A de novo paradigm for male infertility
| Autor(a) principal: | |
|---|---|
| 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/10400.18/8497 |
Resumo: | Genetics 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. |
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A de novo paradigm for male infertilityMale InfertilityInfertile ManSpermatogenesisGenética HumanaDoenças GenéticasGenetics 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.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.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” (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.Nature ResearchRepositório Científico do Instituto Nacional de SaúdeOud, 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, LiinaAston, 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, KristianKrausz, Csilla G.Jarvi, Keith A.Nagirnaja, L.Conrad, D.F.Friedrich, C.Kliesch, S.Aston, K.I.Riera-Escamilla, A.Krausz, C.Gonzaga-Jauregui, C.Santibanez-Koref, M.Elliott, D. J.Vissers, L.E.L.M.Tüttelmann, F.O’Bryan, M.K.Ramos, L.Xavier, M.J.van der Heijden, G.W.Veltman, J.A.2023-02-02T14:37:21Z2022-01-102022-01-10T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.18/8497engNat Commun. 2022 Jan 10;13(1):154. doi: 10.1038/s41467-021-27132-82041-172310.1038/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:RCAAP2023-07-20T15:42:36Zoai:repositorio.insa.pt:10400.18/8497Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T18:43:08.038808Repositório 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. Male Infertility Infertile Man Spermatogenesis Genética Humana Doenças Genéticas |
| 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, Liina 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 Krausz, Csilla G. Jarvi, Keith A. Nagirnaja, L. Conrad, D.F. Friedrich, C. Kliesch, S. Aston, K.I. Riera-Escamilla, A. Krausz, C. Gonzaga-Jauregui, C. Santibanez-Koref, M. Elliott, D. J. Vissers, L.E.L.M. Tüttelmann, F. O’Bryan, M.K. Ramos, L. Xavier, M.J. van der Heijden, G.W. Veltman, J.A. |
| 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, Liina 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 Krausz, Csilla G. Jarvi, Keith A. Nagirnaja, L. Conrad, D.F. Friedrich, C. Kliesch, S. Aston, K.I. Riera-Escamilla, A. Krausz, C. Gonzaga-Jauregui, C. Santibanez-Koref, M. Elliott, D. J. Vissers, L.E.L.M. Tüttelmann, F. O’Bryan, M.K. Ramos, L. Xavier, M.J. van der Heijden, G.W. Veltman, J.A. |
| 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 author author author author author author author author author author author author author author author author author author author |
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Repositório Científico do Instituto Nacional de Saúde |
| 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, Liina 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 Krausz, Csilla G. Jarvi, Keith A. Nagirnaja, L. Conrad, D.F. Friedrich, C. Kliesch, S. Aston, K.I. Riera-Escamilla, A. Krausz, C. Gonzaga-Jauregui, C. Santibanez-Koref, M. Elliott, D. J. Vissers, L.E.L.M. Tüttelmann, F. O’Bryan, M.K. Ramos, L. Xavier, M.J. van der Heijden, G.W. Veltman, J.A. |
| dc.subject.por.fl_str_mv |
Male Infertility Infertile Man Spermatogenesis Genética Humana Doenças Genéticas |
| topic |
Male Infertility Infertile Man Spermatogenesis Genética Humana Doenças Genéticas |
| description |
Genetics 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. |
| publishDate |
2022 |
| dc.date.none.fl_str_mv |
2022-01-10 2022-01-10T00:00:00Z 2023-02-02T14:37:21Z |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
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article |
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publishedVersion |
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http://hdl.handle.net/10400.18/8497 |
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http://hdl.handle.net/10400.18/8497 |
| dc.language.iso.fl_str_mv |
eng |
| language |
eng |
| dc.relation.none.fl_str_mv |
Nat Commun. 2022 Jan 10;13(1):154. doi: 10.1038/s41467-021-27132-8 2041-1723 10.1038/s41467-021-27132-8 |
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openAccess |
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application/pdf |
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Nature Research |
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Nature Research |
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