A de novo paradigm for male infertility
Autor(a) principal: | |
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Data de Publicação: | 2022 |
Outros Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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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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 author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
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 |
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RCAAP |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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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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1817545841483710464 |