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Diverse monogenic subforms of human spermatogenic failure

2022-12-26Artigo científico Acesso aberto
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dc.contributor.authorNagirnaja, Liina
dc.contributor.authorLopes, Alexandra M.
dc.contributor.authorCharng, Wu Lin
dc.contributor.authorMiller, Brian
dc.contributor.authorStakaitis, Rytis
dc.contributor.authorGolubickaite, Ieva
dc.contributor.authorStendahl, Alexandra
dc.contributor.authorLuan, Tianpengcheng
dc.contributor.authorFriedrich, Corinna
dc.contributor.authorMahyari, Eisa
dc.contributor.authorFadial, Eloise
dc.contributor.authorKasak, Laura
dc.contributor.authorVigh-Conrad, Katinka
dc.contributor.authorOud, Manon S.
dc.contributor.authorXavier, Miguel J.
dc.contributor.authorXavier, Miguel
dc.contributor.authorCheers, Samuel R.
dc.contributor.authorJames, Emma R.
dc.contributor.authorGuo, Jingtao
dc.contributor.authorJenkins, Timothy G.
dc.contributor.authorRiera-Escamilla, Antoni
dc.contributor.authorBarros, Alberto
dc.contributor.authorCarvalho, Filipa
dc.contributor.authorFernandes, Susana
dc.contributor.authorGonçalves, João
dc.contributor.authorGurnett, Christina A.
dc.contributor.authorJørgensen, Niels
dc.contributor.authorJezek, Davor
dc.contributor.authorJungheim, Emily S.
dc.contributor.authorKliesch, Sabine
dc.contributor.authorMcLachlan, Robert I.
dc.contributor.authorOmurtag, Kenan R.
dc.contributor.authorPilatz, Adrian
dc.contributor.authorSandlow, Jay I.
dc.contributor.authorSmith, James
dc.contributor.authorEisenberg, Michael L.
dc.contributor.authorHotaling, James M.
dc.contributor.authorJarvi, Keith A.
dc.contributor.authorPunab, Margus
dc.contributor.authorRajpert-De Meyts, Ewa
dc.contributor.authorCarrell, Douglas T.
dc.contributor.authorKrausz, Csilla
dc.contributor.authorLaan, Maris
dc.contributor.authorO'Bryan, Moira K.
dc.contributor.authorSchlegel, Peter N.
dc.contributor.authorTüttelmann, Frank
dc.contributor.authorVeltman, Joris A.
dc.contributor.authorAlmstrup, Kristian
dc.contributor.authorAston, Kenneth I.
dc.contributor.authorConrad, Donald F.
dc.contributor.institutionCentre for Toxicogenomics and Human Health (ToxOmics)
dc.contributor.institutionNOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)
dc.contributor.pblNature Portfolio
dc.date.accessioned2023-01-09T22:16:32Z
dc.date.available2023-01-09T22:16:32Z
dc.date.issued2022-12-26
dc.description.abstractNon-obstructive azoospermia (NOA) is the most severe form of male infertility and typically incurable. Defining the genetic basis of NOA has proven challenging, and the most advanced classification of NOA subforms is not based on genetics, but simple description of testis histology. In this study, we exome-sequenced over 1000 clinically diagnosed NOA cases and identified a plausible recessive Mendelian cause in 20%. We find further support for 21 genes in a 2-stage burden test with 2072 cases and 11,587 fertile controls. The disrupted genes are primarily on the autosomes, enriched for undescribed human "knockouts", and, for the most part, have yet to be linked to a Mendelian trait. Integration with single-cell RNA sequencing data shows that azoospermia genes can be grouped into molecular subforms with synchronized expression patterns, and analogs of these subforms exist in mice. This analysis framework identifies groups of genes with known roles in spermatogenesis but also reveals unrecognized subforms, such as a set of genes expressed across mitotic divisions of differentiating spermatogonia. Our findings highlight NOA as an understudied Mendelian disorder and provide a conceptual structure for organizing the complex genetics of male infertility, which may provide a rational basis for disease classification.en
dc.description.versionpublishersversion
dc.description.versionpublished
dc.format.extent4893338
dc.identifier.doi10.1038/s41467-022-35661-z
dc.identifier.issn2041-1723
dc.identifier.otherPURE: 49544140
dc.identifier.otherPURE UUID: 6f3c65ba-eabb-417c-8e3f-640875ca5c13
dc.identifier.otherScopus: 85144638273
dc.identifier.otherPubMed: 36572685
dc.identifier.otherWOS: 000905505200011
dc.identifier.urihttp://hdl.handle.net/10362/147236
dc.identifier.urlhttps://www.scopus.com/pages/publications/85144638273
dc.language.isoeng
dc.peerreviewedyes
dc.subjectGeneral Chemistry
dc.subjectGeneral Biochemistry,Genetics and Molecular Biology
dc.subjectGeneral
dc.subjectGeneral Physics and Astronomy
dc.subjectSDG 3 - Good Health and Well-being
dc.titleDiverse monogenic subforms of human spermatogenic failureen
dc.typejournal article
degois.publication.issue1
degois.publication.titleNature Communications
degois.publication.volume13
dspace.entity.typePublication
person.familyNameXavier
person.givenNameMiguel
person.identifier.ciencia-idD71F-6F62-6CFA
person.identifier.orcid0000-0003-2698-1284
person.identifier.scopus-author-id7006066808
rcaap.rightsopenAccess
relation.isAuthorOfPublication1f1ba027-e7cf-4b4a-906b-35d61c74eb90
relation.isAuthorOfPublication.latestForDiscovery1f1ba027-e7cf-4b4a-906b-35d61c74eb90

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