Introduction: The zona pellucida (ZP) is a highly organized glycoprotein matrix that surroundsmammalian oocytes and embryos, playing a crucial role in reproduction. It is essential for oocytegrowth, follicle development, sperm-oocyte interactions during fertilization, and the protection ofearly embryos prior to implantation. The human zona pellucida ZP consists of four glycoproteins(ZP۱ to ZP۴) secreted during oocyte growth. ZP۲, ZP۳, and ZP۴ are organized into filaments, withZP۱ homodimers linking these filaments through a common ZP-N structural unit. The aim of thisstudy was to investigate the relationship between
ZP۱ mutations and associated human infertilityphenotypes.Methods: This review utilized keywords such as ZP۱, mutation, and human diseases to search thePubMed, Google Scholar, and Elsevier Science databases for relevant literature.Results: The literature indicates that mutations in the
ZP۱ gene, which typically occur ashomozygous or compound heterozygous variants, have been linked to abnormal oocytephenotypes, including zona pellucida deficiency,
empty follicle syndrome (EFS), and oocytematuration defect (OMD). For instance, a homozygous c.۱۲۲۸C>T (p.Arg۴۱۰Trp) mutation hasbeen reported, which leads to oocyte degeneration due to the absence of a surrounding zonapellucida, underscoring the critical role of
ZP۱ in oocyte development. These mutations disruptthe structural and functional integrity of the zona pellucida, leading to female
infertility andhighlighting the pivotal role of
ZP۱ in oocyte development and reproductive success. To date, approximately ۳۵ variants of
ZP۱ have been identified, including ۱۹ nonsense and missensemutations, six splicing variants, nine small deletions, and one small insertion-deletion variant.Conclusion: This review summarizes human diseases associated with
ZP۱ mutations and theirclinical implications. Developing predictive models that integrate
ZP۱ mutation profiles withclinical characteristics could improve the assessment of pregnancy potential and guidepersonalized treatment strategies, offering valuable insights for reproductive medicine
