Diverse monogenic subforms of human spermatogenic failure
Non-obstructive azoospermia (NOA) is the most severe form of male infertility and typically incurable. Defining the genetic basis of NOA has proven challenging, and the most advanced classification of NOA subforms is not based on genetics, but simple description of testis histology. In this study, w...
| Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2022 |
| País: | España |
| Institución: | Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau) |
| Repositorio: | r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau |
| OAI Identifier: | oai:iibsantpau.fundanetsuite.com:p15442 |
| Acceso en línea: | https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=15442 https://www.scopus.com/inward/record.uri?eid=2-s2.0-85144638273&doi=10.1038%2fs41467-022-35661-z&partnerID=40&md5=1298387d6c807cdd3cf9785378f63e66 |
| Access Level: | acceso abierto |
| Palabra clave: | gene expression genetic analysis genetics histology infertility RNA animal azoospermia human male male infertility mouse pathology spermatogenesis testis Animals Azoospermia Humans Infertility, Male Male Mice Spermatogenesis Testis |
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Diverse monogenic subforms of human spermatogenic failureNagirnaja, LLopes, AMCharng, WLMiller, BStakaitis, RGolubickaite, IStendahl, ALuan, TPCFriedrich, CMahyari, EFadial, EKasak, LVigh-Conrad, KOud, MSXavier, MJCheers, SRJames, ERGuo, JTJenkins, TGRiera-Escamilla, ABarros, ACarvalho, FFernandes, SGoncalves, JGurnett, CAJorgensen, NJezek, DJungheim, ESKliesch, SMcLachlan, RIOmurtag, KRPilatz, ASandlow, JSmith, JEisenberg, MLHotaling, JMJarvi, KAPunab, MRajpert-De Meyts, ECarrell, DTKrausz, CLaan, MO'Bryan, MKSchlegel, PNTuttelmann, FVeltman, JAAlmstrup, KAston, KIConrad, DFgene expressiongenetic analysisgeneticshistologyinfertilityRNAanimalazoospermiageneticshumanmalemale infertilitymousepathologyspermatogenesistestisAnimalsAzoospermiaHumansInfertility, MaleMaleMiceSpermatogenesisTestisNon-obstructive azoospermia (NOA) is the most severe form of male infertility and typically incurable. Defining the genetic basis of NOA has proven challenging, and the most advanced classification of NOA subforms is not based on genetics, but simple description of testis histology. In this study, we exome-sequenced over 1000 clinically diagnosed NOA cases and identified a plausible recessive Mendelian cause in 20%. We find further support for 21 genes in a 2-stage burden test with 2072 cases and 11,587 fertile controls. The disrupted genes are primarily on the autosomes, enriched for undescribed human "knockouts ", and, for the most part, have yet to be linked to a Mendelian trait. Integration with single-cell RNA sequencing data shows that azoospermia genes can be grouped into molecular subforms with synchronized expression patterns, and analogs of these subforms exist in mice. This analysis framework identifies groups of genes with known roles in spermatogenesis but also reveals unrecognized subforms, such as a set of genes expressed across mitotic divisions of differentiating spermatogonia. Our findings highlight NOA as an understudied Mendelian disorder and provide a conceptual structure for organizing the complex genetics of male infertility, which may provide a rational basis for disease classification.NATURE PUBLISHING GROUP2022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=15442https://www.scopus.com/inward/record.uri?eid=2-s2.0-85144638273&doi=10.1038%2fs41467-022-35661-z&partnerID=40&md5=1298387d6c807cdd3cf9785378f63e66Nature CommunicationsISSN: 20411723reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pauinstname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)Inglésinfo:eu-repo/semantics/openAccessoai:iibsantpau.fundanetsuite.com:p154422026-06-14T12:41:47Z |
| dc.title.none.fl_str_mv |
Diverse monogenic subforms of human spermatogenic failure |
| title |
Diverse monogenic subforms of human spermatogenic failure |
| spellingShingle |
Diverse monogenic subforms of human spermatogenic failure Nagirnaja, L gene expression genetic analysis genetics histology infertility RNA animal azoospermia genetics human male male infertility mouse pathology spermatogenesis testis Animals Azoospermia Humans Infertility, Male Male Mice Spermatogenesis Testis |
| title_short |
Diverse monogenic subforms of human spermatogenic failure |
| title_full |
Diverse monogenic subforms of human spermatogenic failure |
| title_fullStr |
Diverse monogenic subforms of human spermatogenic failure |
| title_full_unstemmed |
Diverse monogenic subforms of human spermatogenic failure |
| title_sort |
Diverse monogenic subforms of human spermatogenic failure |
| dc.creator.none.fl_str_mv |
Nagirnaja, L Lopes, AM Charng, WL Miller, B Stakaitis, R Golubickaite, I Stendahl, A Luan, TPC Friedrich, C Mahyari, E Fadial, E Kasak, L Vigh-Conrad, K Oud, MS Xavier, MJ Cheers, SR James, ER Guo, JT Jenkins, TG Riera-Escamilla, A Barros, A Carvalho, F Fernandes, S Goncalves, J Gurnett, CA Jorgensen, N Jezek, D Jungheim, ES Kliesch, S McLachlan, RI Omurtag, KR Pilatz, A Sandlow, J Smith, J Eisenberg, ML Hotaling, JM Jarvi, KA Punab, M Rajpert-De Meyts, E Carrell, DT Krausz, C Laan, M O'Bryan, MK Schlegel, PN Tuttelmann, F Veltman, JA Almstrup, K Aston, KI Conrad, DF |
| author |
Nagirnaja, L |
| author_facet |
Nagirnaja, L Lopes, AM Charng, WL Miller, B Stakaitis, R Golubickaite, I Stendahl, A Luan, TPC Friedrich, C Mahyari, E Fadial, E Kasak, L Vigh-Conrad, K Oud, MS Xavier, MJ Cheers, SR James, ER Guo, JT Jenkins, TG Riera-Escamilla, A Barros, A Carvalho, F Fernandes, S Goncalves, J Gurnett, CA Jorgensen, N Jezek, D Jungheim, ES Kliesch, S McLachlan, RI Omurtag, KR Pilatz, A Sandlow, J Smith, J Eisenberg, ML Hotaling, JM Jarvi, KA Punab, M Rajpert-De Meyts, E Carrell, DT Krausz, C Laan, M O'Bryan, MK Schlegel, PN Tuttelmann, F Veltman, JA Almstrup, K Aston, KI Conrad, DF |
| author_role |
author |
| author2 |
Lopes, AM Charng, WL Miller, B Stakaitis, R Golubickaite, I Stendahl, A Luan, TPC Friedrich, C Mahyari, E Fadial, E Kasak, L Vigh-Conrad, K Oud, MS Xavier, MJ Cheers, SR James, ER Guo, JT Jenkins, TG Riera-Escamilla, A Barros, A Carvalho, F Fernandes, S Goncalves, J Gurnett, CA Jorgensen, N Jezek, D Jungheim, ES Kliesch, S McLachlan, RI Omurtag, KR Pilatz, A Sandlow, J Smith, J Eisenberg, ML Hotaling, JM Jarvi, KA Punab, M Rajpert-De Meyts, E Carrell, DT Krausz, C Laan, M O'Bryan, MK Schlegel, PN Tuttelmann, F Veltman, JA Almstrup, K Aston, KI Conrad, DF |
| 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 |
| dc.subject.none.fl_str_mv |
gene expression genetic analysis genetics histology infertility RNA animal azoospermia genetics human male male infertility mouse pathology spermatogenesis testis Animals Azoospermia Humans Infertility, Male Male Mice Spermatogenesis Testis |
| topic |
gene expression genetic analysis genetics histology infertility RNA animal azoospermia genetics human male male infertility mouse pathology spermatogenesis testis Animals Azoospermia Humans Infertility, Male Male Mice Spermatogenesis Testis |
| description |
Non-obstructive azoospermia (NOA) is the most severe form of male infertility and typically incurable. Defining the genetic basis of NOA has proven challenging, and the most advanced classification of NOA subforms is not based on genetics, but simple description of testis histology. In this study, we exome-sequenced over 1000 clinically diagnosed NOA cases and identified a plausible recessive Mendelian cause in 20%. We find further support for 21 genes in a 2-stage burden test with 2072 cases and 11,587 fertile controls. The disrupted genes are primarily on the autosomes, enriched for undescribed human "knockouts ", and, for the most part, have yet to be linked to a Mendelian trait. Integration with single-cell RNA sequencing data shows that azoospermia genes can be grouped into molecular subforms with synchronized expression patterns, and analogs of these subforms exist in mice. This analysis framework identifies groups of genes with known roles in spermatogenesis but also reveals unrecognized subforms, such as a set of genes expressed across mitotic divisions of differentiating spermatogonia. Our findings highlight NOA as an understudied Mendelian disorder and provide a conceptual structure for organizing the complex genetics of male infertility, which may provide a rational basis for disease classification. |
| publishDate |
2022 |
| dc.date.none.fl_str_mv |
2022 |
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info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
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https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=15442 https://www.scopus.com/inward/record.uri?eid=2-s2.0-85144638273&doi=10.1038%2fs41467-022-35661-z&partnerID=40&md5=1298387d6c807cdd3cf9785378f63e66 |
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Inglés |
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info:eu-repo/semantics/openAccess |
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NATURE PUBLISHING GROUP |
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NATURE PUBLISHING GROUP |
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Nature Communications ISSN: 20411723 reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau instname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau) |
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Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau) |
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r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau |
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r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau |
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