40 results on '"Wyrwoll, Margot J."'
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2. Improved phenotypic classification of male infertility to promote discovery of genetic causes
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Wyrwoll, Margot J., van der Heijden, Godfried W., Krausz, Csilla, Aston, Kenneth I., Kliesch, Sabine, McLachlan, Robert, Ramos, Liliana, Conrad, Donald F., O’Bryan, Moira K., Veltman, Joris A., and Tüttelmann, Frank
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- 2024
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3. DDX3Y is likely the key spermatogenic factor in the AZFa region that contributes to human non-obstructive azoospermia
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Dicke, Ann-Kristin, Pilatz, Adrian, Wyrwoll, Margot J., Punab, Margus, Ruckert, Christian, Nagirnaja, Liina, Aston, Kenneth I., Conrad, Donald F., Di Persio, Sara, Neuhaus, Nina, Fietz, Daniela, Laan, Maris, Stallmeyer, Birgit, and Tüttelmann, Frank
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- 2023
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4. Disorders of Spermatogenesis and Spermiogenesis
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Schuppe, Hans-Christian, Wyrwoll, Margot J., Fietz, Daniela, Tüttelmann, Frank, Nieschlag, Eberhard, editor, Behre, Hermann M., editor, Kliesch, Sabine, editor, and Nieschlag, Susan, editor
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- 2023
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5. Störungen der Spermato- und Spermiogenese
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Schuppe, Hans-Christian, Wyrwoll, Margot J., Fietz, Daniela, Tüttelmann, Frank, Nieschlag, Eberhard, editor, Behre, Hermann M., editor, Kliesch, Sabine, editor, and Nieschlag, Susan, editor
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- 2023
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6. Genetische Diagnostik bei ungewollt kinderlosen Paaren oder wiederholten Fehlgeburten
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Rudnik-Schöneborn, Sabine, Wyrwoll, Margot J., Tüttelmann, Frank, Toth, Bettina, Pinggera, Germar-M., and Zschocke, Johannes
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- 2023
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7. Genetic Architecture of Azoospermia—Time to Advance the Standard of Care
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Wyrwoll, Margot J., Köckerling, Nils, Vockel, Matthias, Dicke, Ann-Kristin, Rotte, Nadja, Pohl, Eva, Emich, Jana, Wöste, Marius, Ruckert, Christian, Wabschke, Rebecca, Seggewiss, Jochen, Ledig, Susanne, Tewes, Ann-Christin, Stratis, Yvonne, Cremers, Jann F., Wistuba, Joachim, Krallmann, Claudia, Kliesch, Sabine, Röpke, Albrecht, Stallmeyer, Birgit, Friedrich, Corinna, and Tüttelmann, Frank
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- 2023
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8. Decreased spermatogonial numbers in boys with severe haematological diseases
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Lahtinen, Atte K., primary, Funke, Miriam, additional, Krallmann, Claudia, additional, Wyrwoll, Margot J., additional, Jarisch, Andrea, additional, Yang, Yifan, additional, Bjarnason, Ragnar, additional, Romerius, Patrik, additional, Sundin, Mikael, additional, Norén‐Nyström, Ulrika, additional, Langenskiöld, Cecilia, additional, Cremers, Jann‐Frederik, additional, Kliesch, Sabine, additional, Stukenborg, Jan‐Bernd, additional, Neuhaus, Nina, additional, and Jahnukainen, Kirsi, additional
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- 2024
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9. Genetik und männliche Infertilität
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Wyrwoll, Margot J. and Tüttelmann, Frank
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- 2022
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10. The piRNA-pathway factor FKBP6 is essential for spermatogenesis but dispensable for control of meiotic LINE-1 expression in humans
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Wyrwoll, Margot J., Gaasbeek, Channah M., Golubickaite, Ieva, Stakaitis, Rytis, Oud, Manon S., Nagirnaja, Liina, Dion, Camille, Sindi, Emad B., Leitch, Harry G., Jayasena, Channa N., Sironen, Anu, Dicke, Ann-Kristin, Rotte, Nadja, Stallmeyer, Birgit, Kliesch, Sabine, Grangeiro, Carlos H.P., Araujo, Thaís F., Lasko, Paul, D’Hauwers, Kathleen, Smits, Roos M., Ramos, Liliana, Xavier, Miguel J., Conrad, Don F., Almstrup, Kristian, Veltman, Joris A., Tüttelmann, Frank, and van der Heijden, Godfried W.
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- 2022
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11. Reproductive genetics and health.
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Wyrwoll, Margot J. and Steingröver, Johanna
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REPRODUCTIVE technology , *INSULIN resistance , *GENETIC variation , *LIFE expectancy , *DISEASE risk factors - Abstract
For those affected, infertility is linked to impaired overall health and reduced life expectancy. In particular, infertile individuals bear an increased risk for cardiovascular disease (CVD) and different types of cancer, partially due to lifestyle differences and to genetic alterations that cause both infertility and an increased cancer risk. Genetic variants causing an increased CVD risk are more commonly found in infertile individuals, but their link to infertility remains unclear. Offspring of infertile couples, conceived via medically assisted reproduction, are as likely as their parents to exhibit or develop adiposity, hormonal alterations such as insulin resistance, and infertility. The effects on health of subsequent generations are completely unclear. [ABSTRACT FROM AUTHOR]
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- 2024
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12. Störungen der Spermato- und Spermiogenese
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Schuppe, Hans-Christian, primary, Wyrwoll, Margot J., additional, Fietz, Daniela, additional, and Tüttelmann, Frank, additional
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- 2022
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13. The Human Phenotype Ontology in 2024: phenotypes around the world
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Gargano, Michael A, primary, Matentzoglu, Nicolas, additional, Coleman, Ben, additional, Addo-Lartey, Eunice B, additional, Anagnostopoulos, Anna V, additional, Anderton, Joel, additional, Avillach, Paul, additional, Bagley, Anita M, additional, Bakštein, Eduard, additional, Balhoff, James P, additional, Baynam, Gareth, additional, Bello, Susan M, additional, Berk, Michael, additional, Bertram, Holli, additional, Bishop, Somer, additional, Blau, Hannah, additional, Bodenstein, David F, additional, Botas, Pablo, additional, Boztug, Kaan, additional, Čady, Jolana, additional, Callahan, Tiffany J, additional, Cameron, Rhiannon, additional, Carbon, Seth J, additional, Castellanos, Francisco, additional, Caufield, J Harry, additional, Chan, Lauren E, additional, Chute, Christopher G, additional, Cruz-Rojo, Jaime, additional, Dahan-Oliel, Noémi, additional, Davids, Jon R, additional, de Dieuleveult, Maud, additional, de Souza, Vinicius, additional, de Vries, Bert B A, additional, de Vries, Esther, additional, DePaulo, J Raymond, additional, Derfalvi, Beata, additional, Dhombres, Ferdinand, additional, Diaz-Byrd, Claudia, additional, Dingemans, Alexander J M, additional, Donadille, Bruno, additional, Duyzend, Michael, additional, Elfeky, Reem, additional, Essaid, Shahim, additional, Fabrizzi, Carolina, additional, Fico, Giovanna, additional, Firth, Helen V, additional, Freudenberg-Hua, Yun, additional, Fullerton, Janice M, additional, Gabriel, Davera L, additional, Gilmour, Kimberly, additional, Giordano, Jessica, additional, Goes, Fernando S, additional, Moses, Rachel Gore, additional, Green, Ian, additional, Griese, Matthias, additional, Groza, Tudor, additional, Gu, Weihong, additional, Guthrie, Julia, additional, Gyori, Benjamin, additional, Hamosh, Ada, additional, Hanauer, Marc, additional, Hanušová, Kateřina, additional, He, Yongqun (Oliver), additional, Hegde, Harshad, additional, Helbig, Ingo, additional, Holasová, Kateřina, additional, Hoyt, Charles Tapley, additional, Huang, Shangzhi, additional, Hurwitz, Eric, additional, Jacobsen, Julius O B, additional, Jiang, Xiaofeng, additional, Joseph, Lisa, additional, Keramatian, Kamyar, additional, King, Bryan, additional, Knoflach, Katrin, additional, Koolen, David A, additional, Kraus, Megan L, additional, Kroll, Carlo, additional, Kusters, Maaike, additional, Ladewig, Markus S, additional, Lagorce, David, additional, Lai, Meng-Chuan, additional, Lapunzina, Pablo, additional, Laraway, Bryan, additional, Lewis-Smith, David, additional, Li, Xiarong, additional, Lucano, Caterina, additional, Majd, Marzieh, additional, Marazita, Mary L, additional, Martinez-Glez, Victor, additional, McHenry, Toby H, additional, McInnis, Melvin G, additional, McMurry, Julie A, additional, Mihulová, Michaela, additional, Millett, Caitlin E, additional, Mitchell, Philip B, additional, Moslerová, Veronika, additional, Narutomi, Kenji, additional, Nematollahi, Shahrzad, additional, Nevado, Julian, additional, Nierenberg, Andrew A, additional, Čajbiková, Nikola Novák, additional, Nurnberger, John I, additional, Ogishima, Soichi, additional, Olson, Daniel, additional, Ortiz, Abigail, additional, Pachajoa, Harry, additional, Perez de Nanclares, Guiomar, additional, Peters, Amy, additional, Putman, Tim, additional, Rapp, Christina K, additional, Rath, Ana, additional, Reese, Justin, additional, Rekerle, Lauren, additional, Roberts, Angharad M, additional, Roy, Suzy, additional, Sanders, Stephan J, additional, Schuetz, Catharina, additional, Schulte, Eva C, additional, Schulze, Thomas G, additional, Schwarz, Martin, additional, Scott, Katie, additional, Seelow, Dominik, additional, Seitz, Berthold, additional, Shen, Yiping, additional, Similuk, Morgan N, additional, Simon, Eric S, additional, Singh, Balwinder, additional, Smedley, Damian, additional, Smith, Cynthia L, additional, Smolinsky, Jake T, additional, Sperry, Sarah, additional, Stafford, Elizabeth, additional, Stefancsik, Ray, additional, Steinhaus, Robin, additional, Strawbridge, Rebecca, additional, Sundaramurthi, Jagadish Chandrabose, additional, Talapova, Polina, additional, Tenorio Castano, Jair A, additional, Tesner, Pavel, additional, Thomas, Rhys H, additional, Thurm, Audrey, additional, Turnovec, Marek, additional, van Gijn, Marielle E, additional, Vasilevsky, Nicole A, additional, Vlčková, Markéta, additional, Walden, Anita, additional, Wang, Kai, additional, Wapner, Ron, additional, Ware, James S, additional, Wiafe, Addo A, additional, Wiafe, Samuel A, additional, Wiggins, Lisa D, additional, Williams, Andrew E, additional, Wu, Chen, additional, Wyrwoll, Margot J, additional, Xiong, Hui, additional, Yalin, Nefize, additional, Yamamoto, Yasunori, additional, Yatham, Lakshmi N, additional, Yocum, Anastasia K, additional, Young, Allan H, additional, Yüksel, Zafer, additional, Zandi, Peter P, additional, Zankl, Andreas, additional, Zarante, Ignacio, additional, Zvolský, Miroslav, additional, Toro, Sabrina, additional, Carmody, Leigh C, additional, Harris, Nomi L, additional, Munoz-Torres, Monica C, additional, Danis, Daniel, additional, Mungall, Christopher J, additional, Köhler, Sebastian, additional, Haendel, Melissa A, additional, and Robinson, Peter N, additional
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- 2023
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14. Genetic dissection of spermatogenic arrest through exome analysis: clinical implications for the management of azoospermic men
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Krausz, Csilla, Riera-Escamilla, Antoni, Moreno-Mendoza, Daniel, Holleman, Kaylee, Cioppi, Francesca, Algaba, Ferran, Pybus, Marc, Friedrich, Corinna, Wyrwoll, Margot J., Casamonti, Elena, Pietroforte, Sara, Nagirnaja, Liina, Lopes, Alexandra M., Kliesch, Sabine, Pilatz, Adrian, Carrell, Douglas T., Conrad, Donald F., Ars, Elisabet, Ruiz-Castañé, Eduard, Aston, Kenneth I., Baarends, Willy M., and Tüttelmann, Frank
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- 2020
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15. Scrutinizing the human TEX genes in the context of human male infertility.
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Sieper, Marie. H., Gaikwad, Avinash S., Fros, Marion, Weber, Philipp, Di Persio, Sara, Oud, Manon S., Kliesch, Sabine, Neuhaus, Nina, Stallmeyer, Birgit, Tüttelmann, Frank, and Wyrwoll, Margot J.
- Abstract
Background: Infertility affects around 15% of all couples worldwide and is increasingly linked to variants in genes specifically expressed in the testis. Well‐established causes of male infertility include pathogenic variants in the genes TEX11, TEX14, and TEX15, while few studies have recently reported variants in TEX13B, TEX13C, FAM9A (TEX39A), and FAM9B (TEX39B). Objectives: We aimed at screening for novel potential candidate genes among the human TEX ("testis expressed") genes as well as verifying previously described disease associations in this set of genes. Materials and methods: To this end, we screened the exome sequencing data of 1305 men, including 1056 crypto‐ and azoospermic individuals, and determined cell‐specific expression by analyzing testis‐specific single‐cell RNA sequencing data for genes with identified variants. To investigate the overarching role in male fertility, we generated testis‐specific knockdown (KD) models of all 10 orthologous TEX genes in Drosophila melanogaster. Results: We detected rare potential disease‐causing variants in TEX10, TEX13A, TEX13B, TEX13C, TEX13D, ZFAND3 (TEX27), TEX33, FAM9A (TEX39A), and FAM9B (TEX39B), in 28 infertile men, of which 15 men carried variants in TEX10, TEX27, and TEX33. The KD of TEX2, TEX9, TEX10, TEX13, ZFAND3 (TEX27), TEX28, TEX30, NFX1 (TEX42), TEX261, and UTP4 (TEX292) in Drosophila resulted in normal fertility. Discussion: Based on our findings, the autosomal dominant predicted genes TEX10 and ZFAND3 (TEX27) and the autosomal recessive predicted gene TEX33, which all three are conceivably required for germ cell maturation, were identified as novel potential candidate genes for human non‐obstructive azoospermia. We additionally identified hemizygous loss‐of‐function (LoF) variants in TEX13B, TEX13C, and FAM9A (TEX39A) as unlikely monogenic culprits of male infertility as LoF variants were also found in control men. Conclusion: Our findings concerning the X‐linked genes TEX13B, TEX13C, and FAM9A (TEX39A) contradict previous reports and will decrease false‐positive reports in genetic diagnostics of azoospermic men. [ABSTRACT FROM AUTHOR]
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- 2024
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16. Improved phenotypic classification of male infertility to promote discovery of genetic causes
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Wyrwoll, Margot J., primary, van der Heijden, Godfried W., additional, Krausz, Csilla, additional, Aston, Kenneth I., additional, Kliesch, Sabine, additional, McLachlan, Robert, additional, Ramos, Liliana, additional, Conrad, Donald F., additional, O’Bryan, Moira K., additional, Veltman, Joris A., additional, and Tüttelmann, Frank, additional
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- 2023
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17. Scrutinizing the human TEX genes in the context of human male infertility
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Sieper, Marie. H., primary, Gaikwad, Avinash S., additional, Fros, Marion, additional, Weber, Philipp, additional, Di Persio, Sara, additional, Oud, Manon S., additional, Kliesch, Sabine, additional, Neuhaus, Nina, additional, Stallmeyer, Birgit, additional, Tüttelmann, Frank, additional, and Wyrwoll, Margot J., additional
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- 2023
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18. Bi-allelic variants in INSL3 and RXFP2 cause bilateral cryptorchidism and male infertility
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Dicke, Ann-Kristin, primary, Albrethsen, Jakob, additional, Hoare, Bradley L, additional, Wyrwoll, Margot J, additional, Busch, Alexander S, additional, Fietz, Daniela, additional, Pilatz, Adrian, additional, Bühlmann, Clara, additional, Juul, Anders, additional, Kliesch, Sabine, additional, Gromoll, Jörg, additional, Bathgate, Ross A D, additional, Tüttelmann, Frank, additional, and Stallmeyer, Birgit, additional
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- 2023
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19. WWC2 expression in the testis: Implications for spermatogenesis and male fertility
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Höffken, Verena, primary, Di Persio, Sara, additional, Laurentino, Sandra, additional, Wyrwoll, Margot J., additional, Terwort, Nicole, additional, Hermann, Anke, additional, Röpke, Albrecht, additional, Oud, Manon S., additional, Wistuba, Joachim, additional, Kliesch, Sabine, additional, Pavenstädt, Hermann J., additional, Tüttelmann, Frank, additional, Neuhaus, Nina, additional, and Kremerskothen, Joachim, additional
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- 2023
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20. Genetik und männliche Infertilität
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Wyrwoll, Margot J. and Tüttelmann, Frank
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Bei etwa der Hälfte der von Infertilität betroffenen Paare wird eine klinisch-deskriptive Diagnose aufseiten des Mannes gestellt. Genetische Analysen können dazu beitragen, eine kausale Diagnose zu stellen, die individuelle Beratung und Behandlung des Paares zu ermöglichen und daraus Therapieentscheidungen abzuleiten. Je nach klinischem Befund sind eine Chromosomenanalyse, Screening nach Y‑chromosomalen AZF-Deletionen (AZF: Azoospermiefaktor) sowie Panel-Untersuchungen von mehreren Genen indiziert. Vor Durchführung einer assistierten Reproduktion sollte, nach Ausschluss anderer Ursachen und unabhängig von den folgenden spezifischen Indikationen, bei beiden Partnern eine Chromosomenanalyse erfolgen. Häufige Ursachen für männliche Infertilität sind das Klinefelter-Syndrom (47,XXY), chromosomale Translokationen, Deletionen der AZF-Region sowie die obstruktive Azoospermie aufgrund von biallelischen pathogenen Varianten (Mutationen) im CFTR-Gen. In den letzten Jahren wurde eine Reihe von Genen identifiziert, die mit morphologischen und funktionellen Auffälligkeiten der Spermien assoziiert sind. Darüber hinaus sind mittlerweile einige Gene bekannt, in denen Mutationen ursächlich für eine nichtobstruktive Azoospermie (NOA) oder einen kongenitalen hypogonadotropen Hypogonadismus (CHH) sind. Der Nachweis der genetischen Ursache der Infertilität ermöglicht das Abschätzen der Erfolgschancen einer Kinderwunschbehandlung und erlaubt es, die Wiederholungsrisiken für Nachkommen anzugeben.
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- 2024
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21. Transcriptome analyses in infertile men reveal germ cell–specific expression and splicing patterns
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Siebert-Kuss, Lara M, primary, Krenz, Henrike, additional, Tekath, Tobias, additional, Wöste, Marius, additional, Di Persio, Sara, additional, Terwort, Nicole, additional, Wyrwoll, Margot J, additional, Cremers, Jann-Frederik, additional, Wistuba, Joachim, additional, Dugas, Martin, additional, Kliesch, Sabine, additional, Schlatt, Stefan, additional, Tüttelmann, Frank, additional, Gromoll, Jörg, additional, Neuhaus, Nina, additional, and Laurentino, Sandra, additional
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- 2022
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22. Transcriptome analyses in infertile men reveal germ cell--specific expression and splicing patterns.
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Siebert-Kuss, Lara M., Krenz, Henrike, Tekath, Tobias, Wöste, Marius, Di Persio, Sara, Terwort, Nicole, Wyrwoll, Margot J., Cremers, Jann-Frederik, Wistuba, Joachim, Dugas, Martin, Kliesch, Sabine, Schlatt, Stefan, Tüttelmann, Frank, Gromoll, Jörg, Neuhaus, Nina, and Laurentino, Sandra
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- 2023
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23. Stage-specific gene and transcript dynamics in human male germ cells
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Siebert-Kuss, Lara Marie, primary, Krenz, Henrike, additional, Tekath, Tobias, additional, Wöste, Marius, additional, Di Persio, Sara, additional, Terwort, Nicole, additional, Wyrwoll, Margot J., additional, Cremers, Jann-Frederik, additional, Wistuba, Joachim, additional, Dugas, Martin, additional, Kliesch, Sabine, additional, Schlatt, Stefan, additional, Tüttelmann, Frank, additional, Gromoll, Jörg, additional, Neuhaus, Nina, additional, and Laurentino, Sandra, additional
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- 2022
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24. The conserved transcriptional program of metazoan male germ cells uncovers ancient origins of human infertility
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Correia, Rion Brattig, primary, Almeida, Joana M., additional, Wyrwoll, Margot J., additional, Julca, Irene, additional, Sobral, Daniel, additional, Misra, Chandra Shekhar, additional, Guilgur, Leonardo G., additional, Schuppe, Hans-Christian, additional, Silva, Neide, additional, Prudêncio, Pedro, additional, Nóvoa, Ana, additional, Leocádio, Ana S., additional, Bom, Joana, additional, Mallo, Moisés, additional, Kliesch, Sabine, additional, Mutwil, Marek, additional, Rocha, Luis M., additional, Tüttelmann, Frank, additional, Becker, Jörg D., additional, and Navarro-Costa, Paulo, additional
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- 2022
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25. Human INHBB gene variant (c.1079T>C:p.Met360Thr) alters testis germ cell content, but does not impact fertility in mice
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Houston, Brendan J, primary, O’Connor, Anne E, additional, Wang, Degang, additional, Goodchild, Georgia, additional, Merriner, D Jo, additional, Luan, Haitong, additional, Conrad, Don F, additional, Nagirnaja, Liina, additional, Aston, Kenneth I, additional, Kliesch, Sabine, additional, Wyrwoll, Margot J, additional, Friedrich, Corinna, additional, Tüttelmann, Frank, additional, Harrison, Craig, additional, O’Bryan, Moira K, additional, and Walton, Kelly, additional
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- 2022
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26. A systematic review of the validated monogenic causes of human male infertility: 2020 update and a discussion of emerging gene–disease relationships
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Houston, Brendan J, primary, Riera-Escamilla, Antoni, additional, Wyrwoll, Margot J, additional, Salas-Huetos, Albert, additional, Xavier, Miguel J, additional, Nagirnaja, Liina, additional, Friedrich, Corinna, additional, Conrad, Don F, additional, Aston, Kenneth I, additional, Krausz, Csilla, additional, Tüttelmann, Frank, additional, O’Bryan, Moira K, additional, Veltman, Joris A, additional, and Oud, Manon S, additional
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- 2021
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27. Variants in GCNA, X-linked germ-cell genome integrity gene, identified in men with primary spermatogenic failure
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Hardy, Jimmaline J., Wyrwoll, Margot J., Mcfadden, William, Malcher, Agnieszka, Rotte, Nadja, Pollock, Nijole C., Munyoki, Sarah, Veroli, Maria V., Houston, Brendan J., Xavier, Miguel J., Kasak, Laura, Punab, Margus, Laan, Maris, Kliesch, Sabine, Schlegel, Peter, Jaffe, Thomas, Hwang, Kathleen, Vukina, Josip, Brieño-Enríquez, Miguel A., Orwig, Kyle, Yanowitz, Judith, Buszczak, Michael, Veltman, Joris A., Oud, Manon, Nagirnaja, Liina, Olszewska, Marta, O’Bryan, Moira K., Conrad, Donald F., Kurpisz, Maciej, Tüttelmann, Frank, Yatsenko, Alexander N., Aston, Kenneth I., Carrell, Douglas T., Hotaling, James M., Jenkins, Timothy G., McLachlan, Rob, 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, Meyts, Ewa Rajpert-De, Jørgensen, Niels, Almstrup, Kristian, Krausz, Csilla G., Jarvi, Keith A., and on behalf of GEMINI Consortium
- Subjects
Male ,Models, Molecular ,Protein Conformation, alpha-Helical ,Gene Expression ,medicine.disease_cause ,Genome ,Male infertility ,Cohort Studies ,Genes, X-Linked ,Testis ,Testosterone ,Genetics (clinical) ,Exome sequencing ,Spermatogenic Failure ,Azoospermia ,Genetics ,0303 health sciences ,Mutation ,education.field_of_study ,030305 genetics & heredity ,Nuclear Proteins ,Spermatozoa ,3. Good health ,Meiosis ,Adult ,Population ,Biology ,Genomic Instability ,Article ,Frameshift mutation ,03 medical and health sciences ,Exome Sequencing ,medicine ,Male Infertility ,Animals ,Humans ,Protein Interaction Domains and Motifs ,education ,Spermatogenesis ,Gene ,Infertility, Male ,030304 developmental biology ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Base Sequence ,Genome, Human ,GCNA ,Luteinizing Hormone ,medicine.disease ,Human genetics ,Doenças Genéticas ,Protein Conformation, beta-Strand ,Follicle Stimulating Hormone - Abstract
Free PMC article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266742/pdf/nihms-1705620.pdf 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. Member of GEMINI Consortium: João Gonçalves (INSA), lista completa na pág 1179. Male infertility impacts millions of couples yet, the etiology of primary infertility remains largely unknown. A critical element of successful spermatogenesis is maintenance of genome integrity. Here, we present a genomic study of spermatogenic failure (SPGF). Our initial analysis (n=176) did not reveal known gene-candidates but identifed a potentially signifcant single-nucleotide variant (SNV) in X-linked germ-cell nuclear antigen (GCNA). Together with a larger follow-up study (n=2049), 7 likely clinically relevant GCNA variants were identifed. GCNA is critical for genome integrity in male meiosis and knockout models exhibit impaired spermatogenesis and infertility. Single-cell RNA-seq and immunohistochemistry confrm human GCNA expression from spermatogonia to elongated spermatids. Five identifed SNVs were located in key functional regions, including N-terminal SUMO-interacting motif and C-terminal Spartan-like protease domain. Notably, variant p.Ala115ProfsTer7 results in an early frameshift, while Spartan-like domain missense variants p.Ser659Trp and p.Arg664Cys change conserved residues, likely afecting 3D structure. For variants within GCNA’s intrinsically disordered region, we performed computational modeling for consensus motifs. Two SNVs were predicted to impact the structure of these consensus motifs. All identifed variants have an extremely low minor allele frequency in the general population and 6 of 7 were not detected in>5000 biological fathers. Considering evidence from animal models, germ-cell-specifc expression, 3D modeling, and computational predictions for SNVs, we propose that identifed GCNA variants disrupt structure and function of the respective protein domains, ultimately arresting germ-cell division. To our knowledge, this is the frst study implicating GCNA, a key genome integrity factor, in human male infertility. This study was supported by The Eunice Kennedy Shriver NICHD Grant HD080755 (ANY), the Magee-Womens Research Institute University of Pittsburgh Start Up Fund (ANY), PA DoH Grant SAP4100085736 (ANY), NIH P50 Specialized Center Grant HD096723 (KO, ANY, DC, PNS, KH, and MBE), German Research Foundation Clinical Research Unit ‘Male Germ Cells’ grant DFG CRU326 (FT), National Science Centre in Poland, grants no.: 2017/26/D/NZ5/00789 (AM) and 2015/17/B/NZ2/01157; NCN 2020/37/B/NZ5/00549 (MK), Magee-Womens Research Institute University of Pittsburgh, Faculty Fellowship Award and NICHD T32 HD087194 (JH), GM125812 (MB), GM127569 (MB, JLY, and ANY), NIH R00H090289 (MABE), National Health and Medical Research Council Project grant APP1120356 (MKOB, JAV, and DC), UUKi Rutherford Fund Fellowship (BJH), Estonian Research Council, grants IUT34-12 and PRG1021 (ML), and The Netherlands Organization for Scientifc Research grant no.: 918-15-667 as well as an Investigator Award in Science from the Wellcome Trust grant no.: 209451 (JAV). Computational analysis was supported in part by the University of Pittsburgh Center for Research Computing through the resources provided. info:eu-repo/semantics/publishedVersion
- Published
- 2021
28. A systematic review of the validated monogenic causes of human male infertility: 2020 update and a discussion of emerging gene-disease relationships
- Author
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Houston, Brendan J., primary, Riera-Escamilla, Antoni, additional, Wyrwoll, Margot J., additional, Salas-Huetos, Albert, additional, Xavier, Miguel J., additional, Nagirnaja, Liina, additional, Friedrich, Corinna, additional, Conrad, Don F., additional, Aston, Kenneth I., additional, Krausz, Csilla, additional, Tüttelmann, Frank, additional, O’Bryan, Moira K., additional, Veltman, Joris A., additional, and Oud, Manon S., additional
- Published
- 2021
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- View/download PDF
29. Genetic counseling and diagnostic guidelines for couples with infertility and/or recurrent miscarriage
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Wyrwoll, Margot J., primary, Rudnik-Schöneborn, Sabine, additional, and Tüttelmann, Frank, additional
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- 2021
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- View/download PDF
30. Bi-allelic Mutations in M1AP Are a Frequent Cause of Meiotic Arrest and Severely Impaired Spermatogenesis Leading to Male Infertility
- Author
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Wyrwoll, Margot J., Temel, Sehime G., Nagirnaja, Liina, Oud, Manon S., Lopes, Alexandra M., van der Heijden, Godfried W., Heald, James S., Rotte, Nadja, Wistuba, Joachim, Woeste, Marius, Ledig, Susanne, Krenz, Henrike, Smits, Roos M., Carvalho, Filipa, Goncalves, Joao, Fietz, Daniela, Turkgenc, Burcu, Ergoren, Mahmut C., Cetinkaya, Murat, Basar, Murad, Kahraman, Semra, McEleny, Kevin, Xavier, Miguel J., Turner, Helen, Pilatz, Adrian, Roepke, Albrecht, Dugas, Martin, Kliesch, Sabine, Neuhaus, Nina, Aston I, Kenneth, Conrad, Donald F., Veltman, Joris A., Friedrich, Corinna, Tuettelmann, Frank, Consortium, G. E. M. I. N. I., Acibadem University Dspace, Bursa Uludağ Üniversitesi/Tıp Fakültesi/Tıbbi Genetik Anabilim Dalı., Temel, Şehime, and AAG-8385-2021
- Subjects
0301 basic medicine ,Male ,Turkey ,Male Infertility ,Azoospermia ,Y Chromosome ,Mouse ,Genetic code ,M1AP ,Procedures ,Gene ,Male infertility ,Mice ,0302 clinical medicine ,Turkey (bird) ,Testis ,Missense mutation ,Spermatid ,Genetics (clinical) ,Priority journal ,Genetics ,Allele ,030219 obstetrics & reproductive medicine ,Genetics & heredity ,Homozygote ,Variants ,Phenotype ,Cryptozoospermia ,Spermatozoa ,Turkish citizen ,Non-obstructive azoospermia (NOA) ,Meiosis ,Germ cell ,Human ,Infertility ,Adult ,Spermatozoon ,Biology ,Article ,Frameshift mutation ,Healthcare improvement science Radboud Institute for Health Sciences [Radboudumc 18] ,Cell cycle arrest ,03 medical and health sciences ,All institutes and research themes of the Radboud University Medical Center ,Cell cycle checkpoints ,Report ,Exome Sequencing ,medicine ,Animals ,Humans ,Family ,MaleI Infertility ,Gene mutation ,Spermatogenesis ,Disease severity ,Alleles ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Animal ,Protein ,Whole exome sequencing ,Proteins ,In vitro study ,Oligospermia ,Cell Cycle Checkpoints ,medicine.disease ,Infertility, male ,Nonhuman ,Doenças Genéticas ,Meiosis 1 arresting protein, mouse ,030104 developmental biology ,Mutation ,Loss of function mutation ,Genetic association ,M1AP gene ,Genetic variability ,Cell cycle checkpoint - Abstract
Male infertility affects ∼7% of men, but its causes remain poorly understood. The most severe form is non-obstructive azoospermia (NOA), which is, in part, caused by an arrest at meiosis. So far, only a few validated disease-associated genes have been reported. To address this gap, we performed whole-exome sequencing in 58 men with unexplained meiotic arrest and identified the same homozygous frameshift variant c.676dup (p.Trp226LeufsTer4) in M1AP, encoding meiosis 1 associated protein, in three unrelated men. This variant most likely results in a truncated protein as shown in vitro by heterologous expression of mutant M1AP. Next, we screened four large cohorts of infertile men and identified three additional individuals carrying homozygous c.676dup and three carrying combinations of this and other likely causal variants in M1AP. Moreover, a homozygous missense variant, c.1166C>T (p.Pro389Leu), segregated with infertility in five men from a consanguineous Turkish family. The common phenotype between all affected men was NOA, but occasionally spermatids and rarely a few spermatozoa in the semen were observed. A similar phenotype has been described for mice with disruption of M1ap. Collectively, these findings demonstrate that mutations in M1AP are a relatively frequent cause of autosomal recessive severe spermatogenic failure and male infertility with strong clinical validity. This work was carried out within the frame of the German Research Foundation Clinical Research Unit ‘‘Male Germ Cells: from Genes to Function’’ (DFG CRU326). Funding for sequencing of the GEMINI cohort was provided by the National Institutes of Health, United States (R01HD078641). The analyses in the Turkish family were supported by a grant from the Bursa University of Uludag Project Unit [KUAP(T)-2014/36]. info:eu-repo/semantics/publishedVersion
- Published
- 2020
31. A systematic review of the validated monogenic causes of human male infertility: 2020 update and a discussion of emerging gene-disease relationships.
- Author
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Houston, Brendan J, Riera-Escamilla, Antoni, Wyrwoll, Margot J, Salas-Huetos, Albert, Xavier, Miguel J, Nagirnaja, Liina, Friedrich, Corinna, Conrad, Don F, Aston, Kenneth I, Krausz, Csilla, Tüttelmann, Frank, O'Bryan, Moira K, Veltman, Joris A, and Oud, Manon S
- Subjects
MALE infertility ,INFERTILITY ,Y chromosome ,GENITALIA ,MEDICAL genetics ,MOLECULAR pathology ,KLINEFELTER'S syndrome ,GENETIC testing ,RESEARCH ,SEQUENCE analysis ,GENETIC mutation ,ANIMAL experimentation ,SYSTEMATIC reviews ,EVALUATION research ,COMPARATIVE studies ,GENOMICS ,RESEARCH funding - Abstract
Background: Human male infertility has a notable genetic component, including well-established diagnoses such as Klinefelter syndrome, Y-chromosome microdeletions and monogenic causes. Approximately 4% of all infertile men are now diagnosed with a genetic cause, but a majority (60-70%) remain without a clear diagnosis and are classified as unexplained. This is likely in large part due to a delay in the field adopting next-generation sequencing (NGS) technologies, and the absence of clear statements from field leaders as to what constitutes a validated cause of human male infertility (the current paper aims to address this). Fortunately, there has been a significant increase in the number of male infertility NGS studies. These have revealed a considerable number of novel gene-disease relationships (GDRs), which each require stringent assessment to validate the strength of genotype-phenotype associations. To definitively assess which of these GDRs are clinically relevant, the International Male Infertility Genomics Consortium (IMIGC) has identified the need for a systematic review and a comprehensive overview of known male infertility genes and an assessment of the evidence for reported GDRs.Objective and Rationale: In 2019, the first standardised clinical validity assessment of monogenic causes of male infertility was published. Here, we provide a comprehensive update of the subsequent 1.5 years, employing the joint expertise of the IMIGC to systematically evaluate all available evidence (as of 1 July 2020) for monogenic causes of isolated or syndromic male infertility, endocrine disorders or reproductive system abnormalities affecting the male sex organs. In addition, we systematically assessed the evidence for all previously reported possible monogenic causes of male infertility, using a framework designed for a more appropriate clinical interpretation of disease genes.Search Methods: We performed a literature search according to the PRISMA guidelines up until 1 July 2020 for publications in English, using search terms related to 'male infertility' in combination with the word 'genetics' in PubMed. Next, the quality and the extent of all evidence supporting selected genes were assessed using an established and standardised scoring method. We assessed the experimental quality, patient phenotype assessment and functional evidence based on gene expression, mutant in-vitro cell and in-vivo animal model phenotypes. A final score was used to determine the clinical validity of each GDR, across the following five categories: no evidence, limited, moderate, strong or definitive. Variants were also reclassified according to the American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines and were recorded in spreadsheets for each GDR, which are available at imigc.org.Outcomes: The primary outcome of this review was an overview of all known GDRs for monogenic causes of human male infertility and their clinical validity. We identified a total of 120 genes that were moderately, strongly or definitively linked to 104 infertility phenotypes.Wider Implications: Our systematic review curates all currently available evidence to reveal the strength of GDRs in male infertility. The existing guidelines for genetic testing in male infertility cases are based on studies published 25 years ago, and an update is far overdue. The identification of 104 high-probability 'human male infertility genes' is a 33% increase from the number identified in 2019. The insights generated in the current review will provide the impetus for an update of existing guidelines, will inform novel evidence-based genetic testing strategies used in clinics, and will identify gaps in our knowledge of male infertility genetics. We discuss the relevant international guidelines regarding research related to gene discovery and provide specific recommendations to the field of male infertility. Based on our findings, the IMIGC consortium recommend several updates to the genetic testing standards currently employed in the field of human male infertility, most important being the adoption of exome sequencing, or at least sequencing of the genes validated in this study, and expanding the patient groups for which genetic testing is recommended. [ABSTRACT FROM AUTHOR]- Published
- 2022
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- View/download PDF
32. Identification of the best index case significantly improves mutation detection rates in families with hereditary breast and ovarian cancer
- Author
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Wyrwoll, Margot J., primary, Fuchs, Lea, additional, and Waschk, Daniel E.J., additional
- Published
- 2019
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- View/download PDF
33. Disruption of human meiotic telomere complex genes TERB1, TERB2 and MAJIN in men with non-obstructive azoospermia.
- Author
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Salas-Huetos, Albert, Tüttelmann, Frank, Wyrwoll, Margot J., Kliesch, Sabine, Lopes, Alexandra M., Goncalves, João, Boyden, Steven E., Wöste, Marius, Hotaling, James M., GEMINI Consortium, Conrad, Donald F., Aston, Kenneth I., Carrell, Douglas T., Nagirnaja, Liina, Jenkins, Timothy G., O'Bryan, Moira K., McLachlan, Rob, Schlegel, Peter N., Eisenberg, Michael L., and Sandlow, Jay I.
- Subjects
GENES ,TELOMERES ,SPERMATOGENESIS ,PHENOTYPES ,GERM cells ,SPERMATOZOA ,TESTIS ,MALE infertility - Abstract
Non-obstructive azoospermia (NOA), the lack of spermatozoa in semen due to impaired spermatogenesis affects nearly 1% of men. In about half of cases, an underlying cause for NOA cannot be identified. This study aimed to identify novel variants associated with idiopathic NOA. We identified a nonconsanguineous family in which multiple sons displayed the NOA phenotype. We performed whole-exome sequencing in three affected brothers with NOA, their two unaffected brothers and their father, and identified compound heterozygous frameshift variants (one novel and one extremely rare) in Telomere Repeat Binding Bouquet Formation Protein 2 (TERB2) that segregated perfectly with NOA. TERB2 interacts with TERB1 and Membrane Anchored Junction Protein (MAJIN) to form the tripartite meiotic telomere complex (MTC), which has been shown in mouse models to be necessary for the completion of meiosis and both male and female fertility. Given our novel findings of TERB2 variants in NOA men, along with the integral role of the three MTC proteins in spermatogenesis, we subsequently explored exome sequence data from 1495 NOA men to investigate the role of MTC gene variants in spermatogenic impairment. Remarkably, we identified two NOA patients with likely damaging rare homozygous stop and missense variants in TERB1 and one NOA patient with a rare homozygous missense variant in MAJIN. Available testis histology data from three of the NOA patients indicate germ cell maturation arrest, consistent with mouse phenotypes. These findings suggest that variants in MTC genes may be an important cause of NOA in both consanguineous and outbred populations. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
34. Nanomechanics of the endothelial glycocalyx contribute to Na+-induced vascular inflammation
- Author
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Schierke, Florian, primary, Wyrwoll, Margot J., additional, Wisdorf, Martin, additional, Niedzielski, Leon, additional, Maase, Martina, additional, Ruck, Tobias, additional, Meuth, Sven G., additional, and Kusche-Vihrog, Kristina, additional
- Published
- 2017
- Full Text
- View/download PDF
35. Human INHBBGene Variant (c.1079T>C:p.Met360Thr) Alters Testis Germ Cell Content, but Does Not Impact Fertility in Mice
- Author
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Houston, Brendan J, O’Connor, Anne E, Wang, Degang, Goodchild, Georgia, Merriner, D Jo, Luan, Haitong, Conrad, Don F, Nagirnaja, Liina, Aston, Kenneth I, Kliesch, Sabine, Wyrwoll, Margot J, Friedrich, Corinna, Tüttelmann, Frank, Harrison, Craig, O’Bryan, Moira K, and Walton, Kelly
- Abstract
Testicular-derived inhibin B (α/β Bdimers) acts in an endocrine manner to suppress pituitary production of follicle-stimulating hormone (FSH), by blocking the actions of activins (β A/B/β A/Bdimers). Previously, we identified a homozygous genetic variant (c.1079T>C:p.Met360Thr) arising from uniparental disomy of chromosome 2 in the INHBBgene (β B-subunit of inhibin B and activin B) in a man suffering from infertility (azoospermia). In this study, we aimed to test the causality of the p.Met360Thr variant in INHBBand testis function. Here, we used CRISPR/Cas9 technology to generate InhbbM364T/M364Tmice, where mouse INHBB p.Met364 corresponds with human p.Met360. Surprisingly, we found that the testes of male InhbbM364T/M364Tmutant mice were significantly larger compared with those of aged-matched wildtype littermates at 12 and 24 weeks of age. This was attributed to a significant increase in Sertoli cell and round spermatid number and, consequently, seminiferous tubule area in InhbbM364T/M364Tmales compared to wildtype males. Despite this testis phenotype, male InhbbM364T/M364Tmutant mice retained normal fertility. Serum hormone analyses, however, indicated that the InhbbM364Tvariant resulted in reduced circulating levels of activin B but did not affect FSH production. We also examined the effect of this p.Met360Thr and an additional INHBBvariant (c.314C>T: p.Thr105Met) found in another infertile man on inhibin B and activin B in vitro biosynthesis. We found that both INHBBvariants resulted in a significant disruption to activin B in vitro biosynthesis. Together, this analysis supports that INHBBvariants that limit activin B production have consequences for testis composition in males.
- Published
- 2022
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36. Correction to: Disruption of human meiotic telomere complex genes TERB1, TERB2 and MAJIN in men with non-obstructive azoospermia.
- Author
-
Salas-Huetos, Albert, Tüttelmann, Frank, Wyrwoll, Margot J., Kliesch, Sabine, Lopes, Alexandra M., Gonçalves, João, Boyden, Steven E., Wöste, Marius, Hotaling, James M., GEMINI Consortium, Conrad, Donald F., Aston, Kenneth I., Carrell, Douglas T., Nagirnaja, Liina, Jenkins, Timothy G., O'Bryan, Moira K., McLachlan, Rob, Schlegel, Peter N., Eisenberg, Michael L., and Sandlow, Jay I.
- Subjects
GENES ,PERSONAL names - Abstract
In the original article published, the family name of the 6th author is published incorrectly. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
37. Nanomechanics of the endothelial glycocalyx contribute to Na+-induced vascular inflammation.
- Author
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Schierke, Florian, Wyrwoll, Margot J., Wisdorf, Martin, Niedzielski, Leon, Maase, Martina, Ruck, Tobias, Meuth, Sven G., and Kusche-Vihrog, Kristina
- Abstract
High dietary salt (NaCl) is a known risk factor for cardiovascular pathologies and inflammation. High plasma Na+ concentrations (high Na+) have been shown to stiffen the endothelial cortex and decrease nitric oxide (NO) release, a hallmark of endothelial dysfunction. Here we report that chronic high Na+ damages the endothelial glycocalyx (eGC), induces release of inflammatory cytokines from the endothelium and promotes monocyte adhesion. Single cell force spectroscopy reveals that high Na+ enhances vascular adhesion protein-1 (VCAM-1)-dependent adhesion forces between monocytes and endothelial surface, giving rise to increased numbers of adherent monocytes on the endothelial surface. Mineralocorticoid receptor antagonism with spironolactone prevents high Na+-induced eGC deterioration, decreases monocyte-endothelium interactions, and restores endothelial function, indicated by increased release of NO. Whereas high Na+ decreases NO release, it induces endothelial release of the pro-inflammatory cytokines IL-1ß and TNFα. However, in contrast to chronic salt load (hours), in vivo and in vitro, an acute salt challenge (minutes) does not impair eGC function. This study identifies the eGC as important mediator of inflammatory processes and might further explain how dietary salt contributes to endothelialitis and cardiovascular pathologies by linking endothelial nanomechanics with vascular inflammation. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
38. The Human Phenotype Ontology in 2024: phenotypes around the world.
- Author
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Gargano MA, Matentzoglu N, Coleman B, Addo-Lartey EB, Anagnostopoulos AV, Anderton J, Avillach P, Bagley AM, Bakštein E, Balhoff JP, Baynam G, Bello SM, Berk M, Bertram H, Bishop S, Blau H, Bodenstein DF, Botas P, Boztug K, Čady J, Callahan TJ, Cameron R, Carbon SJ, Castellanos F, Caufield JH, Chan LE, Chute CG, Cruz-Rojo J, Dahan-Oliel N, Davids JR, de Dieuleveult M, de Souza V, de Vries BBA, de Vries E, DePaulo JR, Derfalvi B, Dhombres F, Diaz-Byrd C, Dingemans AJM, Donadille B, Duyzend M, Elfeky R, Essaid S, Fabrizzi C, Fico G, Firth HV, Freudenberg-Hua Y, Fullerton JM, Gabriel DL, Gilmour K, Giordano J, Goes FS, Moses RG, Green I, Griese M, Groza T, Gu W, Guthrie J, Gyori B, Hamosh A, Hanauer M, Hanušová K, He YO, Hegde H, Helbig I, Holasová K, Hoyt CT, Huang S, Hurwitz E, Jacobsen JOB, Jiang X, Joseph L, Keramatian K, King B, Knoflach K, Koolen DA, Kraus ML, Kroll C, Kusters M, Ladewig MS, Lagorce D, Lai MC, Lapunzina P, Laraway B, Lewis-Smith D, Li X, Lucano C, Majd M, Marazita ML, Martinez-Glez V, McHenry TH, McInnis MG, McMurry JA, Mihulová M, Millett CE, Mitchell PB, Moslerová V, Narutomi K, Nematollahi S, Nevado J, Nierenberg AA, Čajbiková NN, Nurnberger JI Jr, Ogishima S, Olson D, Ortiz A, Pachajoa H, Perez de Nanclares G, Peters A, Putman T, Rapp CK, Rath A, Reese J, Rekerle L, Roberts AM, Roy S, Sanders SJ, Schuetz C, Schulte EC, Schulze TG, Schwarz M, Scott K, Seelow D, Seitz B, Shen Y, Similuk MN, Simon ES, Singh B, Smedley D, Smith CL, Smolinsky JT, Sperry S, Stafford E, Stefancsik R, Steinhaus R, Strawbridge R, Sundaramurthi JC, Talapova P, Tenorio Castano JA, Tesner P, Thomas RH, Thurm A, Turnovec M, van Gijn ME, Vasilevsky NA, Vlčková M, Walden A, Wang K, Wapner R, Ware JS, Wiafe AA, Wiafe SA, Wiggins LD, Williams AE, Wu C, Wyrwoll MJ, Xiong H, Yalin N, Yamamoto Y, Yatham LN, Yocum AK, Young AH, Yüksel Z, Zandi PP, Zankl A, Zarante I, Zvolský M, Toro S, Carmody LC, Harris NL, Munoz-Torres MC, Danis D, Mungall CJ, Köhler S, Haendel MA, and Robinson PN
- Subjects
- Humans, Phenotype, Genomics, Algorithms, Rare Diseases, Biological Ontologies
- Abstract
The Human Phenotype Ontology (HPO) is a widely used resource that comprehensively organizes and defines the phenotypic features of human disease, enabling computational inference and supporting genomic and phenotypic analyses through semantic similarity and machine learning algorithms. The HPO has widespread applications in clinical diagnostics and translational research, including genomic diagnostics, gene-disease discovery, and cohort analytics. In recent years, groups around the world have developed translations of the HPO from English to other languages, and the HPO browser has been internationalized, allowing users to view HPO term labels and in many cases synonyms and definitions in ten languages in addition to English. Since our last report, a total of 2239 new HPO terms and 49235 new HPO annotations were developed, many in collaboration with external groups in the fields of psychiatry, arthrogryposis, immunology and cardiology. The Medical Action Ontology (MAxO) is a new effort to model treatments and other measures taken for clinical management. Finally, the HPO consortium is contributing to efforts to integrate the HPO and the GA4GH Phenopacket Schema into electronic health records (EHRs) with the goal of more standardized and computable integration of rare disease data in EHRs., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Published
- 2024
- Full Text
- View/download PDF
39. Bi-allelic Mutations in M1AP Are a Frequent Cause of Meiotic Arrest and Severely Impaired Spermatogenesis Leading to Male Infertility.
- Author
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Wyrwoll MJ, Temel ŞG, Nagirnaja L, Oud MS, Lopes AM, van der Heijden GW, Heald JS, Rotte N, Wistuba J, Wöste M, Ledig S, Krenz H, Smits RM, Carvalho F, Gonçalves J, Fietz D, Türkgenç B, Ergören MC, Çetinkaya M, Başar M, Kahraman S, McEleny K, Xavier MJ, Turner H, Pilatz A, Röpke A, Dugas M, Kliesch S, Neuhaus N, Aston KI, Conrad DF, Veltman JA, Friedrich C, and Tüttelmann F
- Subjects
- Adult, Alleles, Animals, Azoospermia genetics, Homozygote, Humans, Male, Mice, Phenotype, Spermatozoa abnormalities, Testis abnormalities, Turkey, Exome Sequencing methods, Cell Cycle Checkpoints genetics, Infertility, Male genetics, Meiosis genetics, Mutation genetics, Proteins genetics, Spermatogenesis genetics
- Abstract
Male infertility affects ∼7% of men, but its causes remain poorly understood. The most severe form is non-obstructive azoospermia (NOA), which is, in part, caused by an arrest at meiosis. So far, only a few validated disease-associated genes have been reported. To address this gap, we performed whole-exome sequencing in 58 men with unexplained meiotic arrest and identified the same homozygous frameshift variant c.676dup (p.Trp226LeufsTer4) in M1AP, encoding meiosis 1 associated protein, in three unrelated men. This variant most likely results in a truncated protein as shown in vitro by heterologous expression of mutant M1AP. Next, we screened four large cohorts of infertile men and identified three additional individuals carrying homozygous c.676dup and three carrying combinations of this and other likely causal variants in M1AP. Moreover, a homozygous missense variant, c.1166C>T (p.Pro389Leu), segregated with infertility in five men from a consanguineous Turkish family. The common phenotype between all affected men was NOA, but occasionally spermatids and rarely a few spermatozoa in the semen were observed. A similar phenotype has been described for mice with disruption of M1ap. Collectively, these findings demonstrate that mutations in M1AP are a relatively frequent cause of autosomal recessive severe spermatogenic failure and male infertility with strong clinical validity., (Copyright © 2020 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
40. Nanomechanics of the endothelial glycocalyx contribute to Na + -induced vascular inflammation.
- Author
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Schierke F, Wyrwoll MJ, Wisdorf M, Niedzielski L, Maase M, Ruck T, Meuth SG, and Kusche-Vihrog K
- Subjects
- Animals, Biomechanical Phenomena, Cell Adhesion, Cells, Cultured, Endothelial Cells immunology, Humans, Interleukin-1beta metabolism, Male, Mice, Monocytes cytology, Monocytes metabolism, Nitric Oxide metabolism, Tumor Necrosis Factor-alpha metabolism, Vasculitis chemically induced, Vasculitis immunology, Endothelial Cells metabolism, Glycocalyx metabolism, Sodium Chloride, Dietary adverse effects, Vasculitis metabolism
- Abstract
High dietary salt (NaCl) is a known risk factor for cardiovascular pathologies and inflammation. High plasma Na
+ concentrations (high Na+ ) have been shown to stiffen the endothelial cortex and decrease nitric oxide (NO) release, a hallmark of endothelial dysfunction. Here we report that chronic high Na+ damages the endothelial glycocalyx (eGC), induces release of inflammatory cytokines from the endothelium and promotes monocyte adhesion. Single cell force spectroscopy reveals that high Na+ enhances vascular adhesion protein-1 (VCAM-1)-dependent adhesion forces between monocytes and endothelial surface, giving rise to increased numbers of adherent monocytes on the endothelial surface. Mineralocorticoid receptor antagonism with spironolactone prevents high Na+ -induced eGC deterioration, decreases monocyte-endothelium interactions, and restores endothelial function, indicated by increased release of NO. Whereas high Na+ decreases NO release, it induces endothelial release of the pro-inflammatory cytokines IL-1ß and TNFα. However, in contrast to chronic salt load (hours), in vivo and in vitro, an acute salt challenge (minutes) does not impair eGC function. This study identifies the eGC as important mediator of inflammatory processes and might further explain how dietary salt contributes to endothelialitis and cardiovascular pathologies by linking endothelial nanomechanics with vascular inflammation.- Published
- 2017
- Full Text
- View/download PDF
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