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Diverse monogenic subforms of human spermatogenic failure.
Nagirnaja, Liina; Lopes, Alexandra M; Charng, Wu-Lin; Miller, Brian; Stakaitis, Rytis; Golubickaite, Ieva; Stendahl, Alexandra; Luan, Tianpengcheng; Friedrich, Corinna; Mahyari, Eisa; Fadial, Eloise; Kasak, Laura; Vigh-Conrad, Katinka; Oud, Manon S; Xavier, Miguel J; Cheers, Samuel R; James, Emma R; Guo, Jingtao; Jenkins, Timothy G; Riera-Escamilla, Antoni; Barros, Alberto; Carvalho, Filipa; Fernandes, Susana; Gonçalves, João; Gurnett, Christina A; Jørgensen, Niels; Jezek, Davor; Jungheim, Emily S; Kliesch, Sabine; McLachlan, Robert I; Omurtag, Kenan R; Pilatz, Adrian; Sandlow, Jay I; Smith, James; Eisenberg, Michael L; Hotaling, James M; Jarvi, Keith A; Punab, Margus; Rajpert-De Meyts, Ewa; Carrell, Douglas T; Krausz, Csilla; Laan, Maris; O'Bryan, Moira K; Schlegel, Peter N; Tüttelmann, Frank; Veltman, Joris A; Almstrup, Kristian; Aston, Kenneth I; Conrad, Donald F.
Afiliación
  • Nagirnaja L; Division of Genetics, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, USA.
  • Lopes AM; i3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal.
  • Charng WL; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal.
  • Miller B; Department of Neurology, Washington University, St. Louis, MO, USA.
  • Stakaitis R; Division of Genetics, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, USA.
  • Golubickaite I; Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
  • Stendahl A; International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
  • Luan T; Laboratory of Molecular Neurooncology, Neuroscience Institute, Lithuanian University of Health Sciences, Kaunas, Lithuania.
  • Friedrich C; Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
  • Mahyari E; International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
  • Fadial E; Department of Genetics and Molecular Medicine, Lithuanian University of Health Sciences, Kaunas, Lithuania.
  • Kasak L; Division of Genetics, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, USA.
  • Vigh-Conrad K; School of BioSciences, Faculty of Science, The University of Melbourne, Parkville, VIC, Australia.
  • Oud MS; Institute of Reproductive Genetics, University of Münster, Münster, Germany.
  • Xavier MJ; Division of Genetics, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, USA.
  • Cheers SR; Division of Genetics, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, USA.
  • James ER; Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
  • Guo J; Division of Genetics, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, USA.
  • Jenkins TG; Department of Human Genetics, Radboud University Medical Centre, Nijmegen, Netherlands.
  • Riera-Escamilla A; Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle-upon-Tyne, UK.
  • Barros A; School of BioSciences, Faculty of Science, The University of Melbourne, Parkville, VIC, Australia.
  • Carvalho F; Andrology and IVF Laboratory, Department of Surgery (Urology), University of Utah School of Medicine, Salt Lake City, UT, USA.
  • Fernandes S; Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT, USA.
  • Gonçalves J; Andrology and IVF Laboratory, Department of Surgery (Urology), University of Utah School of Medicine, Salt Lake City, UT, USA.
  • Gurnett CA; Andrology and IVF Laboratory, Department of Surgery (Urology), University of Utah School of Medicine, Salt Lake City, UT, USA.
  • Jørgensen N; Andrology Department, Fundació Puigvert, Universitat Autònoma de Barcelona, Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Barcelona, Catalonia, Spain.
  • Jezek D; Molecular Biology Laboratory, Fundació Puigvert, Instituto de Investigaciones Biomédicas Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Catalonia, 08025, Spain.
  • Jungheim ES; i3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal.
  • Kliesch S; Serviço de Genética, Departamento de Patologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal.
  • McLachlan RI; i3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal.
  • Omurtag KR; Serviço de Genética, Departamento de Patologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal.
  • Pilatz A; i3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal.
  • Sandlow JI; Serviço de Genética, Departamento de Patologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal.
  • Smith J; Departamento de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisboa, Portugal.
  • Eisenberg ML; Centre for Toxicogenomics and Human Health, Nova Medical School, Lisbon, Portugal.
  • Hotaling JM; Department of Neurology, Washington University, St. Louis, MO, USA.
  • Jarvi KA; Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
  • Punab M; International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
  • Rajpert-De Meyts E; Department of Histology and Embryology, University of Zagreb School of Medicine, Zagreb, Croatia.
  • Carrell DT; Department of Obstetrics and Gynecology at Northwestern University, Division of Reproductive Endocrinology, Chicago, IL, USA.
  • Krausz C; Department of Clinical and Surgical Andrology, Centre of Reproductive Medicine and Andrology, University Hospital Münster, Münster, Germany.
  • Laan M; Hudson Institute of Medical Research and the Department of Obstetrics and Gynecology, Monash University, Clayton, VIC, Australia.
  • O'Bryan MK; Department of Obstetrics and Gynecology at Washington University, Division of Reproductive Endocrinology, St. Louis, MO, USA.
  • Schlegel PN; Clinic for Urology, Pediatric Urology and Andrology, Justus Liebig University, Giessen, Germany.
  • Tüttelmann F; Department of Urology, Medical College of Wisconsin, Milwaukee, WI, USA.
  • Veltman JA; Department of Urology, University California San Francisco, San Francisco, CA, USA.
  • Almstrup K; Department of Urology, Stanford University School of Medicine, Stanford, CA, USA.
  • Aston KI; Andrology and IVF Laboratory, Department of Surgery (Urology), University of Utah School of Medicine, Salt Lake City, UT, USA.
  • Conrad DF; Division of Urology, Department of Surgery, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
Nat Commun ; 13(1): 7953, 2022 12 26.
Article en En | MEDLINE | ID: mdl-36572685
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Azoospermia / Infertilidad Masculina Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Azoospermia / Infertilidad Masculina Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido