Zona Pellucida and Reproductive Success: The Critical Role of Zona Pellucida Glycoprotein 2

Reproduction, a fundamental biological process, is vital for ensuring species continuity. Despite its complexity, sexual reproduction increases genetic diversity and allows for more efficient removal of deleterious mutations, ultimately enhancing fitness and survival. However, human fertility rates have been steadily declining, with approximately 17.5% of the global adult population affected by infertility (WHO, 2023). 30%–40% of these cases are attributed to female factors, which can be genetic, chromosomal, hormonal, physiological or epigenetic. Zona Pellucida (ZP), a glycoprotein matrix surrounding a mammalian oocyte, plays a crucial role in folliculogenesis, fertilisation, and embryo protection. Human ZP is made up of four glycoproteins (ZP1–4), out of which ZP2 is essential for species-specific sperm binding, structural integrity, and embryo development. Female knockout mice lacking ZP2 exhibit infertility, indicating its critical role in oocyte maturation and fertilisation. Post-fertilisation, ovastacin-mediated ZP2 cleavage prevents polyspermy, a critical step ensuring viable embryonic development. Hence, female infertility can be caused by mutations in the ZP2 gene, which often present phenotypically as defective ZP formation, impaired oocyte development, and compromised fertilisation in infertile female patients. In this review article, we discuss the role played by ZP2 and how mutations in this gene can cause female infertility. Understanding the effects of mutations in the ZP2 gene in females will provide valuable insights into infertility mechanisms and their possible treatment strategies.