Novel Loss-of-function Variants of ZP3 Associated with Premature Ovarian Insufficiency

Abstract

Premature ovarian insufficiency (POI) is one of the leading causes of female infertility. To date, the genetic etiology of POI has been elucidated in approximately 20-25% of the total cases. The human zona pellucida (ZP) plays an important role in the organization and differentiation of granulosa cells, follicle formation, and sperm recognition. Mutations in ZP1, ZP2, and ZP3 have been reported to cause female infertility due to oocyte degeneration, empty follicle, or in vitro fertilization failure. In this study, we identified three novel missense mutations in ZP3 (NM_001110354.2): c.643G > A (p.Asp215Asn), c.215 C > T (p.Thr72Ile), and c.152T > C (p.Leu51Pro) in three sporadic Han Chinese POI patients through whole-exome sequencing. These variants are absent from population databases and were predicted to be deleterious by multiple in silico tools. Structure prediction analysis showed that the affected amino acid altered the ZP3 protein structure. Western blot further confirmed that these ZP3 variants reduced the expression and secretion of ZP components. In summary, this study reports three novel deleterious variants in ZP3 associated with POI, thereby broadening the mutation spectrum of ZP3 in POI patients.

Keywords: ZP3; Missense mutation; Premature ovarian insufficiency (POI); Protein expression; Whole-exome sequencing (WES).