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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.<\/jats:p>","DOI":"10.1093\/hmg\/ddad070","type":"journal-article","created":{"date-parts":[[2023,5,3]],"date-time":"2023-05-03T15:18:13Z","timestamp":1683127093000},"page":"2326-2334","source":"Crossref","is-referenced-by-count":12,"title":["Bi-allelic variants in<i>ASTL<\/i>cause abnormal fertilization or oocyte maturation defects"],"prefix":"10.1093","volume":"32","author":[{"given":"Yang","family":"Zeng","sequence":"first","affiliation":[{"name":"Institute of Pediatrics , Children\u2019s Hospital of Fudan University, the Institutes of Biomedical Sciences, and the State Key Laboratory of Genetic Engineering, , Shanghai 200032 , China"},{"name":"Fudan University , Children\u2019s Hospital of Fudan University, the Institutes of Biomedical Sciences, and the State Key Laboratory of Genetic Engineering, , Shanghai 200032 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Biaobang","family":"Chen","sequence":"additional","affiliation":[{"name":"NHC Key Lab of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical Technologies), Fudan University , Shanghai 200032 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiming","family":"Sun","sequence":"additional","affiliation":[{"name":"The International Peace Maternity and Child Health Hospital , School of Medicine, , Shanghai 200030 , China"},{"name":"Shanghai Jiao Tong University , School of Medicine, , Shanghai 200030 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aijun","family":"Yang","sequence":"additional","affiliation":[{"name":"Center for Reproductive Medicine, Affiliated Hospital of Jining Medical University , Jining , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Wu","sequence":"additional","affiliation":[{"name":"The Department of Assisted Reproduction, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine , Shanghai 200011 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Li","sequence":"additional","affiliation":[{"name":"The Department of Assisted Reproduction, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine , Shanghai 200011 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Mu","sequence":"additional","affiliation":[{"name":"Institute of Pediatrics , Children\u2019s Hospital of Fudan University, the Institutes of Biomedical Sciences, and the State Key Laboratory of Genetic Engineering, , Shanghai 200032 , China"},{"name":"Fudan University , Children\u2019s Hospital of Fudan University, the Institutes of Biomedical Sciences, and the State Key Laboratory of Genetic Engineering, , Shanghai 200032 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihua","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Pediatrics , Children\u2019s Hospital of Fudan University, the Institutes of Biomedical Sciences, and the State Key Laboratory of Genetic Engineering, , Shanghai 200032 , China"},{"name":"Fudan University , Children\u2019s Hospital of Fudan University, the Institutes of Biomedical Sciences, and the State Key Laboratory of Genetic Engineering, , Shanghai 200032 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjing","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Pediatrics , Children\u2019s Hospital of Fudan University, the Institutes of Biomedical Sciences, and the State Key Laboratory of Genetic Engineering, , Shanghai 200032 , China"},{"name":"Fudan University , Children\u2019s Hospital of Fudan University, the Institutes of Biomedical Sciences, and the State Key Laboratory of Genetic Engineering, , Shanghai 200032 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhou","family":"Zhou","sequence":"additional","affiliation":[{"name":"Institute of Pediatrics , Children\u2019s Hospital of Fudan University, the Institutes of Biomedical Sciences, and the State Key Laboratory of Genetic Engineering, , Shanghai 200032 , China"},{"name":"Fudan University , Children\u2019s Hospital of Fudan University, the Institutes of Biomedical Sciences, and the State Key Laboratory of Genetic Engineering, , Shanghai 200032 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Dong","sequence":"additional","affiliation":[{"name":"Institute of Pediatrics , Children\u2019s Hospital of Fudan University, the Institutes of Biomedical Sciences, and the State Key Laboratory of Genetic Engineering, , Shanghai 200032 , China"},{"name":"Fudan University , Children\u2019s Hospital of Fudan University, the Institutes of Biomedical Sciences, and the State Key Laboratory of Genetic Engineering, , Shanghai 200032 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruyi","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Pediatrics , Children\u2019s Hospital of Fudan University, the Institutes of Biomedical Sciences, and the State Key Laboratory of Genetic Engineering, , Shanghai 200032 , China"},{"name":"Fudan University , Children\u2019s Hospital of Fudan University, the Institutes of Biomedical Sciences, and the State Key Laboratory of Genetic Engineering, , Shanghai 200032 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxi","family":"Luo","sequence":"additional","affiliation":[{"name":"Institute of Pediatrics , Children\u2019s Hospital of Fudan University, the Institutes of Biomedical Sciences, and the State Key Laboratory of Genetic Engineering, , Shanghai 200032 , China"},{"name":"Fudan University , Children\u2019s Hospital of Fudan University, the Institutes of Biomedical Sciences, and the State Key Laboratory of Genetic Engineering, , Shanghai 200032 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxi","family":"Sun","sequence":"additional","affiliation":[{"name":"Shanghai Ji Ai Genetics and IVF Institute , Obstetrics and Gynecology Hospital, , Shanghai 200011 , China"},{"name":"Fudan University , Obstetrics and Gynecology Hospital, , Shanghai 200011 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Sang","sequence":"additional","affiliation":[{"name":"Institute of Pediatrics , Children\u2019s Hospital of Fudan University, the Institutes of Biomedical Sciences, and the State Key Laboratory of Genetic Engineering, , Shanghai 200032 , China"},{"name":"Fudan University , Children\u2019s Hospital of Fudan University, the Institutes of Biomedical Sciences, and the State Key Laboratory of Genetic Engineering, , Shanghai 200032 , China"},{"name":"Zhuhai Fudan Innovation Institute , Zhuhai 519031 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanping","family":"Kuang","sequence":"additional","affiliation":[{"name":"The Department of Assisted Reproduction, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine , Shanghai 200011 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Pediatrics , Children\u2019s Hospital of Fudan University, the Institutes of Biomedical Sciences, and the State Key Laboratory of Genetic Engineering, , Shanghai 200032 , China"},{"name":"Fudan University , Children\u2019s Hospital of Fudan University, the Institutes of Biomedical Sciences, and the State Key Laboratory of Genetic Engineering, , Shanghai 200032 , China"},{"name":"Zhuhai Fudan Innovation Institute , Zhuhai 519031 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,5,3]]},"reference":[{"key":"2023070515075532000_ref1","doi-asserted-by":"crossref","first-page":"1588","DOI":"10.1093\/humrep\/dew082","article-title":"International Committee for Monitoring Assisted Reproductive Technologies world report: assisted reproductive technology 2008, 2009 and 2010","volume":"31","author":"Dyer","year":"2016","journal-title":"Hum. 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Endocrinol."},{"key":"2023070515075532000_ref11","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1002\/mrd.23331","article-title":"Preventing polyspermy in mammalian eggs-contributions of the membrane block and other mechanisms","volume":"87","author":"Evans","year":"2020","journal-title":"Mol. Reprod. Dev."},{"key":"2023070515075532000_ref12","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1038\/nature18595","article-title":"Molecular architecture of the human sperm IZUMO1 and egg JUNO fertilization complex","volume":"534","author":"Aydin","year":"2016","journal-title":"Nature"},{"key":"2023070515075532000_ref13","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1083\/jcb.201112094","article-title":"Ovastacin, a cortical granule protease, cleaves ZP2 in the zona pellucida to prevent polyspermy","volume":"197","author":"Burkart","year":"2012","journal-title":"J. Cell Biol."},{"key":"2023070515075532000_ref14","doi-asserted-by":"crossref","first-page":"e1006580","DOI":"10.1371\/journal.pgen.1006580","article-title":"A unique egg cortical granule localization motif is required for ovastacin sequestration to prevent premature ZP2 cleavage and ensure female fertility in mice","volume":"13","author":"Xiong","year":"2017","journal-title":"PLoS Genet."},{"key":"2023070515075532000_ref15","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1007\/s00439-021-02388-8","article-title":"ASTL is mutated in female infertility","volume":"141","author":"Maddirevula","year":"2022","journal-title":"Hum. Genet."},{"key":"2023070515075532000_ref16","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1515\/hsz-2012-0149","article-title":"Functional and structural insights into astacin metallopeptidases","volume":"393","author":"Gomis-Ruth","year":"2012","journal-title":"Biol. 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