2. Academic Validation
  3. Bi-allelic variants in ASTL cause abnormal fertilization or oocyte maturation defects

Bi-allelic variants in ASTL cause abnormal fertilization or oocyte maturation defects

  • Hum Mol Genet. 2023 May 3;ddad070. doi: 10.1093/hmg/ddad070.
Yang Zeng 1,  Biaobang Chen 2,  Yiming Sun 3,  Aijun Yang 4,  Ling Wu 5,  Bin Li 5,  Jian Mu 1,  Zhihua Zhang 1,  Wenjing Wang 1,  Zhou Zhou 1,  Jie Dong 1,  Ruyi Liu 1,  Yuxi Luo 1,  Xiaoxi Sun 6,  Qing Sang 1 7,  Yanping Kuang 5,  Lei Wang 1 7
Affiliations

Affiliations

  • 1 Institute of Pediatrics, Children's Hospital of Fudan University, the Institutes of Biomedical Sciences, and the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China.
  • 2 NHC Key Lab of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical Technologies), Fudan University, Shanghai, 200032, China.
  • 3 The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
  • 4 Center for Reproductive Medicine, Affiliated Hospital of Jining Medical University, Jining, China.
  • 5 The Department of Assisted Reproduction, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
  • 6 Shanghai Ji Ai Genetics and IVF Institute, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China.
  • 7 Zhuhai Fudan Innovation Institute, Zhuhai, 519031, China.
PMID: 37133443 DOI: 10.1093/hmg/ddad070
Abstract

Fertilization is a fundamental process of development, and the blocking mechanisms act at the zona pellucida (ZP) and plasma membrane of the egg to prevent any additional sperm from binding, permeating, and fusing after fertilization. In clinical practice, some couples undergoing recurrent IVF failures that mature oocytes had abnormal fertilization for unknown reason. Ovastacin encoded by ASTL cleave the ZP protein ZP2 and play a key role in preventing polyspermy. Here, we identified bi-allelic variants in ASTL that are mainly characterized by fertilization problems in humans. All four independent affected individuals had bi-allelic frameshift variants or predicted damaging missense variants, which follow a Mendelian recessive inheritance pattern. The frameshift variants significantly decreased the quantity of ASTL protein in vitro. And all missense variants affected the enzymatic activity that cleaves ZP2 in mouse egg in vitro. Three knock-in female mice (corresponding to three missense variants in patients) all show subfertility due to low embryo developmental potential. This work presents strong evidence that pathogenic variants in ASTL cause female infertility and provides a new genetic marker for the diagnosis of fertilization problems.

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