A de novo paradigm for male infertility

Detalhes bibliográficos
Autor(a) principal: Oud, M. S.
Data de Publicação: 2022
Outros Autores: Smits, R. M., Smith, H. E., Mastrorosa, F. K., Holt, G. S., Houston, B. J., de Vries, P. F., Alobaidi, B. K.S., Batty, L. E., Ismail, H., Greenwood, J., Sheth, H., Mikulasova, A., Astuti, G. D.N., Gilissen, C., McEleny, K., Turner, H., Coxhead, J., Cockell, S., Braat, D. D.M., Fleischer, K., D’Hauwers, K. W.M., Schaafsma, E., Conrad, Donald F., Nagirnaja, L., Aston, Kenneth I., Carrell, Douglas T., Hotaling, James M., Jenkins, Timothy G., McLachlan, Rob, O’Bryan, Moira K., Schlegel, Peter N., Eisenberg, Michael L., Sandlow, Jay I., Jungheim, Emily S., Omurtag, Kenan R., Lopes, Alexandra M., Seixas, Susana, Carvalho, Filipa, Fernandes, Susana, Barros, Alberto, Gonçalves, João, Caetano, Iris, Pinto, Graça, Correia, Sónia, Laan, Maris, Punab, Margus, Meyts, Ewa Rajpert De, Jørgensen, Niels, Almstrup, Kristian
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10362/131758
Resumo: Funding 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).
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spelling A de novo paradigm for male infertilityChemistry(all)Biochemistry, Genetics and Molecular Biology(all)Physics and Astronomy(all)Funding 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).De 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.NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)Centre for Toxicogenomics and Human Health (ToxOmics)RUNOud, M. S.Smits, R. M.Smith, H. E.Mastrorosa, F. K.Holt, G. S.Houston, B. J.de Vries, P. F.Alobaidi, B. K.S.Batty, L. E.Ismail, H.Greenwood, J.Sheth, H.Mikulasova, A.Astuti, G. D.N.Gilissen, C.McEleny, K.Turner, H.Coxhead, J.Cockell, S.Braat, D. D.M.Fleischer, K.D’Hauwers, K. W.M.Schaafsma, E.Conrad, Donald F.Nagirnaja, L.Aston, Kenneth I.Carrell, Douglas T.Hotaling, James M.Jenkins, Timothy G.McLachlan, RobO’Bryan, Moira K.Schlegel, Peter N.Eisenberg, Michael L.Sandlow, Jay I.Jungheim, Emily S.Omurtag, Kenan R.Lopes, Alexandra M.Seixas, SusanaCarvalho, FilipaFernandes, SusanaBarros, AlbertoGonçalves, JoãoCaetano, IrisPinto, GraçaCorreia, SóniaLaan, MarisPunab, MargusMeyts, Ewa Rajpert DeJørgensen, NielsAlmstrup, Kristian2022-01-28T00:27:43Z2022-01-102022-01-10T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10362/131758eng2041-1723PURE: 36415117https://doi.org/10.1038/s41467-021-27132-8info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-05-22T17:58:46Zoai:run.unl.pt:10362/131758Portal AgregadorONGhttps://www.rcaap.pt/oai/openairemluisa.alvim@gmail.comopendoar:71602024-05-22T17:58:46Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv A de novo paradigm for male infertility
title A de novo paradigm for male infertility
spellingShingle A de novo paradigm for male infertility
Oud, M. S.
Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)
title_short A de novo paradigm for male infertility
title_full A de novo paradigm for male infertility
title_fullStr A de novo paradigm for male infertility
title_full_unstemmed A de novo paradigm for male infertility
title_sort A de novo paradigm for male infertility
author Oud, M. S.
author_facet Oud, M. S.
Smits, R. M.
Smith, H. E.
Mastrorosa, F. K.
Holt, G. S.
Houston, B. J.
de Vries, P. F.
Alobaidi, B. K.S.
Batty, L. E.
Ismail, H.
Greenwood, J.
Sheth, H.
Mikulasova, A.
Astuti, G. D.N.
Gilissen, C.
McEleny, K.
Turner, H.
Coxhead, J.
Cockell, S.
Braat, D. D.M.
Fleischer, K.
D’Hauwers, K. W.M.
Schaafsma, E.
Conrad, Donald F.
Nagirnaja, L.
Aston, Kenneth I.
Carrell, Douglas T.
Hotaling, James M.
Jenkins, Timothy G.
McLachlan, Rob
O’Bryan, Moira K.
Schlegel, Peter N.
Eisenberg, Michael L.
Sandlow, Jay I.
Jungheim, Emily S.
Omurtag, Kenan R.
Lopes, Alexandra M.
Seixas, Susana
Carvalho, Filipa
Fernandes, Susana
Barros, Alberto
Gonçalves, João
Caetano, Iris
Pinto, Graça
Correia, Sónia
Laan, Maris
Punab, Margus
Meyts, Ewa Rajpert De
Jørgensen, Niels
Almstrup, Kristian
author_role author
author2 Smits, R. M.
Smith, H. E.
Mastrorosa, F. K.
Holt, G. S.
Houston, B. J.
de Vries, P. F.
Alobaidi, B. K.S.
Batty, L. E.
Ismail, H.
Greenwood, J.
Sheth, H.
Mikulasova, A.
Astuti, G. D.N.
Gilissen, C.
McEleny, K.
Turner, H.
Coxhead, J.
Cockell, S.
Braat, D. D.M.
Fleischer, K.
D’Hauwers, K. W.M.
Schaafsma, E.
Conrad, Donald F.
Nagirnaja, L.
Aston, Kenneth I.
Carrell, Douglas T.
Hotaling, James M.
Jenkins, Timothy G.
McLachlan, Rob
O’Bryan, Moira K.
Schlegel, Peter N.
Eisenberg, Michael L.
Sandlow, Jay I.
Jungheim, Emily S.
Omurtag, Kenan R.
Lopes, Alexandra M.
Seixas, Susana
Carvalho, Filipa
Fernandes, Susana
Barros, Alberto
Gonçalves, João
Caetano, Iris
Pinto, Graça
Correia, Sónia
Laan, Maris
Punab, Margus
Meyts, Ewa Rajpert De
Jørgensen, Niels
Almstrup, Kristian
author2_role author
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dc.contributor.none.fl_str_mv NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)
Centre for Toxicogenomics and Human Health (ToxOmics)
RUN
dc.contributor.author.fl_str_mv Oud, M. S.
Smits, R. M.
Smith, H. E.
Mastrorosa, F. K.
Holt, G. S.
Houston, B. J.
de Vries, P. F.
Alobaidi, B. K.S.
Batty, L. E.
Ismail, H.
Greenwood, J.
Sheth, H.
Mikulasova, A.
Astuti, G. D.N.
Gilissen, C.
McEleny, K.
Turner, H.
Coxhead, J.
Cockell, S.
Braat, D. D.M.
Fleischer, K.
D’Hauwers, K. W.M.
Schaafsma, E.
Conrad, Donald F.
Nagirnaja, L.
Aston, Kenneth I.
Carrell, Douglas T.
Hotaling, James M.
Jenkins, Timothy G.
McLachlan, Rob
O’Bryan, Moira K.
Schlegel, Peter N.
Eisenberg, Michael L.
Sandlow, Jay I.
Jungheim, Emily S.
Omurtag, Kenan R.
Lopes, Alexandra M.
Seixas, Susana
Carvalho, Filipa
Fernandes, Susana
Barros, Alberto
Gonçalves, João
Caetano, Iris
Pinto, Graça
Correia, Sónia
Laan, Maris
Punab, Margus
Meyts, Ewa Rajpert De
Jørgensen, Niels
Almstrup, Kristian
dc.subject.por.fl_str_mv Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)
topic Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)
description Funding 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).
publishDate 2022
dc.date.none.fl_str_mv 2022-01-28T00:27:43Z
2022-01-10
2022-01-10T00:00:00Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10362/131758
url http://hdl.handle.net/10362/131758
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv 2041-1723
PURE: 36415117
https://doi.org/10.1038/s41467-021-27132-8
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron:RCAAP
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
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reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
repository.mail.fl_str_mv mluisa.alvim@gmail.com
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