{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T03:46:56Z","timestamp":1791172016910,"version":"4.1.0"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2021,4,12]],"date-time":"2021-04-12T00:00:00Z","timestamp":1618185600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Clinical Research Programs of Dongfang Hospital","award":["2019L02"],"award-info":[{"award-number":["2019L02"]}]},{"name":"Clinical Research Programs of Dongfang Hospital","award":["2019L18"],"award-info":[{"award-number":["2019L18"]}]},{"name":"Clinical Research Programs of Dongfang Hospital","award":["2020L14"],"award-info":[{"award-number":["2020L14"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,5,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Acephalic spermatozoa syndrome (ASS) is a rare teratozoospermia that leads to male infertility. Previous work suggested a genetic origin. Variants of Sad1 and UNC84 domain containing 5 (SUN5) are the main genetic cause of ASS; however, its pathogenesis remains unclear. Here, we performed whole-exome sequencing in 10 unrelated ASS and identified 2 homozygous variants, c.381delA[p.V128Sfs7*] and c.675C&amp;gt;A[p.Y225X], and 1 compound variant, c.88 C\u2009&amp;gt;\u2009T[p.R30X] and c.381 delA [p.V128Sfs7*], in SUN5 in 4 patients. The c.381delA variant had been identified as pathogenic in previous reports, while c.675C&amp;gt;A and c.88 C\u2009&amp;gt;\u2009T were two novel variants which could lead to a premature termination codon (PTC) and resulted in loss of SUN5, and may also be pathogenic. SUN5 mRNA and protein were present at very low levels in ASS patients with SUN5 nonsense mutation. Furthermore, the distribution of outer dense fiber protein 1 (ODF1) and Nesprin3 was altered in sperm of ASS patients with SUN5 variants. The co-immunoprecipitation analysis indicated that SUN5 and ODF1, SUN5 and Nesprin3, and ODF1 and Nesprin3 interacted with each other in transfected HEK293T cells. Thus, we propose that SUN5, Nesprin3, and ODF1 may form a \u2018triplet\u2019 structure through interactions at neck of sperm. When gene variants resulted in a loss of SUN5, the \u2018triplet\u2019 structure disappears and then the head-tail junction becomes fragile, leading to the occurrence of ASS.<\/jats:p>","DOI":"10.1093\/molehr\/gaab028","type":"journal-article","created":{"date-parts":[[2021,4,10]],"date-time":"2021-04-10T15:18:27Z","timestamp":1618067907000},"source":"Crossref","is-referenced-by-count":32,"title":["Pathogenesis of acephalic spermatozoa syndrome caused by SUN5 variant"],"prefix":"10.1093","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2028-4680","authenticated-orcid":false,"given":"Duo","family":"Zhang","sequence":"first","affiliation":[{"name":"Laboratory of Basic Medicine, Dongfang Hospital (900th Hospital of the Joint Logistics Team), Xiamen University, Fuzhou, China"},{"name":"Laboratory of Basic Medicine, Fuzong Clinical College of Fujian Medical University, Fuzhou, China"},{"name":"Fujian Provincial Key Laboratory of Transplant Biology, Dongfang Hospital (900th Hospital of the Joint Logistics Team), Xiamen University, Fuzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wu-Jian","family":"Huang","sequence":"additional","affiliation":[{"name":"Center for Reproductive Medicine, Dongfang Hospital (900th Hospital of the Joint Logistics Team), Xiamen University, Fuzhou, China"},{"name":"Center for Reproductive Medicine, Fuzong Clinical College of Fujian Medical University, Fuzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guo-Yong","family":"Chen","sequence":"additional","affiliation":[{"name":"Center for Reproductive Medicine, Dongfang Hospital (900th Hospital of the Joint Logistics Team), Xiamen University, Fuzhou, China"},{"name":"Center for Reproductive Medicine, Fuzong Clinical College of Fujian Medical University, Fuzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Hong","family":"Dong","sequence":"additional","affiliation":[{"name":"The Department of Clinical Laboratory, Fuzong Clinical College of Fujian University, Fuzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Tang","sequence":"additional","affiliation":[{"name":"Laboratory of Basic Medicine, Dongfang Hospital (900th Hospital of the Joint Logistics Team), Xiamen University, Fuzhou, China"},{"name":"Laboratory of Basic Medicine, Fuzong Clinical College of Fujian Medical University, Fuzhou, China"},{"name":"Fujian Provincial Key Laboratory of Transplant Biology, Dongfang Hospital (900th Hospital of the Joint Logistics Team), Xiamen University, Fuzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Laboratory of Basic Medicine, Dongfang Hospital (900th Hospital of the Joint Logistics Team), Xiamen University, Fuzhou, China"},{"name":"Laboratory of Basic Medicine, Fuzong Clinical College of Fujian Medical University, Fuzhou, China"},{"name":"Fujian Provincial Key Laboratory of Transplant Biology, Dongfang Hospital (900th Hospital of the Joint Logistics Team), Xiamen University, Fuzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing-Qin","family":"Li","sequence":"additional","affiliation":[{"name":"Laboratory of Basic Medicine, Dongfang Hospital (900th Hospital of the Joint Logistics Team), Xiamen University, Fuzhou, China"},{"name":"Laboratory of Basic Medicine, Fuzong Clinical College of Fujian Medical University, Fuzhou, China"},{"name":"Fujian Provincial Key Laboratory of Transplant Biology, Dongfang Hospital (900th Hospital of the Joint Logistics Team), Xiamen University, Fuzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Yan","family":"Mei","sequence":"additional","affiliation":[{"name":"Center for Reproductive Medicine, Dongfang Hospital (900th Hospital of the Joint Logistics Team), Xiamen University, Fuzhou, China"},{"name":"Center for Reproductive Medicine, Fuzong Clinical College of Fujian Medical University, Fuzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi-Hong","family":"Wang","sequence":"additional","affiliation":[{"name":"Laboratory of Basic Medicine, Dongfang Hospital (900th Hospital of the Joint Logistics Team), Xiamen University, Fuzhou, China"},{"name":"Laboratory of Basic Medicine, Fuzong Clinical College of Fujian Medical University, Fuzhou, China"},{"name":"Fujian Provincial Key Laboratory of Transplant Biology, Dongfang Hospital (900th Hospital of the Joint Logistics Team), Xiamen University, Fuzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9417-0817","authenticated-orcid":false,"given":"Feng-Hua","family":"Lan","sequence":"additional","affiliation":[{"name":"Laboratory of Basic Medicine, Dongfang Hospital (900th Hospital of the Joint Logistics Team), Xiamen University, Fuzhou, China"},{"name":"Laboratory of Basic Medicine, Fuzong Clinical College of Fujian Medical University, Fuzhou, China"},{"name":"Fujian Provincial Key Laboratory of Transplant Biology, Dongfang Hospital (900th Hospital of the Joint Logistics Team), Xiamen University, Fuzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,4,12]]},"reference":[{"key":"2021070802590191600_gaab028-B1","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.ydbio.2015.09.010","article-title":"SUN4 is essential for nuclear remodeling during mammalian spermiogenesis","volume":"407","author":"Calvi","year":"2015","journal-title":"Dev Biol"},{"key":"2021070802590191600_gaab028-B2","doi-asserted-by":"crossref","first-page":"1811","DOI":"10.1093\/humrep\/14.7.1811","article-title":"Acephalic spermatozoa and abnormal development of the head-neck attachment: a human syndrome of genetic origin","volume":"14","author":"Chemes","year":"1999","journal-title":"Hum Reprod"},{"key":"2021070802590191600_gaab028-B3","volume-title":"WHO Laboratory Manual for the Examination and Processing of Human Semen","author":"Cooper","year":"2010","edition":"5th edn"},{"key":"2021070802590191600_gaab028-B4","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1093\/molehr\/gaq099","article-title":"SPAG4L\/SPAG4L-2 are testis-specific SUN domain proteins restricted to the apical nuclear envelope of round spermatids facing the acrosome","volume":"17","author":"Frohnert","year":"2011","journal-title":"Mol Hum Reprod"},{"key":"2021070802590191600_gaab028-B5","first-page":"1","article-title":"Patients with acephalic spermatozoa syndrome linked to SUN5 mutations have a favorable pregnancy outcome from ICSI","volume":"201","author":"Fang","year":"2018","journal-title":"Hum Reprod"},{"key":"2021070802590191600_gaab028-B6","doi-asserted-by":"crossref","first-page":"e12072","DOI":"10.1371\/journal.pone.0012072","article-title":"Mammalian sperm head formation involves different polarization of two novel LINC complexes","volume":"5","author":"G\u00f6b","year":"2010","journal-title":"PLoS One"},{"key":"2021070802590191600_gaab028-B7","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1111\/j.1365-313X.2009.04038.x","article-title":"Characterization of SUN-domain proteins at the higher plant nuclear envelope","volume":"61","author":"Graumann","year":"2010","journal-title":"Plant J"},{"key":"2021070802590191600_gaab028-B8","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.1093\/hmg\/11.14.1647","article-title":"The Hook1 gene is non-functional in the abnormal spermatozoon head shape (Azh) mutant mouse","volume":"11","author":"Irene","year":"2002","journal-title":"Hum Mol Genet"},{"key":"2021070802590191600_gaab028-B9","first-page":"783","article-title":"X. Sperm-associated antigen 4 (SPAG4) as a new cancer marker interacts with Nesprin3 to regulate cell migration in lung carcinoma","volume":"40","author":"Ji","year":"2018","journal-title":"Oncol Rep"},{"key":"2021070802590191600_gaab028-B10","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1089\/dna.2010.1161","article-title":"SPAG4L, a novel nuclear envelope protein involved in the meiotic stage of spermatogenesis","volume":"30","author":"Jiang","year":"2011","journal-title":"DNA Cell Biol"},{"key":"2021070802590191600_gaab028-B30","doi-asserted-by":"crossref","first-page":"19914","DOI":"10.18632\/oncotarget.15251","article-title":"Whole-exome sequencing identified a homozygous BRDT mutation in a patient with acephalic spermatozoa","volume":"8","author":"Li","year":"2017","journal-title":"Oncotarget"},{"key":"2021070802590191600_gaab028-B11","doi-asserted-by":"crossref","first-page":"3171","DOI":"10.1242\/dev.126.14.3171","article-title":"UNC-84 localizes to the nuclear envelope and is required for nuclear migration and anchoring during C. elegans development","volume":"126","author":"Malone","year":"1999","journal-title":"Development"},{"key":"2021070802590191600_gaab028-B12","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet Med"},{"key":"2021070802590191600_gaab028-B13","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1111\/cge.13140","article-title":"TSGA10 is a novel candidate gene associated with acephalic spermatozoa","volume":"93","author":"Sha","year":"2018","journal-title":"Clin Genet"},{"key":"2021070802590191600_gaab028-B29","doi-asserted-by":"crossref","first-page":"e28199","DOI":"10.7554\/eLife.28199","article-title":"Essential role for SUN5 in anchoring sperm head to the tail","volume":"6","author":"Shang","year":"2017","journal-title":"eLife"},{"key":"2021070802590191600_gaab028-B14","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1006\/dbio.1999.9297","article-title":"Spag4, a novel sperm protein, binds outer dense-fiber protein Odf1 and localizes to microtubules of manchette and axoneme","volume":"211","author":"Shao","year":"1999","journal-title":"Dev Biol"},{"key":"2021070802590191600_gaab028-B15","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1016\/j.cell.2012.03.046","article-title":"LINC Complexes form by binding of three KASH peptides to the interfaces of trimeric SUN proteins","volume":"149","author":"Sosa","year":"2012","journal-title":"Cell"},{"key":"2021070802590191600_gaab028-B16","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1146\/annurev-cellbio-100109-104037","article-title":"Interactions between nuclei and the cytoskeleton are mediated by SUN-KASH nuclear-envelope bridges","volume":"26","author":"Starr","year":"2010","journal-title":"Annu Rev Cell Dev Biol"},{"key":"2021070802590191600_gaab028-B17","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.ceb.2012.10.014","article-title":"Connecting the nucleus to the cytoskeleton by SUN-KASH bridges across the nuclear envelope","volume":"25","author":"Tapley","year":"2013","journal-title":"Curr Opin Cell Biol"},{"key":"2021070802590191600_gaab028-B18","doi-asserted-by":"crossref","first-page":"e1000712","DOI":"10.1371\/journal.pgen.1000712","article-title":"OAZ-t\/OAZ3 is essential for rigid connection of sperm tails to heads in mouse","volume":"5","author":"Tokuhiro","year":"2009","journal-title":"PLoS Genet"},{"key":"2021070802590191600_gaab028-B19","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1038\/nrm2003","article-title":"SUN-domain proteins: \u2018Velcro\u2019 that links the nucleoskeleton to the cytoskeleton","volume":"7","author":"Tzur","year":"2006","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2021070802590191600_gaab028-B20","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1530\/REP-14-0370","article-title":"Haplo-deficiency of ODF1\/HSPB10 in mouse sperm causes relaxation of head-to-tail linkage","volume":"148","author":"Yang","year":"2014","journal-title":"Reproduction"},{"key":"2021070802590191600_gaab028-B21","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1128\/MCB.06158-11","article-title":"The small heat shock protein ODF1\/HSPB10 is essential for tight linkage of sperm head to tail and male fertility in mice","volume":"32","author":"Yang","year":"2012","journal-title":"Mol Cell Biol"},{"key":"2021070802590191600_gaab028-B22","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1089\/dna.2006.25.554","article-title":"Characterization of the structures involved in localization of the SUN proteins to the nuclear envelope and the centrosome","volume":"5","author":"Wang","year":"2006","journal-title":"DNA Cell Biol"},{"key":"2021070802590191600_gaab028-B23","doi-asserted-by":"crossref","first-page":"e1284","DOI":"10.1002\/mgg3.1284","article-title":"Loss-of-function mutation in TSGA10 causes acephalic spermatozoa phenotype in human","volume":"8","author":"Ye","year":"2020","journal-title":"Mol Genet Genomic Med"},{"key":"2021070802590191600_gaab028-B24","doi-asserted-by":"crossref","first-page":"2776","DOI":"10.1128\/MCB.00486-14","article-title":"Nuclear lamins and neurobiology","volume":"34","author":"Young","year":"2014","journal-title":"Mol Cell Biol"},{"key":"2021070802590191600_gaab028-B25","doi-asserted-by":"crossref","first-page":"E430","DOI":"10.1073\/pnas.1424648112","article-title":"Spata6 is required for normal assembly of the sperm connecting piece and tight head-tail conjunction","volume":"112","author":"Yuan","year":"2015","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2021070802590191600_gaab028-B26","volume-title":"Techniques of human andrology","author":"Zaneveld","year":"1977"},{"key":"2021070802590191600_gaab028-B27","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.ajhg.2018.06.010","article-title":"Mutations in PMFBP1 cause acephalic spermatozoa syndrome","volume":"103","author":"Zhu","year":"2018","journal-title":"Am J Hum Genet"},{"key":"2021070802590191600_gaab028-B28","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ajhg.2016.11.002","article-title":"Biallelic SUN5 mutations cause autosomal-recessive acephalic spermatozoa syndrome","volume":"99","author":"Zhu","year":"2016","journal-title":"Am J Hum Genet"}],"container-title":["Molecular Human Reproduction"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/molehr\/advance-article-pdf\/doi\/10.1093\/molehr\/gaab028\/37051983\/gaab028.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/molehr\/article-pdf\/27\/5\/gaab028\/37905313\/gaab028.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/molehr\/article-pdf\/27\/5\/gaab028\/37905313\/gaab028.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,8]],"date-time":"2021-07-08T03:17:14Z","timestamp":1625714234000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/molehr\/article\/doi\/10.1093\/molehr\/gaab028\/6225007"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,12]]},"references-count":30,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2021,5,8]]}},"URL":"https:\/\/doi.org\/10.1093\/molehr\/gaab028","relation":{},"ISSN":["1360-9947","1460-2407"],"issn-type":[{"value":"1360-9947","type":"print"},{"value":"1460-2407","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,5,1]]},"published":{"date-parts":[[2021,4,12]]},"article-number":"gaab028"}}