{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T00:54:08Z","timestamp":1793321648827,"version":"4.5.0"},"reference-count":10,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2023,1,13]],"date-time":"2023-01-13T00:00:00Z","timestamp":1673568000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100005150","name":"Chinese Academy of Medical Sciences","doi-asserted-by":"publisher","award":["2020RU001"],"award-info":[{"award-number":["2020RU001"]}],"id":[{"id":"10.13039\/501100005150","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2021YFC2700400"],"award-info":[{"award-number":["2021YFC2700400"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2021YFC2700701"],"award-info":[{"award-number":["2021YFC2700701"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82192874"],"award-info":[{"award-number":["82192874"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31871509"],"award-info":[{"award-number":["31871509"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82071606"],"award-info":[{"award-number":["82071606"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2023,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Total fertilization failure (TFF), which refers to fertilization failure in all mature oocytes, accounting for 5%\u201310% of in vitro fertilization (IVF) cycles and 1%\u20133% of intracytoplasmic sperm injection (ICSI) cycles in human. In this study, we recruited three unrelated primary infertile men with repeated cycles of TFF and performed whole\u2010exome sequencing to identify the potential pathogenic variants. We identified homozygous or compound\u2010heterozygous variants of paternal\u2010effect genes <jats:italic>ACTL7A<\/jats:italic> and <jats:italic>PLCZ1<\/jats:italic> that followed a Mendelian recessive inheritance pattern. Novel homozygous nonsense variant in <jats:italic>ACTL7A<\/jats:italic> [c.C146G: p.S49*] was identified in case 1, who came from a consanguineous family. Ultrastructural observation of <jats:italic>ACTL7A<\/jats:italic>\u2010mutated spermatozoa by transmission electron microscopy (TEM) indicated that apparent increased thickness of perinuclear matrix and the acrosome was detached from the nuclear envelop. Besides, two novel compound\u2010heterozygous variants in <jats:italic>PLCZ1<\/jats:italic> were identified in case 2 [c.1174+3A&gt;C:p.?; c.A1274G:p.N425S] and case 3 [c.136\u20101G&gt;C:p.?; c.G1358A:p.G453D]. Mutated spermatozoa from case 2 with reduced expression of <jats:italic>PLCZ1<\/jats:italic> showed apparent acrosome detachment by TEM analysis. And ICSI with assisted oocyte activation (ICSI\u2010AOA) treatment can partly rescue the TFF. Taken together, our findings revealed that novel biallelic variants in the paternal\u2010effect genes <jats:italic>ACTL7A<\/jats:italic> and <jats:italic>PLCZ1<\/jats:italic> were associated with human TFF, which expanding the spectrum of genetic causes and facilitating the genetic diagnosis of male infertility with TFF.<\/jats:p>","DOI":"10.1111\/cge.14293","type":"journal-article","created":{"date-parts":[[2023,1,3]],"date-time":"2023-01-03T05:01:45Z","timestamp":1672722105000},"page":"603-608","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Novel variants in <scp><i>ACTL7A<\/i><\/scp> and <scp><i>PLCZ1<\/i><\/scp> are associated with male infertility and total fertilization failure"],"prefix":"10.1111","volume":"103","author":[{"given":"Shuai","family":"Zhao","sequence":"first","affiliation":[{"name":"Center for Reproductive Medicine, Shandong University, Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong Key Laboratory of Reproductive Medicine Shandong Provincial Clinical Research Center for Reproductive Health  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Cui","sequence":"additional","affiliation":[{"name":"Center for Reproductive Medicine, Shandong University, Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong Key Laboratory of Reproductive Medicine Shandong Provincial Clinical Research Center for Reproductive Health  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunli","family":"Guo","sequence":"additional","affiliation":[{"name":"Center for Reproductive Medicine, Shandong University, Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong Key Laboratory of Reproductive Medicine Shandong Provincial Clinical Research Center for Reproductive Health  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1285-4842","authenticated-orcid":false,"given":"Boyang","family":"Liu","sequence":"additional","affiliation":[{"name":"Center for Reproductive Medicine, Shandong University, Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong Key Laboratory of Reproductive Medicine Shandong Provincial Clinical Research Center for Reproductive Health  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuehong","family":"Bian","sequence":"additional","affiliation":[{"name":"Center for Reproductive Medicine, Shandong University, Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong Key Laboratory of Reproductive Medicine Shandong Provincial Clinical Research Center for Reproductive Health  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Center for Reproductive Medicine, Shandong University, Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong Key Laboratory of Reproductive Medicine Shandong Provincial Clinical Research Center for Reproductive Health  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zijiang","family":"Chen","sequence":"additional","affiliation":[{"name":"Center for Reproductive Medicine, Shandong University, Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong Key Laboratory of Reproductive Medicine Shandong Provincial Clinical Research Center for Reproductive Health  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Zhao","sequence":"additional","affiliation":[{"name":"Center for Reproductive Medicine, Shandong University, Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong Key Laboratory of Reproductive Medicine Shandong Provincial Clinical Research Center for Reproductive Health  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,1,13]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/00001703-200306000-00001"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-015-0792-0"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2018.11.018"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aaz4796"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/der285"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/dez282"},{"issue":"1226","key":"e_1_2_11_8_1","first-page":"e1","article-title":"Anti\u2010ACTL7a antibodies: a cause of infertility","volume":"97","author":"Fu J","year":"2012","journal-title":"Fertil Steril"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.21454"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.rbmo.2014.01.008"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.humrep.a019071"}],"container-title":["Clinical 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