{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T05:16:42Z","timestamp":1792300602896,"version":"4.4.0"},"reference-count":34,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2022,2,25]],"date-time":"2022-02-25T00:00:00Z","timestamp":1645747200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31701085 and 81901473"],"award-info":[{"award-number":["31701085 and 81901473"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2018YFC1002804, 2017YFC1001500 and 2016YFC1000200"],"award-info":[{"award-number":["2018YFC1002804, 2017YFC1001500 and 2016YFC1000200"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004739","name":"Youth Innovation Promotion Association CAS","doi-asserted-by":"publisher","award":["2017114"],"award-info":[{"award-number":["2017114"]}],"id":[{"id":"10.13039\/501100004739","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>STUDY QUESTION<\/jats:title>\n                  <jats:p>Is a recurrent heterozygous mutation in ZP2, c.1925G&amp;gt;A (p.R642Q), associated with the Empty follicle syndrome (EFS)?<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>SUMMARY ANSWER<\/jats:title>\n                  <jats:p>ZP2, c.1925G&amp;gt;A (p.R642Q), led to female infertility related to EFS in humans and mice and resulted in ZP2 accumulation in the cytoplasm of oocytes.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>WHAT IS KNOWN ALREADY<\/jats:title>\n                  <jats:p>EFS is a complex disease defined as a complete failure of oocyte retrieval after ovarian stimulation and after repeated aspirations and flushing of mature ovarian follicles. Furin-mediated cleavage is a post-translational modification (PTM) involved in various physiological processes, but the clear role of PTM mediated by furin cleavage of ZP2 protein on female fertility needs to be further explored. PTM is required for proteins to function in physiological conditions, and its perturbation has been linked to a growing number of human pathologies. Zona pellucida (ZP) proteins, which are important for oocyte development, are regulated post-translationally by well-characterized glycosylation events, as well as by furin-mediated cleavage. However, knowledge of the relevance of the consensus furin cleavage site of ZP proteins in female reproduction remains lacking.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>STUDY DESIGN, SIZE, DURATION<\/jats:title>\n                  <jats:p>This was a basic medical research project to assess the pathogenicity of a heterozygous mutation in the ZP2 gene in EFS.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>PARTICIPANTS\/MATERIALS, SETTING, METHODS<\/jats:title>\n                  <jats:p>We studied 3 families with EFS and a control group 2213 women with proven fertility. Whole-exome sequencing detected a heterozygous mutation in the ZP2 gene in all EFS patients. The mouse strain Zp2Arg635Gln\/+ (ZP2R642Q) was generated by CRISPR-Cas9-mediated genome editing. RNA-sequencing was applied to investigate transcriptional changes in the ovaries of heterozygous ZP2R642Q knock-in (KI) mice compared to WT mice.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>MAIN RESULTS AND THE ROLE OF CHANCE<\/jats:title>\n                  <jats:p>We found a heterozygous mutation of ZP2, c.1925G&amp;gt;A (p.R642Q), in unrelated females with EFS, which was inherited in an autosomal-dominant manner. We used CRISPR-Cas9 to generate a mouse model encoding the orthologous variant of ZP2R642Q detected in humans, and the female ZP2R642Q KI mice recapitulated the human EFS phenotype. We further found the decreased expression of key genes involved in oocyte maturation in ZP2R642Q KI mice compared to WT mice by RNA-sequencing analysis.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>LARGE SCALE DATA<\/jats:title>\n                  <jats:p>N\/A.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>LIMITATIONS, REASONS FOR CAUTION<\/jats:title>\n                  <jats:p>Only three families affected by EFS with the mutation were available because of its rare incidence. Although we have found different expressions of the several indispensable genes related to oocyte development between WT mice and ZP2R642Q KI mice through RNA-sequencing analysis, the specific regulatory mechanisms of the oocyte apoptosis in ZP2R642Q KI mice need to be studied further.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>WIDER IMPLICATIONS OF THE FINDINGS<\/jats:title>\n                  <jats:p>These results are expected to open new avenues for researchers in the exploration of potential therapeutic strategies in treating EFS.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>STUDY FUNDING\/COMPETING INTEREST(S)<\/jats:title>\n                  <jats:p>This project is funded by the National Key Research and Development Program of China (2018YFC1002804, 2017YFC1001500 and 2016YFC1000200). All authors declared no competing interests.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>TRIAL REGISTRATION NUMBER<\/jats:title>\n                  <jats:p>N\/A.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/humrep\/deac026","type":"journal-article","created":{"date-parts":[[2022,2,10]],"date-time":"2022-02-10T20:11:22Z","timestamp":1644523882000},"page":"859-872","source":"Crossref","is-referenced-by-count":17,"title":["Identification of a heterozygous variant of <i>ZP2<\/i> as a novel cause of empty follicle syndrome in humans and mice"],"prefix":"10.1093","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6346-1002","authenticated-orcid":false,"given":"Ying","family":"Shen","sequence":"first","affiliation":[{"name":"Department of Obstetrics\/Gynecology, Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan 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