{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:08:39Z","timestamp":1791331719974,"version":"4.3.1"},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2022,1,6]],"date-time":"2022-01-06T00:00:00Z","timestamp":1641427200000},"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":["81725006, 81822019, 81771581, 81971450, 81971382, 82001538 and 82071642"],"award-info":[{"award-number":["81725006, 81822019, 81771581, 81971450, 81971382, 82001538 and 82071642"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Shanghai Municipal Science and Technology Major Project","award":["2017SHZDZX01"],"award-info":[{"award-number":["2017SHZDZX01"]}]},{"name":"Project of the Shanghai Municipal Science and Technology Commission","award":["19JC1411001"],"award-info":[{"award-number":["19JC1411001"]}]},{"DOI":"10.13039\/100007219","name":"Natural Science Foundation of Shanghai","doi-asserted-by":"publisher","award":["19ZR1444500 and 21ZR1404800"],"award-info":[{"award-number":["19ZR1444500 and 21ZR1404800"]}],"id":[{"id":"10.13039\/100007219","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Shuguang Program of the Shanghai Education Development Foundation and the Shanghai Municipal Education Commission","award":["18SG03"],"award-info":[{"award-number":["18SG03"]}]},{"name":"Foundation of the Shanghai Health and Family Planning Commission","award":["20154Y0162"],"award-info":[{"award-number":["20154Y0162"]}]},{"name":"Capacity Building Planning Program for Shanghai Women"},{"name":"Children\u2019s Health Service"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>STUDY QUESTION<\/jats:title>\n                  <jats:p>Are mutations in MOS (MOS proto-oncogene, serine\/threonine kinase) involved in early embryonic arrest in infertile women?<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>SUMMARY ANSWER<\/jats:title>\n                  <jats:p>We identified mutations in MOS that may cause human female infertility characterized by preimplantation embryonic arrest (PREMBA), and the effects of the mutations in human embryonic kidney 293T (HEK293T cells) and mouse oocytes provided evidence for a causal relation between MOS and female infertility.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>WHAT IS KNOWN ALREADY<\/jats:title>\n                  <jats:p>MOS, an activator of mitogen-activated protein kinase, mediates germinal vesicle breakdown and metaphase II arrest. Female MOS knockout mice are viable but sterile. Thus, MOS seems to be an important part of the mammalian cell cycle mechanism that regulates female meiosis.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>STUDY DESIGN, SIZE, DURATION<\/jats:title>\n                  <jats:p>Whole-exome sequencing, bioinformatics filtering analysis and genetic analysis were performed to identify two different biallelic mutations in MOS in two independent families. The infertile patients presenting with early embryonic arrest were recruited from October 2018 to June 2020.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>PARTICIPANTS\/MATERIALS, SETTING, METHODS<\/jats:title>\n                  <jats:p>The female patients diagnosed with primary infertility were recruited from the reproduction centres of local hospitals. Genomic DNA from the affected individuals, their family members and healthy controls was extracted from peripheral blood. We performed whole-exome sequencing in patients diagnosed with PREMBA. Functional effects of the mutations were investigated in HEK293T cells by western blotting and in mouse oocytes by microinjection and immunofluorescence.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>MAIN RESULTS AND THE ROLE OF CHANCE<\/jats:title>\n                  <jats:p>We identified the homozygous missense mutation c.285C&amp;gt;A (p.(Asn95Lys)) and the compound heterozygous mutations c.467delG (p.(Gly156Alafs*18)) and c.956G&amp;gt;A (p.(Arg319His)) in MOS in two independent patients. The mutations c.285C&amp;gt;A (p.(Asn95Lys)) and c.467delG (p.(Gly156Alafs*18)) reduced the protein level of MOS, and all mutations reduced the ability of MOS to phosphorylate its downstream target, extracellular signal-regulated kinase1\/2. In addition, the identified mutations reduced the capacity of exogenous human MOS to rescue the metaphase II exit phenotype, and the F-actin cytoskeleton of mouse oocytes was affected by the patient-derived mutations.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>LIMITATIONS, REASONS FOR CAUTION<\/jats:title>\n                  <jats:p>Owing to the lack of in vivo data from patient oocytes, the exact molecular mechanism affected by MOS mutations and leading to PREMBA is still unknown and should be further investigated using knock-out or knock-in mice.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>WIDER IMPLICATIONS OF THE FINDINGS<\/jats:title>\n                  <jats:p>We identified recessive mutations in MOS in two independent patients with the PREMBA phenotype. Our findings reveal the important role of MOS during human oocyte meiosis and embryonic development and suggest that mutations in MOS may be precise diagnostic markers for clinical genetic counselling.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>STUDY FUNDING\/COMPETING INTEREST(S)<\/jats:title>\n                  <jats:p>This work was supported by the National Natural Science Foundation of China (81725006, 81822019, 81771581, 81971450, 81971382,82001538 and 82071642), the project supported by the Shanghai Municipal Science and Technology Major Project (2017SHZDZX01), the Project of the Shanghai Municipal Science and Technology Commission (19JC1411001), the Natural Science Foundation of Shanghai (19ZR1444500 and 21ZR1404800), the Shuguang Program of the Shanghai Education Development Foundation and the Shanghai Municipal Education Commission (18SG03), the Foundation of the Shanghai Health and Family Planning Commission (20154Y0162), the Capacity Building Planning Program for Shanghai Women and Children\u2019s Health Service and the collaborative innovation centre project construction for Shanghai Women and Children\u2019s Health. The authors have no conflicts of interest to declare.<\/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\/deab281","type":"journal-article","created":{"date-parts":[[2021,12,16]],"date-time":"2021-12-16T12:09:19Z","timestamp":1639656559000},"page":"612-620","source":"Crossref","is-referenced-by-count":34,"title":["Bi-allelic mutations in <i>MOS<\/i> cause female infertility characterized by preimplantation embryonic arrest"],"prefix":"10.1093","volume":"37","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, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juanzi","family":"Shi","sequence":"additional","affiliation":[{"name":"Reproductive Center, Northwest Women\u2019s and Children\u2019s Hospital, Xi'an, Shaanxi, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiru","family":"Xu","sequence":"additional","affiliation":[{"name":"Fertility Center, Shenzhen Zhongshan Urology Hospital, Shenzhen, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Shi","sequence":"additional","affiliation":[{"name":"Reproductive Center, Northwest Women\u2019s and Children\u2019s Hospital, Xi'an, Shaanxi, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tonghua","family":"Wu","sequence":"additional","affiliation":[{"name":"Fertility Center, Shenzhen Zhongshan Urology Hospital, Shenzhen, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyan","family":"Li","sequence":"additional","affiliation":[{"name":"Fertility Center, Shenzhen Zhongshan Urology Hospital, Shenzhen, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Xue","sequence":"additional","affiliation":[{"name":"Reproductive Center, Northwest Women\u2019s and Children\u2019s Hospital, Xi'an, Shaanxi, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanchang","family":"Zhu","sequence":"additional","affiliation":[{"name":"Fertility Center, Shenzhen Zhongshan Urology Hospital, Shenzhen, Guangdong, 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, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9895-1394","authenticated-orcid":false,"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, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3400-0434","authenticated-orcid":false,"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, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,1,6]]},"reference":[{"key":"2022030206054509700_deab281-B1","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1186\/s13059-015-0792-0","article-title":"TLE6 mutation causes the earliest known human embryonic lethality","volume":"16","author":"Alazami","year":"2015","journal-title":"Genome Biol"},{"key":"2022030206054509700_deab281-B2","doi-asserted-by":"crossref","first-page":"gaab043","DOI":"10.1093\/molehr\/gaab043","article-title":"The subcortical maternal complex: emerging roles and novel perspectives","volume":"27","author":"Bebbere","year":"2021","journal-title":"Mol Hum Reprod"},{"key":"2022030206054509700_deab281-B3","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1038\/ncb2799","article-title":"A soft cortex is essential for asymmetric spindle positioning in mouse oocytes","volume":"15","author":"Chaigne","year":"2013","journal-title":"Nat Cell Biol"},{"key":"2022030206054509700_deab281-B4","doi-asserted-by":"crossref","first-page":"7032","DOI":"10.1073\/pnas.93.14.7032","article-title":"The Mos\/mitogen-activated protein kinase (MAPK) pathway regulates the size and degradation of the first polar body in maturing mouse oocytes","volume":"93","author":"Choi","year":"1996","journal-title":"Proc Natl Acad Sci USA"},{"key":"2022030206054509700_deab281-B5","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1038\/370065a0","article-title":"Disruption of c-mos causes parthenogenetic development of unfertilized mouse eggs","volume":"370","author":"Colledge","year":"1994","journal-title":"Nature"},{"key":"2022030206054509700_deab281-B6","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/biolre\/ioy163","article-title":"Actin cytoskeleton dynamics in mammalian oocyte meiosis","volume":"100","author":"Duan","year":"2019","journal-title":"Biol Reprod"},{"key":"2022030206054509700_deab281-B7","doi-asserted-by":"crossref","first-page":"350412","DOI":"10.1155\/2011\/350412","article-title":"Mos in the oocyte: how to use MAPK independently of growth factors and transcription to control meiotic divisions","volume":"2011","author":"Dupr\u00e9","year":"2011","journal-title":"J Signal Transduct"},{"key":"2022030206054509700_deab281-B8","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1126\/science.8235656","article-title":"Induction of metaphase arrest in cleaving Xenopus embryos by MAP kinase","volume":"262","author":"Haccard","year":"1993","journal-title":"Science"},{"key":"2022030206054509700_deab281-B9","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1038\/370068a0","article-title":"Parthenogenetic activation of oocytes in c-mos-deficient mice","volume":"370","author":"Hashimoto","year":"1994","journal-title":"Nature"},{"key":"2022030206054509700_deab281-B10","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1038\/nature05688","article-title":"A direct link of the Mos\u2013MAPK pathway to Erp1\/Emi2 in meiotic arrest of Xenopus laevis eggs","volume":"446","author":"Inoue","year":"2007","journal-title":"Nature"},{"key":"2022030206054509700_deab281-B11","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1007\/s004270000083","article-title":"The Mos\/MAPK pathway is involved in metaphase II arrest as a cytostatic factor but is neither necessary nor sufficient for initiating oocyte maturation in goldfish","volume":"210","author":"Kajiura-Kobayashi","year":"2000","journal-title":"Dev Genes Evol"},{"key":"2022030206054509700_deab281-B12","doi-asserted-by":"crossref","first-page":"1372","DOI":"10.1016\/S0006-291X(02)02070-3","article-title":"Successful inactivation of endogenous Oct-3\/4 and c-mos genes in mouse preimplantation embryos and oocytes using short interfering RNAs","volume":"296","author":"Kim","year":"2002","journal-title":"Biochem Biophys Res Commun"},{"key":"2022030206054509700_deab281-B13","doi-asserted-by":"crossref","first-page":"34736","DOI":"10.1074\/jbc.M606607200","article-title":"The anaphase-promoting complex\/cyclosome inhibitor Emi2 is essential for meiotic but not mitotic cell cycles","volume":"281","author":"Liu","year":"2006","journal-title":"J Biol Chem"},{"key":"2022030206054509700_deab281-B14","doi-asserted-by":"crossref","first-page":"1458","DOI":"10.1016\/j.cub.2005.07.030","article-title":"Calcium elevation at fertilization coordinates phosphorylation of XErp1\/Emi2 by Plx1 and CaMK II to release metaphase arrest by cytostatic factor","volume":"15","author":"Liu","year":"2005","journal-title":"Curr Biol"},{"key":"2022030206054509700_deab281-B15","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1083\/jcb.200604140","article-title":"Mouse Emi2 is required to enter meiosis II by reestablishing cyclin B1 during interkinesis","volume":"174","author":"Madgwick","year":"2006","journal-title":"J Cell Biol"},{"key":"2022030206054509700_deab281-B16","doi-asserted-by":"crossref","first-page":"103651","DOI":"10.1016\/j.ejmg.2019.04.008","article-title":"Abnormal cleavage and developmental arrest of human preimplantation embryos in vitro","volume":"63","author":"McCollin","year":"2020","journal-title":"Eur J Med Genet"},{"key":"2022030206054509700_deab281-B17","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1136\/jmedgenet-2018-105936","article-title":"Mutations in NLRP2 and NLRP5 cause female infertility characterised by early embryonic arrest","volume":"56","author":"Mu","year":"2019","journal-title":"J Med Genet"},{"key":"2022030206054509700_deab281-B18","first-page":"2546","article-title":"Mos stimulates MAP kinase in Xenopus oocytes and activates a MAP kinase in vitro","volume":"13","author":"Posada","year":"1993","journal-title":"Mol Cell Biol"},{"key":"2022030206054509700_deab281-B19","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1038\/315516a0","article-title":"Expression of c-mos proto-oncogene transcripts in mouse tissues","volume":"315","author":"Propst","year":"1985","journal-title":"Nature"},{"key":"2022030206054509700_deab281-B20","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1038\/342512a0","article-title":"The c-mos proto-oncogene product is a cytostatic factor responsible for meiotic arrest in vertebrate eggs","volume":"342","author":"Sagata","year":"1989","journal-title":"Nature"},{"key":"2022030206054509700_deab281-B21","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1101\/gad.320705","article-title":"Xenopus polo-like kinase Plx1 regulates XErp1, a novel inhibitor of APC\/C activity","volume":"19","author":"Schmidt","year":"2005","journal-title":"Genes Dev"},{"key":"2022030206054509700_deab281-B22","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1242\/jcs.02919","article-title":"Cytostatic factor: an activity that puts the cell cycle on hold","volume":"119","author":"Schmidt","year":"2006","journal-title":"J Cell Sci"},{"key":"2022030206054509700_deab281-B23","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1038\/sj.emboj.7600953","article-title":"Mammalian Emi2 mediates cytostatic arrest and transduces the signal for meiotic exit via Cdc20","volume":"25","author":"Shoji","year":"2006","journal-title":"EMBO J"},{"key":"2022030206054509700_deab281-B24","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1016\/S0960-9822(00)00753-3","article-title":"Asymmetric division in mouse oocytes: with or without Mos","volume":"10","author":"Verlhac","year":"2000","journal-title":"Curr Biol"},{"key":"2022030206054509700_deab281-B25","doi-asserted-by":"crossref","first-page":"2392","DOI":"10.1093\/humrep\/deab131","article-title":"FBXO43 variants in patients with female infertility characterized by early embryonic arrest","volume":"36","author":"Wang","year":"2021","journal-title":"Hum Reprod"},{"key":"2022030206054509700_deab281-B26","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/0012-1606(91)90347-6","article-title":"C-mos proto-oncogene product is partly degraded after release from meiotic arrest and persists during interphase in mouse zygotes","volume":"148","author":"Weber","year":"1991","journal-title":"Dev Biol"},{"key":"2022030206054509700_deab281-B27","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1016\/j.ajhg.2016.06.024","article-title":"Mutations in PADI6 cause female infertility characterized by early embryonic arrest","volume":"99","author":"Xu","year":"2016","journal-title":"Am J Hum Genet"},{"key":"2022030206054509700_deab281-B28","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1038\/355649a0","article-title":"Meiotic initiation by the mos protein in Xenopus","volume":"355","author":"Yew","year":"1992","journal-title":"Nature"},{"key":"2022030206054509700_deab281-B29","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1093\/molehr\/gau116","article-title":"Identification of a human subcortical maternal complex","volume":"21","author":"Zhu","year":"2015","journal-title":"Mol Hum Reprod"}],"container-title":["Human Reproduction"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/humrep\/article-pdf\/37\/3\/612\/42673891\/deab281.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/humrep\/article-pdf\/37\/3\/612\/42673891\/deab281.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,2]],"date-time":"2022-03-02T06:09:20Z","timestamp":1646201360000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/humrep\/article\/37\/3\/612\/6498326"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,6]]},"references-count":29,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,1,6]]},"published-print":{"date-parts":[[2022,3,1]]}},"URL":"https:\/\/doi.org\/10.1093\/humrep\/deab281","relation":{},"ISSN":["0268-1161","1460-2350"],"issn-type":[{"value":"0268-1161","type":"print"},{"value":"1460-2350","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,3,1]]},"published":{"date-parts":[[2022,1,6]]}}}