c.1924C > T significantly decreased the expression of truncated ZP2 message RNA by the nonsense-mediated decay pathway. Minigene assays showed the c.1695-2A > G variant led to an extra-61-nt preservation of intron 15 at the junction between exons 15 and 16 during transcription. Both variants (c.1924C > T and c.1695-2A > G) resulted in truncated ZP2 proteins (p.R642X and p.C566Hfs*2) that lost the transmembrane domain, which prevented the secretion of the mutant ZP2 proteins and produced a structurally abnormal ZP, thus resulting in female infertility. This study further elucidated the pathogenic mechanism of these two variants and provided new support for the genetic diagnosis of female infertility.

Keywords: ZP2; Compound heterozygous variants; Female infertility; Oocyte maturation defect; Zona pellucida.

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Conflict of interest statement

Declarations. Ethics Approval: The publication of this manuscript has been reviewed and approved by the ethics committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (reference TJ-IRB20210111). Patient Consent: We obtained fully informed written consent from all participants for participation in this study and publication of this study. Competing Interests: The authors declare no financial or non-financial interests that are directly or indirectly related to the work submitted for publication.

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