Novel biallelic ASTL variants are associated with polyspermy and female infertility: A successful live birth following ICSI treatment

• Published in: Gene 2023-12, Vol.887, p.147745-147745, Article 147745
• Main Authors: Wu, Huixia, Che, Jianfang, Zheng, Wei, Cheng, Dehua, Gong, Fei, Lu, Guangxiu, Lin, Ge, Dai, Can
• Format: Article
• Language: English
• Subjects: active sites; ASTL; eggs; embryogenesis; enzyme stability; enzymes; female fertility; Female infertility; genes; homozygosity; human fertility; hydrogen; in vitro fertilization; intracytoplasmic sperm injection; oocytes; Ovastacin; Polyspermy; spermatozoa; women
• ISSN: 0378-1119; 1879-0038
• DOI: 10.1016/j.gene.2023.147745

•Two ASTL variants, one of which is novel, were associated with female infertility that was characterized by polyspermy in vitro and was inherited recessively in a Chinese family.•ASTL-related polyspermy is characterized by sperm bound avidly to the zona pellucida, extra sperm in the perivitelline space, and delay in multiple pronucleus formation.•ASTL-related defect in polyspermy blocking could be bypassed by intracytoplasmic sperm injection. Fertilization of the egg by the sperm is the first vital stage of embryogenesis. In mammals, only one sperm is incorporated into the oocyte. Polyspermy is a key anomaly of fertilization that is generally lethal to the embryo. To date, only a few causative genes for polyspermy have been reported. In a recent study, a homozygous variant in astacin-like metalloendopeptidase (ASTL), which encodes the ovastacin enzyme that cleaves ZP2 to prevent polyspermy, was found to be associated with female infertility characterized by polyspermy in vitro. Herein, we identified two ASTL variants in a Chinese woman likely responsible for her primary infertility and polyspermy in in vitro fertilization. Both variants were located within the key catalytic domain and predicted to alter hydrogen bonds, potentially impairing protein stability. Moreover, expression and immunoblot analyses in CHO-K1 cells indicated abnormal ovastacin zymogen activation or decreased enzyme stability. Intracytoplasmic sperm injection treatment successfully bypassed the defect in polyspermy blocking and resulted in a live birth. Our study associates ASTL variants with human infertility and further supports the contribution of this gene to blocking polyspermy in humans. Our findings expand the spectrum of ASTL mutations and should facilitate the diagnosis of oocyte-borne polyspermy.