{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T12:13:55Z","timestamp":1775477635923,"version":"3.50.1"},"reference-count":22,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2023,1,27]],"date-time":"2023-01-27T00:00:00Z","timestamp":1674777600000},"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\/501100004912","name":"Sichuan University","doi-asserted-by":"publisher","award":["20H2025"],"award-info":[{"award-number":["20H2025"]}],"id":[{"id":"10.13039\/501100004912","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004912","name":"Sichuan University","doi-asserted-by":"publisher","award":["21H0036"],"award-info":[{"award-number":["21H0036"]}],"id":[{"id":"10.13039\/501100004912","id-type":"DOI","asserted-by":"publisher"}]},{"name":"West China Second University Hospital of Sichuan University","award":["KS275"],"award-info":[{"award-number":["KS275"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,5,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The testis-specific adenosine deaminase domain-containing (ADAD) protein family, including ADAD1 and ADAD2, has been confirmed to be essential in mouse male fertility. However, the roles of ADAD1 and ADAD2 in human reproductive biology are unclear. Herein, whole-exome sequencing was conducted for 337 infertile patients to detect pathogenic variants in ADAD1 and ADAD2. Importantly, a novel deleterious biallelic variant of NM_001159285.2:c.1408G\u2009&amp;gt;\u2009T (p.V470F) and NM_001159285.2:c.1418A\u2009&amp;gt;\u2009G (p.E473G) in ADAD1 and a pathogenic homozygous missense variant of NM_001145400.2:c.1381C\u2009&amp;gt;\u2009T (p.R461W) in ADAD2 were identified in this infertile cohort with frequencies of 0.29 (1\/337) and 0.59% (2\/337), respectively. Electron microscopy revealed an abnormal morphology and severely disorganized ultrastructure of sperm from the patients. Immunofluorescence and western blotting showed a sharp decrease in ADAD1 and ADAD2 expression in sperm from the patients. Mechanistically, bioinformatics analysis suggested that ADAD2 interacts with DNAH17. Furthermore, we demonstrated that the expression of DNAH17 was markedly downregulated in the sperm of patients harboring ADAD2 variants. In addition, the expression of several autophagy regulators was significantly disrupted in the sperm of patients harboring ADAD2 variants. In conclusion, we identified novel ADAD1 and ADAD2 variants in three infertile patients from a large infertile cohort, first providing evidence that ADAD1 and ADAD2 variants might be a candidate genetic cause of human male infertility. Moreover, an important new dimension to our understanding of the genotype\u2013phenotype correlations between the ADAD gene family and male infertility in humans has been uncovered, providing valuable information for the genetic diagnosis of male infertility.<\/jats:p>","DOI":"10.1093\/hmg\/ddad012","type":"journal-article","created":{"date-parts":[[2023,1,28]],"date-time":"2023-01-28T08:16:31Z","timestamp":1674893791000},"page":"1814-1825","source":"Crossref","is-referenced-by-count":12,"title":["Population-based genetic analysis in infertile men reveals novel mutations of <i>ADAD<\/i> family members in patients with impaired spermatogenesis"],"prefix":"10.1093","volume":"32","author":[{"given":"Siyu","family":"Dai","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, , Chengdu 610041 , China"},{"name":"Sichuan University , Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, , Chengdu 610041 , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohan","family":"Liu","sequence":"additional","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, , Chengdu 610041 , China"},{"name":"Sichuan University , Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, , Chengdu 610041 , China"},{"name":"State Key Laboratory of Biotherapy and Cancer Center , West China Hospital, , Chengdu 610041 , China"},{"name":"Sichuan University and Collaborative Innovation Center , West China Hospital, , Chengdu 610041 , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Man","family":"Liu","sequence":"additional","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, , Chengdu 610041 , China"},{"name":"Sichuan University , Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, , Chengdu 610041 , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chuan","family":"Jiang","sequence":"additional","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, , Chengdu 610041 , China"},{"name":"Sichuan University , Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, , Chengdu 610041 , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanting","family":"Yang","sequence":"additional","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, , Chengdu 610041 , China"},{"name":"Sichuan University , Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, , Chengdu 610041 , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huifeng","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics, Berry Genomics Co., Ltd. , Beijing, 102206 , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yihong","family":"Yang","sequence":"additional","affiliation":[{"name":"Reproduction Medical Center of West China Second University Hospital , Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, , Chengdu 610041 , China"},{"name":"Sichuan University , Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, , Chengdu 610041 , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaohui","family":"Jiang","sequence":"additional","affiliation":[{"name":"Human Sperm Bank , Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, , Chengdu 610041 , China"},{"name":"West China Second University Hospital, Sichuan University , Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, , Chengdu 610041 , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1484-0807","authenticated-orcid":false,"given":"Ying","family":"Shen","sequence":"additional","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, , Chengdu 610041 , China"},{"name":"Sichuan University , Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, , Chengdu 610041 , China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2023,1,27]]},"reference":[{"key":"2023051907043175400_ref1","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1006\/dbio.1998.9156","article-title":"Regulation of meiosis during mammalian spermatogenesis: the A-type cyclins and their associated cyclin-dependent kinases are differentially expressed in the germ-cell lineage","volume":"207","author":"Ravnik","year":"1999","journal-title":"Dev. Biol."},{"key":"2023051907043175400_ref2","doi-asserted-by":"crossref","first-page":"a016626","DOI":"10.1101\/cshperspect.a016626","article-title":"Recombination, pairing, and synapsis of homologs during meiosis","volume":"7","author":"Zickler","year":"2015","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"2023051907043175400_ref3","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.acuro.2019.10.007","article-title":"Empiric therapy for idiopathic oligoasthenoteratozoospermia. Tratamiento emp\u00edrico de la oligoastenoteratozoospermia idiop\u00e1tica","volume":"44","author":"Garc\u00eda-Baquero","year":"2020","journal-title":"Actas Urol. Esp. (Engl. Ed.)"},{"key":"2023051907043175400_ref4","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1111\/andr.12502","article-title":"European academy of andrology guideline management of oligo-astheno-teratozoospermia","volume":"6","author":"Colpi","year":"2018","journal-title":"Andrology"},{"key":"2023051907043175400_ref5","doi-asserted-by":"crossref","first-page":"11536","DOI":"10.1038\/s41598-020-67834-5","article-title":"ADAD1 and ADAD2, testis-specific adenosine deaminase domain-containing proteins, are required for male fertility","volume":"10","author":"Snyder","year":"2020","journal-title":"Sci. Rep."},{"key":"2023051907043175400_ref6","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.ydbio.2004.10.009","article-title":"Disruption of murine Tenr results in teratospermia and male infertility","volume":"278","author":"Connolly","year":"2005","journal-title":"Dev. Biol."},{"key":"2023051907043175400_ref7","doi-asserted-by":"crossref","first-page":"7566","DOI":"10.1093\/nar\/gkv726","article-title":"Dynamic profiling of double-stranded RNA binding proteins","volume":"43","author":"Wang","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"2023051907043175400_ref8","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0127007","article-title":"Differential genes expression between fertile and infertile spermatozoa revealed by transcriptome analysis","volume":"10","author":"Bansal","year":"2015","journal-title":"PLoS One"},{"key":"2023051907043175400_ref9","doi-asserted-by":"crossref","first-page":"2584","DOI":"10.1038\/s41598-022-06476-1","article-title":"Using publicly available transcriptomic data to identify mechanistic and diagnostic biomarkers in azoospermia and overall male infertility","volume":"12","author":"Omolaoye","year":"2022","journal-title":"Sci. Rep."},{"key":"2023051907043175400_ref10","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.1080\/15548627.2020.1783822","article-title":"Autophagy core protein ATG5 is required for elongating spermatid development, sperm individualization and normal fertility in male mice","volume":"17","author":"Huang","year":"2021","journal-title":"Autophagy"},{"key":"2023051907043175400_ref11","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1016\/j.rbmo.2021.05.009","article-title":"A novel mutation in DNAH17 is present in a patient with multiple morphological abnormalities of the flagella","volume":"43","author":"Zheng","year":"2021","journal-title":"Reprod. BioMed. Online"},{"key":"2023051907043175400_ref12","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1093\/hmg\/ddq031","article-title":"Deletion of the parkin co-regulated gene causes defects in ependymal ciliary motility and hydrocephalus in the quakingviable mutant mouse","volume":"19","author":"Wilson","year":"2010","journal-title":"Hum. Mol. Genet."},{"key":"2023051907043175400_ref13","doi-asserted-by":"crossref","first-page":"323","DOI":"10.4161\/auto.4012","article-title":"LC3, an autophagosome marker, can be incorporated into protein aggregates independent of autophagy: caution in the interpretation of LC3 localization","volume":"3","author":"Kuma","year":"2007","journal-title":"Autophagy"},{"key":"2023051907043175400_ref14","doi-asserted-by":"crossref","first-page":"4672","DOI":"10.1111\/febs.13540","article-title":"p62\/SQSTM1 functions as a signaling hub and an autophagy adaptor","volume":"282","author":"Katsuragi","year":"2015","journal-title":"FEBS J."},{"key":"2023051907043175400_ref15","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.molcel.2019.09.005","article-title":"A diversity of selective autophagy receptors determines the specificity of the autophagy pathway","volume":"76","author":"Kirkin","year":"2019","journal-title":"Mol. Cell"},{"key":"2023051907043175400_ref16","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1038\/nature13939","article-title":"Cell metabolism: autophagy transcribed","volume":"516","author":"Settembre","year":"2014","journal-title":"Nature"},{"key":"2023051907043175400_ref17","first-page":"200","article-title":"Autophagy: a multifaceted player in the fate of sperm","volume":"28","author":"Wang","year":"2022","journal-title":"Hum. Reprod."},{"key":"2023051907043175400_ref18","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1038\/cr.2014.70","article-title":"Atg7 is required for acrosome biogenesis during spermatogenesis in mice","volume":"24","author":"Wang","year":"2014","journal-title":"Cell Res."},{"key":"2023051907043175400_ref19","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","article-title":"Fast and accurate short read alignment with burrows-wheeler transform","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"2023051907043175400_ref20","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkq603","article-title":"ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"2023051907043175400_ref21","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1016\/j.ajhg.2018.08.005","article-title":"ClinPred: prediction tool to identify disease-relevant nonsynonymous single-nucleotide variants","volume":"103","author":"Alirezaie","year":"2018","journal-title":"Am. J. Hum. Genet."},{"key":"2023051907043175400_ref22","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."}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/hmg\/advance-article-pdf\/doi\/10.1093\/hmg\/ddad012\/49225092\/ddad012.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/32\/11\/1814\/50388871\/ddad012.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/32\/11\/1814\/50388871\/ddad012.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,19]],"date-time":"2023-05-19T07:05:46Z","timestamp":1684479946000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/32\/11\/1814\/7008454"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,27]]},"references-count":22,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2023,1,27]]},"published-print":{"date-parts":[[2023,5,18]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddad012","relation":{},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"value":"0964-6906","type":"print"},{"value":"1460-2083","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,6,1]]},"published":{"date-parts":[[2023,1,27]]}}}