Genetic variations in zona pellucida glycoproteins: Implications for fertility and ART outcomes

The success of Assisted Reproductive Technologies (ART), such as IVF and ICSI, relies heavily on the health of the oocyte, with abnormalities in oocyte morphology often leading to ART failure. The zona pellucida (ZP), an extracellular matrix surrounding the oocyte, plays a crucial role in sperm-egg recognition, species-specific fertilization, and protecting the embryo until implantation. This article investigates the impact of single nucleotide polymorphisms (SNPs) in the genes encoding ZP glycoproteins (hZP1, hZP2, hZP3, and hZP4) on fertility. Through a comprehensive meta-analysis of existing data, we identified 47 SNPs in hZP1, 17 in hZP2, 8 in hZP3, and 2 in hZP4 from female patients undergoing infertility treatment. Most of these SNPs are localized within the zona domain, which is crucial for the polymerization and structural integrity of the ZP. Functional predictions, based on in silico tools, suggest that these SNPs lead to impaired ZP glycoprotein secretion, crosslinking, and fibril formation; resulting in conditions like empty follicle syndrome (EFS) or oocytes with a thin or absent ZP. These deficiencies could significantly affect oocyte viability and reduce ART success rates. It could also affect folliculogenesis. Our results highlight the importance of genetic screening in women experiencing ART failure, especially those with ZP abnormalities. Additionally, the absence of reported SNPs in the N-terminal domain of ZP2 which is crucial for sperm interaction, suggests a potential area for further investigation, particularly in morphologically normal oocytes that may harbor undetected SNPs.