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A de novo paradigm for male infertility

2022-01-10Artigo científico Acesso aberto
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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, L.
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.institutionNOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)
dc.contributor.institutionCentre for Toxicogenomics and Human Health (ToxOmics)
dc.contributor.pblNature Portfolio
dc.date.accessioned2022-01-28T00:27:43Z
dc.date.available2022-01-28T00:27:43Z
dc.date.issued2022-01-10
dc.descriptionFunding Information: (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. Funding Information: We are grateful for the participation of all patients and their parents in this study. We thank Laurens van de Wiel (Radboudumc), Sebastian Judd-Mole (Monash University), Arron Scott and Bryan Hepworth (Newcastle University) for technical support, and Margot J Wyrwoll (University of Münster) for help with handling MERGE samples and data. This 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” Publisher Copyright: © 2022, The Author(s).
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.en
dc.description.versionpublishersversion
dc.description.versionpublished
dc.format.extent1627029
dc.identifier.doi10.1038/s41467-021-27132-8
dc.identifier.issn2041-1723
dc.identifier.otherPURE: 36415117
dc.identifier.otherPURE UUID: ed839601-0885-4195-85ca-35d1acbbe72a
dc.identifier.otherScopus: 85122860866
dc.identifier.urihttp://hdl.handle.net/10362/131758
dc.identifier.urlhttps://www.scopus.com/pages/publications/85122860866
dc.language.isoeng
dc.peerreviewedyes
dc.subjectGeneral Chemistry
dc.subjectGeneral Biochemistry,Genetics and Molecular Biology
dc.subjectGeneral Physics and Astronomy
dc.titleA de novo paradigm for male infertilityen
dc.typejournal article
degois.publication.issue1
degois.publication.titleNature Communications
degois.publication.volume13
dspace.entity.typePublication
rcaap.rightsopenAccess

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