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A de novo paradigm for male infertility

2022-01-10Journal article Open access
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dc.contributor.authorOud, M.S.
dc.contributor.authorSmits, R.M.
dc.contributor.authorSmith, H.E.
dc.contributor.authorMastrorosa, F.K.
dc.contributor.authorHolt, G.S.
dc.contributor.authorHouston, B.J.
dc.contributor.authorde Vries, P.F.
dc.contributor.authorAlobaidi, B.K.S.
dc.contributor.authorBatty, L.E.
dc.contributor.authorIsmail, H.
dc.contributor.authorGreenwood, J.
dc.contributor.authorSheth, H.
dc.contributor.authorMikulasova, A.
dc.contributor.authorAstuti, G.D.N.
dc.contributor.authorGilissen, C.
dc.contributor.authorMcEleny, K.
dc.contributor.authorTurner, H.
dc.contributor.authorCoxhead, J.
dc.contributor.authorCockell, S.
dc.contributor.authorBraat, D.D.M.
dc.contributor.authorFleischer, K.
dc.contributor.authorD’Hauwers, K.W.M.
dc.contributor.authorSchaafsma, E.
dc.contributor.authorConrad, Donald F.
dc.contributor.authorNagirnaja, Liina
dc.contributor.authorAston, Kenneth I.
dc.contributor.authorCarrell, Douglas T.
dc.contributor.authorHotaling, James M.
dc.contributor.authorJenkins, Timothy G.
dc.contributor.authorMcLachlan, Rob
dc.contributor.authorO’Bryan, Moira K.
dc.contributor.authorSchlegel, Peter N.
dc.contributor.authorEisenberg, Michael L.
dc.contributor.authorSandlow, Jay I.
dc.contributor.authorJungheim, Emily S.
dc.contributor.authorOmurtag, Kenan R.
dc.contributor.authorLopes, Alexandra M.
dc.contributor.authorSeixas, Susana
dc.contributor.authorCarvalho, Filipa
dc.contributor.authorFernandes, Susana
dc.contributor.authorBarros, Alberto
dc.contributor.authorGonçalves, João
dc.contributor.authorCaetano, Iris
dc.contributor.authorPinto, Graça
dc.contributor.authorCorreia, Sónia
dc.contributor.authorLaan, Maris
dc.contributor.authorPunab, Margus
dc.contributor.authorMeyts, Ewa Rajpert-De
dc.contributor.authorJørgensen, Niels
dc.contributor.authorAlmstrup, Kristian
dc.contributor.authorKrausz, Csilla G.
dc.contributor.authorJarvi, Keith A.
dc.contributor.authorNagirnaja, L.
dc.contributor.authorConrad, D.F.
dc.contributor.authorFriedrich, C.
dc.contributor.authorKliesch, S.
dc.contributor.authorAston, K.I.
dc.contributor.authorRiera-Escamilla, A.
dc.contributor.authorKrausz, C.
dc.contributor.authorGonzaga-Jauregui, C.
dc.contributor.authorSantibanez-Koref, M.
dc.contributor.authorElliott, D. J.
dc.contributor.authorVissers, L.E.L.M.
dc.contributor.authorTüttelmann, F.
dc.contributor.authorO’Bryan, M.K.
dc.contributor.authorRamos, L.
dc.contributor.authorXavier, M.J.
dc.contributor.authorvan der Heijden, G.W.
dc.contributor.authorVeltman, J.A.
dc.date.accessioned2023-02-02T14:37:21Z
dc.date.available2023-02-02T14:37:21Z
dc.date.issued2022-01-10
dc.descriptionGenetics of Male Infertility Initiative (GEMINI) consortium: Donald F. Conrad, Liina Nagirnaja, Kenneth I. Aston, Douglas T. Carrell, James M. Hotaling, Timothy G. Jenkins, Rob McLachlan, Moira K. O’Bryan, Peter N. Schlegel, Michael L. Eisenberg, Jay I. Sandlow, Emily S. Jungheim, Kenan R. Omurtag, Alexandra M. Lopes, Susana Seixas, Filipa Carvalho, Susana Fernandes, Alberto Barros, João Gonçalves, Iris Caetano, Graça Pinto, Sónia Correia, Maris Laan, Margus Punab, Ewa Rajpert-De Meyts, Niels Jørgensen, Kristian Almstrup, Csilla G. Krausz & Keith A. Jarvi.
dc.description.abstractDe novo mutations are known to play a prominent role in sporadic disorders with reduced fitness. We hypothesize that de novo mutations play an important role in severe male infertility and explain a portion of the genetic causes of this understudied disorder. To test this hypothesis, we utilize trio-based exome sequencing in a cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare (MAF < 0.1%) protein-altering de novo mutations are classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of loss-of-function de novo mutations in loss-of-function-intolerant genes (p-value = 1.00 × 10−5) in infertile men compared to controls. Additionally, we detected a significant increase in predicted pathogenic de novo missense mutations affecting missense-intolerant genes (p-value = 5.01 × 10−4) in contrast to predicted benign de novo mutations. One gene we identify, RBM5, is an essential regulator of male germ cell pre-mRNA splicing and has been previously implicated in male infertility in mice. In a follow-up study, 6 rare pathogenic missense mutations affecting this gene are observed in a cohort of 2,506 infertile patients, whilst we find no such mutations in a cohort of 5,784 fertile men (p-value = 0.03). Our results provide evidence for the role of de novo mutations in severe male infertility and point to new candidate genes affecting fertility.pt_PT
dc.description.sponsorshipThis project was funded by The Netherlands Organization for Scientific Research (918-15-667) to J.A.V. as well as an Investigator Award in Science from the Wellcome Trust (209451) to J.A.V. a grant from the Catherine van Tussenbroek Foundation to M.S.O. a grant from MERCK to R.S. a UUKi Rutherford Fund Fellowship awarded to B.J.H. and the German Research Foundation Clinical Research Unit “Male Germ Cells” (DFG, CRU326) to C.F. and F.T. This project was also supported in part by funding from the Australian National Health and Medical Research Council (APP1120356) to M.K.O.B., by grants from the National Institutes of Health of the United States of America (R01HD078641 to D.F.C. and K.I.A., P50HD096723 to D.F.C.) and from the Biotechnology and Biological Sciences Research Council (BB/S008039/1) to D.J.E.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationNat Commun. 2022 Jan 10;13(1):154. doi: 10.1038/s41467-021-27132-8pt_PT
dc.identifier.doi10.1038/s41467-021-27132-8pt_PT
dc.identifier.issn2041-1723
dc.identifier.urihttp://hdl.handle.net/10400.18/8497
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherNature Researchpt_PT
dc.relationCentre for Toxicogenomics and Human Health
dc.relationUnraveling genetic causes and risk factors for severe male infertility
dc.relation.publisherversionhttps://www.nature.com/articles/s41467-021-27132-8pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectMale Infertilitypt_PT
dc.subjectInfertile Manpt_PT
dc.subjectSpermatogenesispt_PT
dc.subjectGenética Humanapt_PT
dc.subjectDoenças Genéticaspt_PT
dc.titleA de novo paradigm for male infertilitypt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleCentre for Toxicogenomics and Human Health
oaire.awardTitleUnraveling genetic causes and risk factors for severe male infertility
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F00009%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/WT/Genetics, Genomics and Population Research/209451
oaire.citation.issue1pt_PT
oaire.citation.startPage154pt_PT
oaire.citation.titleNature Communicationspt_PT
oaire.citation.volume13pt_PT
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStreamGenetics, Genomics and Population Research
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
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/100010269
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameWellcome Trust
rcaap.embargofctAcesso de acordo com política editorial da revista.pt_PT
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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