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Diverse monogenic subforms of human spermatogenic failure

2022-12-26Journal article Open access
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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.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.date.accessioned2023-02-02T10:49:35Z
dc.date.available2023-02-02T10:49:35Z
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 chal lenging, 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 classificationpt_PT
dc.description.sponsorshipThe study has been funded by the follow- ing resources. National Institutes of Health of the United States of America grant R01HD078641 (D.F.C, K.I.A) National Institutes of Health of the United States of America grant P50HD096723 (D.F.C.) National Health and Medical Research Council of Australia grant APP1120356 (M.O., D.C., K.I.A., R.M., and J.A.V.) Spanish Ministry of Health Instituto Carlos III-FIS grant FIS/FEDER- PI20/01562 (C.K., A.R.-E.). Estonian Research Council grants IUT34-12 and PRG1021 (M.L., M.P.) ReproUnion and the Innovation Fund Denmark grant 14-2013-4 (K.A.) German Research Foundation Clinical Research Unit ‘Male Germ Cells’ grant DFG CRU326 (C.F., F.T.) The Netherlands Organization for Scientific Research VICI grant 918-15-667 (J.A.V.) Investigator Award in Science from the Wellcome Trust grant 209451 (J.A.V.). FCT/MCTES, through national funds attributed to Centre for Toxicogenomics and Human Health—ToxOmics, grant UID/BIM/00009/2016 (J.Go.) National Insti- tute of Mental Health of the National Institutes of Health grant T32- MH014677 (W.-L.C).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationNat Commun. 2022 Dec 26;13(1):7953. doi: 10.1038/s41467-022-35661-zpt_PT
dc.identifier.doi10.1038/s41467-022-35661-zpt_PT
dc.identifier.issn2041-1723
dc.identifier.urihttp://hdl.handle.net/10400.18/8492
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherNature Researchpt_PT
dc.relation.publisherversionhttps://www.nature.com/articles/s41467-022-35661-zpt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectNon-obstructive Azoospermiapt_PT
dc.subjectAzoospermiapt_PT
dc.subjectSpermatogenesispt_PT
dc.subjectMale Infertilitypt_PT
dc.subjectSpermatogoniapt_PT
dc.subjectGenética Humanapt_PT
dc.subjectDoenças Genéticaspt_PT
dc.titleDiverse monogenic subforms of human spermatogenic failurept_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.issue1pt_PT
oaire.citation.startPage7953pt_PT
oaire.citation.titleNature Communicationspt_PT
oaire.citation.volume13pt_PT
person.familyNameGonçalves
person.givenNameJoão
person.identifier.ciencia-id5710-1FAE-5FAB
person.identifier.orcid0000-0001-9359-8774
person.identifier.ridL-2265-2014
person.identifier.scopus-author-id55934387500
rcaap.embargofctAcesso de acordo com política editorial da revista.pt_PT
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication6bbd19e6-ea9c-4502-b972-ec6997e9c481
relation.isAuthorOfPublication.latestForDiscovery6bbd19e6-ea9c-4502-b972-ec6997e9c481

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