{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T15:53:05Z","timestamp":1791129185344,"version":"4.1.0"},"reference-count":65,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T00:00:00Z","timestamp":1791072000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T00:00:00Z","timestamp":1791072000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82471650"],"award-info":[{"award-number":["82471650"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Although hundreds of genes have been shown to impair fertility in animal models, the identification of corresponding genetic causes in humans remains largely unknown. Here, we identified biallelic pathogenic variants in\n                    <jats:italic>WFS1<\/jats:italic>\n                    in three unrelated infertile men presenting with oligoasthenoteratozoospermia and fertilization failure. Remarkably, using the establishment of a\n                    <jats:italic>Wfs1<\/jats:italic>\n                    knockout (KO) mouse model, we found that WFS1 deficiency leads to disorganized sperm mitochondrial sheath assembly, structural abnormalities in the sperm head\u2013neck junction, and defects in the sperm acrosome, which are consistent with the infertile phenotypes observed in affected individuals. Furthermore, meiotic defects were observed in spermatocytes from KO mice, particularly manifested as impaired sex chromosome synapsis. Mechanistically, WFS1 interacts with PIAS4 to promote the SUMOylation of key spermatogenesis\u2010associated proteins, including SUN5, HSF5, CFAP74, and IZUMO4, which in turn competitively inhibits their K48\u2010linked ubiquitin\u2010mediated degradation during spermatogenesis. Collectively, our study was the first to establish a critical role for WFS1 in human reproduction and to uncover the molecular mechanisms underlying WFS1\u2010mediated regulation of spermatogenesis. These findings provided both fundamental insights and important clinical implications for reproductive medicine.\n                  <\/jats:p>","DOI":"10.1002\/advs.78060","type":"journal-article","created":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T15:47:46Z","timestamp":1791128866000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["WFS1 Deficiency Impairs PIAS4\u2010Associated SUMOylation and Increases Ubiquitin\u2010Mediated Spermatogenesis\u2010Related Protein Degradation Leading to Testicular Male Infertility"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-3431-1137","authenticated-orcid":false,"given":"Yunchuan","family":"Tian","sequence":"first","affiliation":[{"name":"Department of Major Genetic Diseases, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guicheng","family":"Zhao","sequence":"additional","affiliation":[{"name":"Reproductive Andrology and Sichuan Human Sperm Bank, Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8930-6801","authenticated-orcid":false,"given":"Xiang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Major Genetic Diseases, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyao","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Major 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and Children (Sichuan University), Ministry of Education, West China Second University Hospital Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyue","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Major Genetic Diseases, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liangchai","family":"Zhuo","sequence":"additional","affiliation":[{"name":"Department of Major Genetic Diseases, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital Sichuan University  Chengdu 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