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1. EMBRYOLOGY

Author

Furia, G. U., primary, Kostelijk, E. H., additional, Vergouw, C. G., additional, Lee, H., additional, Lee, S., additional, Park, D., additional, Kang, H., additional, Lim, C., additional, Yang, K., additional, Park, Y., additional, Shin, M., additional, Beyhan, Z., additional, Fisch, J. D., additional, Sher, G., additional, Keskintepe, L., additional, VerMilyea, M. D., additional, Anthony, J. T., additional, Graham, J. R., additional, Tucker, M. J., additional, Freour, T., additional, Lattes, S., additional, Lammers, J., additional, Mansour, W., additional, Jean, M., additional, Barriere, P., additional, El Danasouri, I., additional, Gagsteiger, F., additional, Rinaldi, L., additional, Selman, H., additional, Antonova, I., additional, Milachich, T., additional, Valkova, L., additional, Shterev, A., additional, Barcroft, J., additional, Dayoub, N., additional, Thong, J., additional, Abdel Reda, H., additional, Khalaf, Y., additional, El Touky, T., additional, Cabry, R., additional, Brzakowski, R., additional, Lourdel, E., additional, Brasseur, F., additional, Copin, H., additional, Merviel, P., additional, Yamada, M., additional, Takanashi, K., additional, Hamatani, T., additional, Akutsu, H., additional, Fukunaga, T., additional, Inoue, O., additional, Ogawa, S., additional, Sugawara, K., additional, Okumura, N., additional, Chikazawa, N., additional, Kuji, N., additional, Umezawa, A., additional, Tomita, M., additional, Yoshimura, Y., additional, Van der Jeught, M., additional, Ghimire, S., additional, O'Leary, T., additional, Lierman, S., additional, Deforce, D., additional, Chuva de Sousa Lopes, S., additional, Heindryckx, B., additional, De Sutter, P., additional, Herrero, J., additional, Tejera, A., additional, De los Santos, M. J., additional, Castello, D., additional, Romero, J. L., additional, Meseguer, M., additional, Leperlier, F., additional, Mirallie, S., additional, Schats, R., additional, Al-Nofal, M., additional, Lens, J. W., additional, Rooth, H., additional, Hompes, P. G., additional, Lambalk, C. B., additional, Hreinsson, J., additional, Karlstrom, P. O., additional, Wanggren, K., additional, Lundqvist, M., additional, Vahabi, Z., additional, Eftekhari-Yazdi, P., additional, Dalman, A., additional, Ebrahimi, B., additional, Daneshzadeh, M. T., additional, Rajabpour Niknam, M., additional, Choi, E. G., additional, Rho, Y. H., additional, Oh, D. S., additional, Park, L. S., additional, Cheon, H. S., additional, Lee, C. S., additional, Kong, I. K., additional, Lee, S. C., additional, Liebenthron, J., additional, Montag, M., additional, Koster, M., additional, Toth, B., additional, Reinsberg, J., additional, van der Ven, H., additional, Strowitzki, T., additional, Morita, H., additional, Hirosawa, T., additional, Watanabe, S., additional, Wada, T., additional, Kamihata, M., additional, Kuwahata, A., additional, Ochi, M., additional, Horiuchi, T., additional, Fatemeh, H., additional, Karimian, L., additional, Fazel, M., additional, Fouladi, H., additional, Johansson, L., additional, Ruttanajit, T., additional, Chanchamroen, S., additional, Sopaboon, P., additional, Seweewanlop, S., additional, Sawakwongpra, K., additional, Jindasri, P., additional, Jantanalapruek, T., additional, Charoonchip, K., additional, Vajta, G., additional, Quangkananurug, W., additional, Yi, G., additional, Jo, J. W., additional, Jee, B. C., additional, Suh, C. S., additional, Kim, S. H., additional, Zhang, Y., additional, Zhao, H. J., additional, Cui, Y. G., additional, Gao, C., additional, Gao, L. L., additional, Liu, J. Y., additional, Sozen, E., additional, Buluc, B., additional, Vicdan, K., additional, Akarsu, C., additional, Tuncay, G., additional, Hambiliki, F., additional, Bungum, M., additional, Agapitou, K., additional, Makrakis, E., additional, Liarmakopoulou, S., additional, Anagnostopoulou, C., additional, Moustakarias, T., additional, Giannaris, D., additional, Wang, J., additional, Andonov, M., additional, Linara, E., additional, Charleson, C., additional, Ahuja, K. K., additional, Ozsoy, S., additional, Morris, M. B., additional, Day, M. L., additional, Cobo, A., additional, Viloria, T., additional, Campos, P., additional, Vallejo, B., additional, Remohi, J., additional, Roldan, M., additional, Perez-Cano, I., additional, Cruz, M., additional, Martinez, M., additional, Gadea, B., additional, Munoz, M., additional, Garrido, N., additional, Mesut, N., additional, Ciray, H. N., additional, Mesut, A., additional, Isler, A., additional, Bahceci, M., additional, Fortuno, S., additional, Legidos, V., additional, Muela, L., additional, Galindo, N., additional, Gunasheela, S., additional, Gunasheela, D., additional, Ueno, S., additional, Uchiyama, K., additional, Kondo, M., additional, Ito, M., additional, Kato, K., additional, Takehara, Y., additional, Kato, O., additional, Edgar, D. H., additional, Krapez, J. A., additional, Bacer Kermavner, L., additional, Virant-Klun, I., additional, Pinter, B., additional, Tomazevic, T., additional, Vrtacnik-Bokal, E., additional, Lee, S. G., additional, Kang, S. M., additional, Lee, S. W., additional, Jeong, H. J., additional, Lee, Y. C., additional, Lim, J. H., additional, Bochev, I., additional, Kyurkchiev, S., additional, Wilding, M., additional, Coppola, G., additional, Di Matteo, L., additional, Dale, B., additional, Hormann-Kropfl, M., additional, Kastelic, D., additional, Schenk, M., additional, Fourati Ben Mustapha, S., additional, Khrouf, M., additional, Braham, M., additional, Kallel, L., additional, Elloumi, H., additional, Merdassi, G., additional, Chaker, A., additional, Ben Meftah, M., additional, Zhioua, F., additional, Zhioua, A., additional, Kocent, J., additional, Neri, Q. V., additional, Rosenwaks, Z., additional, Palermo, G. D., additional, Best, L., additional, Campbell, A., additional, Fishel, S., additional, Calimlioglu, N., additional, Sahin, G., additional, Akdogan, A., additional, Susamci, T., additional, Bilgin, M., additional, Goker, E. N. T., additional, Tavmergen, E., additional, Cantatore, C., additional, Ding, J., additional, Depalo, R., additional, Smith, G. D., additional, Kasapi, E., additional, Panagiotidis, Y., additional, Papatheodorou, A., additional, Goudakou, M., additional, Pasadaki, T., additional, Nikolettos, N., additional, Asimakopoulos, B., additional, Prapas, Y., additional, Soydan, E., additional, Gulebenzer, G., additional, Karatekelioglu, E., additional, Budak, E., additional, Pehlivan Budak, T., additional, Alegretti, J., additional, Cuzzi, J., additional, Negrao, P. M., additional, Moraes, M. P., additional, Bueno, M. B., additional, Serafini, P., additional, Motta, E. L. A., additional, Elaimi, A., additional, Harper, J. C., additional, Stecher, A., additional, Baborova, P., additional, Wirleitner, B., additional, Schwerda, D., additional, Vanderzwalmen, P., additional, Zech, N. H., additional, Stanic, P., additional, Hlavati, V., additional, Gelo, N., additional, Pavicic-Baldani, D., additional, Sprem-Goldstajn, M., additional, Radakovic, B., additional, Kasum, M., additional, Strelec, M., additional, Simunic, V., additional, Vrcic, H., additional, Khan, I., additional, Urich, M., additional, Abozaid, T., additional, Ullah, K., additional, Abuzeid, M., additional, Fakih, M., additional, Shamma, N., additional, Ayers, J., additional, Ashraf, M., additional, Milik, S., additional, Pirkevi, C., additional, Atayurt, Z., additional, Yazici, S., additional, Yelke, H., additional, Kahraman, S., additional, Dal Canto, M., additional, Coticchio, G., additional, Brambillasca, F., additional, Mignini Renzini, M., additional, Novara, P., additional, Maragno, L., additional, Karagouga, G., additional, De Ponti, E., additional, Fadini, R., additional, Resta, S., additional, Magli, M. C., additional, Cavallini, G., additional, Muzzonigro, F., additional, Ferraretti, A. P., additional, Gianaroli, L., additional, Barberi, M., additional, Orlando, G., additional, Sciajno, R., additional, Serrao, L., additional, Fava, L., additional, Preti, S., additional, Bonu, M. A., additional, Borini, A., additional, Varras, M., additional, Polonifi, A., additional, Mantzourani, M., additional, Mavrogianni, D., additional, Stefanidis, K., additional, Griva, T., additional, Bletsa, R., additional, Dinopoulou, V., additional, Drakakis, P., additional, Loutradis, D., additional, Hickman, C. F. L., additional, Duffy, S., additional, Bowman, N., additional, Gardner, K., additional, Sati, L., additional, Zeiss, C., additional, Demir, R., additional, McGrath, J., additional, Yildiz, S., additional, Unal, S., additional, Kumtepe, Y., additional, Aljaser, F., additional, Hernandez, J., additional, Tomlinson, M., additional, Campbell, B., additional, Fosas, N., additional, Redondo Ania, M., additional, Marina, F., additional, Molfino, F., additional, Martin, P., additional, Perez, N., additional, Carrasco, A., additional, Garcia, N., additional, Gonzalez, S., additional, Marina, S., additional, Scaruffi, P., additional, Stigliani, S., additional, Tonini, G. P., additional, Venturini, P. L., additional, Anserini, P., additional, Guglielmo, M. C., additional, Albertini, D. F., additional, Lain, M., additional, Caliari, I., additional, Oikonomou, Z., additional, Chatzimeletiou, K., additional, Sioga, A., additional, Oikonomou, L., additional, Kolibianakis, E., additional, Tarlatzis, B., additional, Nottola, S. A., additional, Bianchi, V., additional, Lorenzo, C., additional, Maione, M., additional, Macchiarelli, G., additional, Gomez, E., additional, Gil, M. A., additional, Sanchez-Osorio, J., additional, Maside, C., additional, Martinez, M. J., additional, Torres, I., additional, Rodenas, C., additional, Cuello, C., additional, Parrilla, I., additional, Molina, G., additional, Garcia, A., additional, Margineda, J., additional, Navarro, S., additional, Roca, J., additional, Martinez, E. A., additional, Avcil, F., additional, Ozden, H., additional, Candan, Z. N., additional, Uslu, H., additional, Karaman, Y., additional, Gioacchini, G., additional, Giorgini, E., additional, Carnevali, O., additional, Ferraris, P., additional, Vaccari, L., additional, Choe, S., additional, Tae, J., additional, Kim, C., additional, Lee, J., additional, Hwang, D., additional, Kim, K., additional, Suh, C., additional, Jee, B., additional, Catt, S. L., additional, Sorenson, H., additional, Vela, M., additional, Duric, V., additional, Chen, P., additional, Temple-Smith, P. D., additional, Pangestu, M., additional, Yoshimura, T., additional, Fukunaga, N., additional, Nagai, R., additional, Kitasaka, H., additional, Tamura, F., additional, Hasegawa, N., additional, Kato, M., additional, Nakayama, K., additional, Takeuchi, M., additional, Aoyagi, N., additional, Yasue, K., additional, Watanabe, H., additional, Asano, E., additional, Hashiba, Y., additional, Asada, Y., additional, Iwata, K., additional, Yumoto, K., additional, Mizoguchi, C., additional, Sargent, H., additional, Kai, Y., additional, Ueda, M., additional, Tsuchie, Y., additional, Imajo, A., additional, Iba, Y., additional, Mio, Y., additional, Els-Smit, C. L., additional, Botha, M. H., additional, Sousa, M., additional, Windt-De Beer, M., additional, Kruger, T. F., additional, Muller, N., additional, Magli, C., additional, Corani, G., additional, Giusti, A., additional, Castelletti, E., additional, Gambardella, L., additional, Seshadri, S., additional, Sunkara, S. K., additional, El-Toukhy, T., additional, Kishi, I., additional, Maruyama, T., additional, Ohishi, M., additional, Akiba, Y., additional, Asada, H., additional, Konishi, Y., additional, Nakano, M., additional, Kamei, K., additional, Lee, J. H., additional, Lee, K. H., additional, Park, I. H., additional, Sun, H. G., additional, Kim, S. G., additional, Kim, Y. Y., additional, Choi, E. M., additional, Lee, D. H., additional, Chavez, S. L., additional, Loewke, K. E., additional, Behr, B., additional, Han, J., additional, Moussavi, F., additional, Reijo Pera, R. A., additional, Yokota, H., additional, Yokota, Y., additional, Yokota, M., additional, Sato, S., additional, Nakagawa, M., additional, Sato, M., additional, Anazawa, I., additional, Araki, Y., additional, Knez, K., additional, Pozlep, B., additional, Vermilyea, M. D., additional, Levy, M. J., additional, Carvalho, M., additional, Cordeiro, I., additional, Leal, F., additional, Aguiar, A., additional, Nunes, J., additional, Rodrigues, C., additional, Soares, A. P., additional, Sousa, S., additional, Calhaz-Jorge, C., additional, Braga, D. P. A. F., additional, Setti, A. S., additional, Figueira, R. C. S., additional, Aoki, T., additional, Iaconelli, A., additional, Borges, E., additional, Ozkavukcu, S., additional, Sonmezer, M., additional, Atabekoglu, C., additional, Berker, B., additional, Ozmen, B., additional, Isbacar, S., additional, Ibis, E., additional, Menezes, J., additional, Lalitkumar, P. G. L., additional, Borg, P., additional, Ekwurtzel, E., additional, Nordqvist, S., additional, Vaegter, K., additional, Tristen, C., additional, Sjoblom, P., additional, Azevedo, M. C., additional, Remohi Gimenez, J., additional, Gamiz, P., additional, Albert, C., additional, Ferreira, R. C., additional, Resende, S., additional, Colturato, S. S., additional, Ferrer Buitrago, M., additional, Ferrer Robles, E., additional, Munoz Soriano, P., additional, Ruiz-Jorro, M., additional, Calatayud Lliso, C., additional, Rawe, V. Y., additional, Hanrieder, J., additional, Gulen-Yaldir, F., additional, Bergquist, J., additional, Stavreus-Evers, A., additional, Grunskis, A., additional, Bazarova, A., additional, Dundure, I., additional, Fodina, V., additional, Brikune, J., additional, Lakutins, J., additional, Pribenszky, C., additional, Cornea, M., additional, Reichart, A., additional, Uhereczky, G., additional, Losonczy, E., additional, Ficsor, L., additional, Lang, Z., additional, Ohgi, S., additional, Nakamura, C., additional, Hagiwara, C., additional, Kawashima, M., additional, Yanaihara, A., additional, Jones, G. M., additional, Biba, M., additional, Kokkali, G., additional, Vaxevanoglou, T., additional, Chronopoulou, M., additional, Petroutsou, K., additional, Sfakianoudis, K., additional, Pantos, K., additional, Romano, S., additional, Albricci, L., additional, Stoppa, M., additional, Cerza, C., additional, Sanges, F., additional, Fusco, S., additional, Capalbo, A., additional, Maggiulli, R., additional, Ubaldi, F., additional, Rienzi, L., additional, Ulrick, J., additional, Kilani, S., additional, Chapman, M., additional, Losada, C., additional, Ortega, I., additional, Pacheco, A., additional, Bronet, F., additional, Aguilar, J., additional, Ojeda, M., additional, Taboas, E., additional, Perez, M., additional, Munoz, E., additional, Pellicer, A., additional, Boumela, I., additional, Assou, S., additional, Haouzi, D., additional, Monzo, C., additional, Dechaud, H., additional, Hamamah, S., additional, Nakaoka, Y., additional, Hashimoto, S., additional, Amo, A., additional, Yamagata, K., additional, Nakano, T., additional, Akamatsu, Y., additional, Mezawa, T., additional, Ohnishi, Y., additional, Himeno, T., additional, Inoue, T., additional, Ito, K., additional, and Morimoto, Y., additional

Published
2012
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2. POSTER VIEWING SESSION - EMBRYOLOGY

Author

Fourati Ben Mustapha, S., primary, Khrouf, M., additional, Kacem Ben Rejeb, K., additional, Elloumi Chaabene, H., additional, Merdassi, G., additional, Wahbi, D., additional, Ben Meftah, M., additional, Zhioua, F., additional, Zhioua, A., additional, Azzarello, A., additional, Host, T., additional, Mikkelsen, A. L., additional, Theofanakis, C. P., additional, Dinopoulou, V., additional, Mavrogianni, D., additional, Partsinevelos, G. A., additional, Drakakis, P., additional, Stefanidis, K., additional, Bletsa, A., additional, Loutradis, D., additional, Rienzi, L., additional, Cobo, A., additional, Paffoni, A., additional, Scarduelli, C., additional, Capalbo, A., additional, Garrido, N., additional, Remohi, J., additional, Ragni, G., additional, Ubaldi, F. M., additional, Herrer, R., additional, Quera, M., additional, GIL, E., additional, Serna, J., additional, Grondahl, M. L., additional, Bogstad, J., additional, Agerholm, I. E., additional, Lemmen, J. G., additional, Bentin-Ley, U., additional, Lundstrom, P., additional, Kesmodel, U. S., additional, Raaschou-Jensen, M., additional, Ladelund, S., additional, Guzman, L., additional, Ortega, C., additional, Albuz, F. K., additional, Gilchrist, R. B., additional, Devroey, P., additional, Smitz, J., additional, De Vos, M., additional, Bielanska, M., additional, Leveille, M. C., additional, Borghi, E., additional, Magli, M. C., additional, Figueroa, M. J., additional, Mascaretti, G., additional, Ferraretti, A. P., additional, Gianaroli, L., additional, Szlit, E., additional, Leocata Nieto, F., additional, Maggiotto, G., additional, Arenas, G., additional, Tarducci Bonfiglio, N., additional, Ahumada, A., additional, Asch, R., additional, Sciorio, R., additional, Dayoub, N., additional, Thong, J., additional, Pickering, S., additional, Ten, J., additional, Carracedo, M. A., additional, Guerrero, J., additional, Rodriguez-Arnedo, A., additional, Llacer, J., additional, Bernabeu, R., additional, Tatone, C., additional, Heizenrieder, T., additional, Di Emidio, G., additional, Treffon, P., additional, Seidel, T., additional, Eichenlaub-Ritter, U., additional, Cortezzi, S. S., additional, Cabral, E. C., additional, Ferreira, C. R., additional, Trevisan, M. G., additional, Figueira, R. C. S., additional, Braga, D. P. A. F., additional, Eberlin, M. N., additional, Iaconelli Jr., A., additional, Borges Jr., E., additional, Zabala, A., additional, Pessino, T., additional, Blanco, L., additional, Rey Valzacchi, G., additional, Leocata, F., additional, Vanden Meerschaut, F., additional, Heindryckx, B., additional, Qian, C., additional, Deforce, D., additional, Leybaert, L., additional, De Sutter, P., additional, De las Heras, M., additional, De Pablo, J. L., additional, Navarro, B., additional, Agirregoikoa, J. A., additional, Barrenetxea, G., additional, Cruz, M., additional, Perez-Cano, I., additional, Gadea, B., additional, Herrero, J., additional, Martinez, M., additional, Roldan, M., additional, Munoz, M., additional, Pellicer, A., additional, Meseguer, M., additional, Galindo, N., additional, Scarselli, F., additional, Alviggi, E., additional, Colasante, A., additional, Minasi, M. G., additional, Rubino, P., additional, Lobascio, M., additional, Ferrero, S., additional, Litwicka, K., additional, Varricchio, M. T., additional, Giannini, P., additional, Piscitelli, P., additional, Franco, G., additional, Zavaglia, D., additional, Nagy, Z. P., additional, Greco, E., additional, Urner, F., additional, Wirthner, D., additional, Murisier, F., additional, Mock, P., additional, Germond, M., additional, Amorocho Llanos, B., additional, Calderon, G., additional, Lopez, D., additional, Fernandez, L., additional, Nicolas, M., additional, Landeras, J., additional, Finn-Sell, S. L., additional, Leandri, R., additional, Fleming, T. P., additional, Macklon, N. S., additional, Cheong, Y. C., additional, Eckert, J. J., additional, Lee, J. H., additional, Jung, Y. J., additional, Hwang, H. K., additional, Kang, A., additional, An, S. J., additional, Jung, J. Y., additional, Kwon, H. C., additional, Lee, S. J., additional, Palini, S., additional, Zolla, L., additional, De Stefani, S., additional, Scala, V., additional, D'Alessandro, A., additional, Polli, V., additional, Rocchi, P., additional, Tiezzi, A., additional, Pelosi, E., additional, Dusi, L., additional, Bulletti, C., additional, Fadini, R., additional, Lain, M., additional, Mignini Renzini, M., additional, Brambillasca, F., additional, Coticchio, G., additional, Merola, M., additional, Guglielmo, M. C., additional, Dal Canto, M., additional, Figueira, R., additional, Setti, A. S., additional, Worrilow, K. C., additional, Uzochukwu, C. D., additional, Eid, S., additional, Le Gac, S., additional, Esteves, T. C., additional, van Rossem, F., additional, van den Berg, A., additional, Boiani, M., additional, Kasapi, E., additional, Panagiotidis, Y., additional, Goudakou, M., additional, Papatheodorou, A., additional, Pasadaki, T., additional, Prapas, N., additional, Prapas, Y., additional, Vanderzwalmen, P., additional, Norasing, S., additional, Atchajaroensatit, P., additional, Tawiwong, W., additional, Thepmanee, O., additional, Saenlao, S., additional, Aojanepong, J., additional, Hunsajarupan, P., additional, Sajjachareonpong, K., additional, Punyatanasakchai, P., additional, Maneepalviratn, S., additional, Jetsawangsri, U., additional, Tejera, A., additional, Rubio, I., additional, Romero, J. L., additional, Nordhoff, V., additional, Schlatt, S., additional, Schuring, A. N., additional, Kiesel, L., additional, Kliesch, S., additional, Azambuja, R., additional, Okada, L., additional, Lazzari, V., additional, Dorfman, L., additional, Michelon, J., additional, Badalotti, M., additional, Badalotti, F., additional, Petracco, A., additional, Schwarzer, C., additional, Versieren, K., additional, De Croo, I., additional, Lierman, S., additional, De Vos, W., additional, Van den Abbeel, E., additional, Gerris, J., additional, Milacic, I., additional, Borogovac, D., additional, Veljkovic, M., additional, Arsic, B., additional, Jovic Bojovic, D., additional, Lekic, D., additional, Pavlovic, D., additional, Garalejic, E., additional, Albertini, D. F., additional, De Ponti, E., additional, Sanges, F., additional, Talevi, R., additional, Papini, L., additional, Mollo, V., additional, Rienzi, L. F., additional, Gualtieri, R., additional, Orteg, C., additional, Choi, J., additional, Lee, H., additional, Ku, S., additional, Kim, S., additional, Choi, Y., additional, Kim, J., additional, Moon, S., additional, Demilly, E., additional, Assou, S., additional, Moussaddykine, S., additional, Dechaud, H., additional, Hamamah, S., additional, Takisawa, T., additional, Doshida, M., additional, Hattori, H., additional, Nakamura, Y., additional, Kyoya, T., additional, Shibuya, Y., additional, Nakajo, Y., additional, Tasaka, A., additional, Toya, M., additional, Kyono, K., additional, Novo, S., additional, Penon, O., additional, Gomez, R., additional, Barrios, L., additional, Duch, M., additional, Santalo, J., additional, Esteve, J., additional, Nogues, C., additional, Plaza, J. A., additional, Perez-Garcia, L., additional, Ibanez, E., additional, Chavez, S., additional, Loewke, K., additional, Behr, B., additional, Reijo Pera, R., additional, Huang, S., additional, Wang, H., additional, Soong, Y., additional, Chang, C., additional, Okimura, T., additional, Kuwayama, M., additional, Mori, C., additional, Morita, M., additional, Uchiyama, K., additional, Aono, F., additional, Kato, K., additional, Takehara, Y., additional, Kato, O., additional, Minasi, M., additional, Casciani, V., additional, Arizzi, L., additional, Mencacci, C., additional, Piscitelli, C., additional, Cucinelli, F., additional, Tocci, A., additional, Wydooghe, E., additional, Vandaele, L., additional, Dewulf, J., additional, Van Soom, A., additional, Moon, J. H., additional, Son, W. Y., additional, Mahfoudh, A., additional, Henderson, S., additional, Jin, S. G., additional, Shalom-Paz, E., additional, Dahan, M., additional, Holzer, H., additional, Mahmoud, K., additional, Triki-Hmam, C., additional, Terras, K., additional, Hfaiedh, T., additional, Ben Aribia, M. H., additional, Otsubo, H., additional, Egashira, A., additional, Tanaka, K., additional, Matsuguma, T., additional, Murakami, M., additional, Murakami, K., additional, Otsuka, M., additional, Yoshioka, N., additional, Araki, Y., additional, Kuramoto, T., additional, Smit, J. G., additional, Sterrenburg, M. D., additional, Eijkemans, M. J. C., additional, Al-Inany, H. G., additional, Youssef, M. A. F. M., additional, Broekmans, F. J. M., additional, Willoughby, K., additional, DiPaolo, L., additional, Deys, L., additional, Lagunov, A., additional, Amin, S., additional, Faghih, M., additional, Hughes, E., additional, Karnis, M., additional, Ashkar, F., additional, King, W. A., additional, Neal, M. S., additional, Antonova, I., additional, Veleva, L., additional, Petkova, L., additional, Shterev, A., additional, Nogales, C., additional, Martinez, E., additional, Ariza, M., additional, Cernuda, D., additional, Gaytan, M., additional, Linan, A., additional, Guillen, A., additional, Bronet, F., additional, Cottin, V., additional, Fabian, D., additional, Allemann, F., additional, Koller, A., additional, Spira, J. C., additional, Agudo, D., additional, Martinez-Burgos, M., additional, Arnanz, A., additional, Basile, N., additional, Rodriguez, A., additional, Cho, Y. S., additional, Filioli Uranio, M., additional, Ambruosi, B., additional, Paternoster, M. S., additional, Totaro, P., additional, Sardanelli, A. M., additional, Dell'Aquila, M. E., additional, Zollner, U., additional, Hofmann, T., additional, Zollner, K. 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Published
2011
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3. Genetic causes of macrozoospermia and proposal for an optimized genetic diagnosis strategy based on sperm parameters.

Author

Coudert A, Cazin C, Amiri-Yekta A, Fourati Ben Mustapha S, Zouari R, Bessonat J, Zoghmar A, Clergeau A, Metzler-Guillemain C, Triki C, Lejeune H, Sermondade N, Pipiras E, Prisant N, Cedrin I, Koscinski I, Keskes L, Lestrade F, Hesters L, Rives N, Dorphin B, Guichet A, Patrat C, Dulioust E, Feraille A, Robert F, Brouillet S, Morel F, Perrin A, Rougier N, Bieth E, Sorlin A, Siffroi JP, Ben Khelifa M, Boiterelle F, Hennebicq S, Satre V, Arnoult C, Coutton C, Barbotin AL, Thierry-Mieg N, Kherraf ZE, and Ray PF

Subjects
Male, Humans, Spermatozoa, Semen, Infertility, Male diagnosis, Infertility, Male genetics
Abstract

Competing Interests: Conflict of interest The authors declare no conflict of interest.

Published
2023
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4. A recurrent ZP1 variant is responsible for oocyte maturation defect with degenerated oocytes in infertile females.

Author

Loeuillet C, Dhellemmes M, Cazin C, Kherraf ZE, Fourati Ben Mustapha S, Zouari R, Thierry-Mieg N, Arnoult C, and Ray PF

Subjects
Cohort Studies, Female, Humans, Oogenesis, Tubulin genetics, Exome Sequencing, Zona Pellucida Glycoproteins genetics, Infertility, Female genetics, Oocytes metabolism
Abstract

A female factor is present in approximately 70% of couple infertility, often due to ovulatory disorders. In oocyte maturation defect (OMD), affected patients have a primary infertility with normal menstrual cycles but produce no oocyte, degenerated (atretic) or abnormal oocytes blocked at different stages of maturation. Four genes have so far been associated with OMD: PATL2, TUBB8, WEE2, and ZP1. In our initial study, 6 out of 23 OMD subjects were shown to carry the same PATL2 homozygous loss of function variant and one patient had a TUBB8 truncating variant. Here, we included four additional OMD patients and reanalyzed all 27 subjects. In addition to the seven patients with a previously identified defect, five carried the same deleterious homozygous ZP1 variant (c.1097G>A; p.Arg366Gln). All the oocytes from ZP1-associated patients appeared shriveled and dark indicating that the abnormal ZP1 protein induced oocyte death and degeneration. Overall ZP1-associated patients had degenerated or absent oocytes contrary to PATL2-associated subjects who had immature oocytes blocked mainly at the germinal vesicle stage. In this cohort of North African OMD patients, whole exome sequencing permitted to diagnose 44% of the patients studied and to identify a new frequent ZP1 variant., (© 2022 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

Published
2022
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5. Whole-exome sequencing improves the diagnosis and care of men with non-obstructive azoospermia.

Author

Kherraf ZE, Cazin C, Bouker A, Fourati Ben Mustapha S, Hennebicq S, Septier A, Coutton C, Raymond L, Nouchy M, Thierry-Mieg N, Zouari R, Arnoult C, and Ray PF

Subjects
DNA Helicases metabolism, DNA-Binding Proteins genetics, Humans, Male, Sperm Retrieval, Testis metabolism, Exome Sequencing, Azoospermia diagnosis, Azoospermia genetics
Abstract

Non-obstructive azoospermia (NOA) is a severe and frequent cause of male infertility, often treated by testicular sperm extraction followed by intracytoplasmic sperm injection. The aim of this study is to improve the genetic diagnosis of NOA, by identifying new genes involved in human NOA and to better assess the chances of successful sperm extraction according to the individual's genotype. Exome sequencing was performed on 96 NOA-affected individuals negative for routine genetic tests. Bioinformatics analysis was limited to a panel of 151 genes selected as known causal or candidate genes for NOA. Only highly deleterious homozygous or hemizygous variants were retained as candidates. A likely causal defect was identified in 16 genes in a total of 22 individuals (23%). Six genes had not been described in man (DDX25, HENMT1, MCMDC2, MSH5, REC8, TDRKH) and 10 were previously reported (C14orf39, DMC1, FANCM, GCNA, HFM1, MCM8, MEIOB, PDHA2, TDRD9, TERB1). Seven individuals had defects in genes from piwi or DNA repair pathways, three in genes involved in post-meiotic maturation, and 12 in meiotic processes. Interestingly, all individuals with defects in meiotic genes had an unsuccessful sperm retrieval, indicating that genetic diagnosis prior to TESE could help identify individuals with low or null chances of successful sperm retrieval and thus avoid unsuccessful surgeries., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Published
2022
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6. CFAP61 is required for sperm flagellum formation and male fertility in human and mouse.

Author

Liu S, Zhang J, Kherraf ZE, Sun S, Zhang X, Cazin C, Coutton C, Zouari R, Zhao S, Hu F, Fourati Ben Mustapha S, Arnoult C, Ray PF, and Liu M

Subjects
Animals, Axoneme genetics, Axoneme metabolism, Humans, Male, Mice, Mice, Knockout, RNA Splicing, Infertility, Male genetics, Infertility, Male metabolism, Membrane Proteins genetics, Membrane Proteins metabolism, Point Mutation, Sperm Tail metabolism, Spermatids metabolism, Spermatogenesis genetics
Abstract

Defects in the structure or motility of cilia and flagella may lead to severe diseases such as primary ciliary dyskinesia (PCD), a multisystemic disorder with heterogeneous manifestations affecting primarily respiratory and reproductive functions. We report that CFAP61 is a conserved component of the calmodulin- and radial spoke-associated complex (CSC) of cilia. We find that a CFAP61 splice variant, c.143+5G>A, causes exon skipping/intron retention in human, inducing a multiple morphological abnormalities of the flagella (MMAF) phenotype. We generated Cfap61 knockout mice that recapitulate the infertility phenotype of the human CFAP61 mutation, but without other symptoms usually observed in PCD. We find that CFAP61 interacts with the CSC, radial spoke stalk and head. During early stages of Cfap61-/- spermatid development, the assembly of radial spoke components is impaired. As spermiogenesis progresses, the axoneme in Cfap61-/- cells becomes unstable and scatters, and the distribution of intraflagellar transport proteins is disrupted. This study reveals an organ-specific mechanism of axoneme stabilization that is related to male infertility., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

Published
2021
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7. Identification and Characterization of the Most Common Genetic Variant Responsible for Acephalic Spermatozoa Syndrome in Men Originating from North Africa.

Author

Cazin C, Boumerdassi Y, Martinez G, Fourati Ben Mustapha S, Whitfield M, Coutton C, Thierry-Mieg N, Di Pizio P, Rives N, Arnoult C, Touré A, Ray PF, Zouari R, Sifer C, and Kherraf ZE

Subjects
Adult, Africa, Northern, Aneuploidy, Case-Control Studies, Genetic Variation, Haplotypes, Homozygote, Humans, In Situ Hybridization, Fluorescence, Male, Membrane Proteins metabolism, Middle Aged, Spermatozoa metabolism, Spermatozoa physiology, Exome Sequencing, Membrane Proteins genetics, Spermatozoa ultrastructure, Teratozoospermia genetics
Abstract

Acephalic spermatozoa syndrome (ASS) is a rare but extremely severe type of teratozoospermia, defined by the presence of a majority of headless flagella and a minority of tail-less sperm heads in the ejaculate. Like the other severe monomorphic teratozoospermias, ASS has a strong genetic basis and is most often caused by bi-allelic variants in SUN5 (Sad1 and UNC84 domain-containing 5). Using whole exome sequencing (WES), we investigated a cohort of nine infertile subjects displaying ASS. These subjects were recruited in three centers located in France and Tunisia, but all originated from North Africa. Sperm from subjects carrying candidate genetic variants were subjected to immunofluorescence analysis and transmission electron microscopy. Moreover, fluorescent in situ hybridization (FISH) was performed on sperm nuclei to assess their chromosomal content. Variant filtering permitted us to identify the same SUN5 homozygous frameshift variant (c.211+1_211+2dup) in 7/9 individuals (78%). SUN5 encodes a protein localized on the posterior part of the nuclear envelope that is necessary for the attachment of the tail to the sperm head. Immunofluorescence assays performed on sperm cells from three mutated subjects revealed a total absence of SUN5, thus demonstrating the deleterious impact of the identified variant on protein expression. Transmission electron microscopy showed a conserved flagellar structure and a slightly decondensed chromatin. FISH did not highlight a higher rate of chromosome aneuploidy in spermatozoa from SUN5 patients compared to controls, indicating that intra-cytoplasmic sperm injection (ICSI) can be proposed for patients carrying the c.211+1_211+2dup variant. These results suggest that the identified SUN5 variant is the main cause of ASS in the North African population. Consequently, a simple and inexpensive genotyping of the 211+1_211+2dup variant could be beneficial for affected men of North African origin before resorting to more exhaustive genetic analyses.

Published
2021
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8. Tunisian Recommendations for resumption of Reproductive Medicine activity in the Covid-19 pandemic.

Author

Braham M, Khrouf M, Chaabene K, Fourati Ben Mustapha S, Hacheni F, Halouani L, Kacem Berjeb K, Kerkeni W, Mouelhi C, Attia Mahbouli L, Ajina M, Midassi H, Ben Brahem Touil A, Ouertatani H, and Ben Hamouda M

Subjects
COVID-19, Female, Fertilization in Vitro methods, Humans, Pandemics, Pregnancy, Tunisia epidemiology, Coronavirus Infections epidemiology, Fertilization in Vitro statistics & numerical data, Pneumonia, Viral epidemiology, Reproductive Medicine statistics & numerical data, Reproductive Techniques, Assisted statistics & numerical data
Abstract

The activity of the Reproductive Medicine poses a dilemma in this pandemic Covid-19. In fact, this is a theoretically non-emergency activity except for fertility preservation with oncological reasons. The majority of fertility societies in the world such as the American Society for Reproductive Medicine (ASRM) and the European Society of Human Reproduction and Embryology (ESHRE) recommended stopping the inclusion of new patients and continuing only the In Vitro Fertilization (IVF) cycles that have already been initiated by promoting Freeze-all as much as possible. Initilaly, the "Société Tunisienne de Gynécologie Obstétrique" (STGO) issued national recommendations that echo the international recommendations. These recommendations were followed by the majority of IVF center in Tunisia. However, a number of new data are prompting us to update these recommendations.

Published
2020

9. Mutations in TTC29, Encoding an Evolutionarily Conserved Axonemal Protein, Result in Asthenozoospermia and Male Infertility.

Author

Lorès P, Dacheux D, Kherraf ZE, Nsota Mbango JF, Coutton C, Stouvenel L, Ialy-Radio C, Amiri-Yekta A, Whitfield M, Schmitt A, Cazin C, Givelet M, Ferreux L, Fourati Ben Mustapha S, Halouani L, Marrakchi O, Daneshipour A, El Khouri E, Do Cruzeiro M, Favier M, Guillonneau F, Chaudhry M, Sakheli Z, Wolf JP, Patrat C, Gacon G, Savinov SN, Hosseini SH, Robinson DR, Zouari R, Ziyyat A, Arnoult C, Dulioust E, Bonhivers M, Ray PF, and Touré A

Subjects
Animals, Asthenozoospermia metabolism, Asthenozoospermia pathology, Axoneme genetics, Axoneme metabolism, Evolution, Molecular, Female, Fertilization in Vitro, Flagella genetics, Flagella metabolism, Humans, Infertility, Male metabolism, Infertility, Male pathology, Male, Mice, Inbred C57BL, Trypanosoma brucei brucei physiology, Trypanosomiasis, Asthenozoospermia etiology, Axoneme pathology, Flagella pathology, Infertility, Male etiology, Microtubule-Associated Proteins genetics, Mutation
Abstract

In humans, structural or functional defects of the sperm flagellum induce asthenozoospermia, which accounts for the main sperm defect encountered in infertile men. Herein we focused on morphological abnormalities of the sperm flagellum (MMAF), a phenotype also termed "short tails," which constitutes one of the most severe sperm morphological defects resulting in asthenozoospermia. In previous work based on whole-exome sequencing of a cohort of 167 MMAF-affected individuals, we identified bi-allelic loss-of-function mutations in more than 30% of the tested subjects. In this study, we further analyzed this cohort and identified five individuals with homozygous truncating variants in TTC29, a gene preferentially and highly expressed in the testis, and encoding a tetratricopeptide repeat-containing protein related to the intraflagellar transport (IFT). One individual carried a frameshift variant, another one carried a homozygous stop-gain variant, and three carried the same splicing variant affecting a consensus donor site. The deleterious effect of this last variant was confirmed on the corresponding transcript and protein product. In addition, we produced and analyzed TTC29 loss-of-function models in the flagellated protist T. brucei and in M. musculus. Both models confirmed the importance of TTC29 for flagellar beating. We showed that in T. brucei the TPR structural motifs, highly conserved between the studied orthologs, are critical for TTC29 axonemal localization and flagellar beating. Overall our work demonstrates that TTC29 is a conserved axonemal protein required for flagellar structure and beating and that TTC29 mutations are a cause of male sterility due to MMAF., (Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Published
2019
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10. Whole exome sequencing of men with multiple morphological abnormalities of the sperm flagella reveals novel homozygous QRICH2 mutations.

Author

Kherraf ZE, Cazin C, Coutton C, Amiri-Yekta A, Martinez G, Boguenet M, Fourati Ben Mustapha S, Kharouf M, Gourabi H, Hosseini SH, Daneshipour A, Touré A, Thierry-Mieg N, Zouari R, Arnoult C, and Ray PF

Subjects
Abnormalities, Multiple pathology, Africa, Northern epidemiology, Axoneme, Cohort Studies, Cytoskeletal Proteins, Europe epidemiology, Homozygote, Humans, Infertility, Male pathology, Iran epidemiology, Male, Mutation genetics, Sperm Tail metabolism, Sperm Tail pathology, Spermatozoa growth & development, Spermatozoa pathology, Abnormalities, Multiple genetics, Infertility, Male genetics, Microtubule Proteins genetics
Abstract

Multiple morphological anomalies of the sperm flagella (MMAF syndrome) is a severe male infertility phenotype which has so far been formally linked to the presence of biallelic mutations in nine genes mainly coding for axonemal proteins overexpressed in the sperm flagellum. Homozygous mutations in QRICH2, a gene coding for a protein known to be required for stabilizing proteins involved in sperm flagellum biogenesis, have recently been identified in MMAF patients from two Chinese consanguineous families. Here, in order to better assess the contribution of QRICH2 in the etiology of the MMAF phenotype, we analyzed all QRICH2 variants from whole exome sequencing data of a cohort of 167 MMAF-affected subjects originating from North Africa, Iran, and Europe. We identified a total of 14 potentially deleterious variants in 18 unrelated individuals. Two unrelated subjects, representing 1% of the cohort, carried a homozygous loss-of-function variant: c.3501C>G [p.Tyr1167Ter] and c.4614C>G [p.Tyr1538Ter], thus confirming the implication of QRICH2 in the MMAF phenotype and human male infertility. Sixteen MMAF patients (9.6%) carried a heterozygous QRICH2 potentially deleterious variant. This rate was comparable to what was observed in a control group (15.5%) suggesting that the presence of QRICH2 heterozygous variants is not associated with MMAF syndrome., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Published
2019
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11. Bi-allelic Mutations in ARMC2 Lead to Severe Astheno-Teratozoospermia Due to Sperm Flagellum Malformations in Humans and Mice.

Author

Coutton C, Martinez G, Kherraf ZE, Amiri-Yekta A, Boguenet M, Saut A, He X, Zhang F, Cristou-Kent M, Escoffier J, Bidart M, Satre V, Conne B, Fourati Ben Mustapha S, Halouani L, Marrakchi O, Makni M, Latrous H, Kharouf M, Pernet-Gallay K, Bonhivers M, Hennebicq S, Rives N, Dulioust E, Touré A, Gourabi H, Cao Y, Zouari R, Hosseini SH, Nef S, Thierry-Mieg N, Arnoult C, and Ray PF

Subjects
Animals, CRISPR-Cas Systems, Cell Cycle Proteins deficiency, Humans, Infertility, Male genetics, Infertility, Male pathology, Male, Mice, Microtubule Proteins deficiency, Proteins, Alleles, Asthenozoospermia genetics, Asthenozoospermia pathology, Cytoskeletal Proteins genetics, Flagella genetics, Mutation, Spermatozoa abnormalities, Spermatozoa pathology
Abstract

Male infertility is a major health concern. Among its different causes, multiple morphological abnormalities of the flagella (MMAF) induces asthenozoospermia and is one of the most severe forms of qualitative sperm defects. Sperm of affected men display short, coiled, absent, and/or irregular flagella. To date, six genes (DNAH1, CFAP43, CFAP44, CFAP69, FSIP2, and WDR66) have been found to be recurrently associated with MMAF, but more than half of the cases analyzed remain unresolved, suggesting that many yet-uncharacterized gene defects account for this phenotype. Here, whole-exome sequencing (WES) was performed on 168 infertile men who had a typical MMAF phenotype. Five unrelated affected individuals carried a homozygous deleterious mutation in ARMC2, a gene not previously linked to the MMAF phenotype. Using the CRISPR-Cas9 technique, we generated homozygous Armc2 mutant mice, which also presented an MMAF phenotype, thus confirming the involvement of ARMC2 in human MMAF. Immunostaining experiments in AMRC2-mutated individuals and mutant mice evidenced the absence of the axonemal central pair complex (CPC) proteins SPAG6 and SPEF2, whereas the other tested axonemal and peri-axonemal components were present, suggesting that ARMC2 is involved in CPC assembly and/or stability. Overall, we showed that bi-allelic mutations in ARMC2 cause male infertility in humans and mice by inducing a typical MMAF phenotype, indicating that this gene is necessary for sperm flagellum structure and assembly., (Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Published
2019
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12. Whole-exome sequencing identifies mutations in FSIP2 as a recurrent cause of multiple morphological abnormalities of the sperm flagella.

Author

Martinez G, Kherraf ZE, Zouari R, Fourati Ben Mustapha S, Saut A, Pernet-Gallay K, Bertrand A, Bidart M, Hograindleur JP, Amiri-Yekta A, Kharouf M, Karaouzène T, Thierry-Mieg N, Dacheux-Deschamps D, Satre V, Bonhivers M, Touré A, Arnoult C, Ray PF, and Coutton C

Subjects
Adult, Case-Control Studies, Humans, Infertility, Male genetics, Male, Middle Aged, Mutation, RNA, Messenger, Real-Time Polymerase Chain Reaction, Retrospective Studies, Reverse Transcriptase Polymerase Chain Reaction, Sperm Tail ultrastructure, Teratozoospermia diagnosis, Exome Sequencing methods, Sperm Tail pathology, Teratozoospermia genetics
Abstract

Study Question: Can whole-exome sequencing (WES) of infertile patients identify new genes responsible for multiple morphological abnormalities of the sperm flagella (MMAF)?, Summary Answer: WES analysis of 78 infertile men with a MMAF phenotype permitted the identification of four homozygous mutations in the fibrous sheath (FS) interacting protein 2 (FSIP2) gene in four unrelated individuals., What Is Known Already: The use of high-throughput sequencing techniques revealed that mutations in the dynein axonemal heavy chain 1 (DNAH1) gene, and in the cilia and flagella associated protein 43 (CFAP43) and 44 (CFAP44) genes account for approximately one-third of MMAF cases thus indicating that other relevant genes await identification., Study Design, Size, Duration: This was a retrospective genetics study of 78 patients presenting a MMAF phenotype who were recruited in three fertility clinics between 2008 and 2015. Control sperm samples were obtained from normospermic donors. Allelic frequency for control subjects was derived from large public databases., Participants/materials, Setting, Methods: WES was performed for all 78 subjects. All identified variants were confirmed by Sanger sequencing. Relative mRNA expression levels for the selected candidate gene (FSIP2) was assessed by quantitative RT-PCR in a panel of normal human and mouse tissues. To characterize the structural and ultrastructural anomalies present in patients' sperm, immunofluorescence (IF) was performed on sperm samples from two subjects with a mutation and one control and transmission electron microscopy (TEM) analyses was performed on sperm samples from one subject with a mutation and one control., Main Results and the Role of Chance: We identified four unrelated patients (4/78, 5.1%) with homozygous loss of function mutations in the FSIP2 gene, which encodes a protein of the sperm FS and is specifically expressed in human and mouse testis. None of these mutations were reported in control sequence databases. TEM analyses showed a complete disorganization of the FS associated with axonemal defects. IF analyses confirmed that the central-pair microtubules and the inner and outer dynein arms of the axoneme were abnormal in all four patients carrying FSIP2 mutations. Importantly, and in contrast to what was observed in patients with MMAF and mutations in other MMAF-related genes (DNAH1, CFAP43 and CFAP44), mutations in FSIP2 led to the absence of A-kinase anchoring protein 4 (AKAP4)., Limitations, Reasons for Caution: The low number of biological samples and the absence of a reliable anti-FSIP2 antibody prevented the formal demonstration that the FSIP2 protein was absent in sperm from subjects with a FSIP2 mutation., Wider Implications of the Findings: Our findings indicate that FSIP2 is one of the main genes involved in MMAF syndrome. In humans, genes previously associated with a MMAF phenotype encoded axonemal-associated proteins (DNAH1, CFAP43 and CFAP44). We show here that FSIP2, a protein of the sperm FS, is also logically associated with MMAF syndrome as we showed that it is necessary for FS assembly and for the overall axonemal and flagellar biogenesis. As was suggested before in mouse and man, our results also suggest that defects in AKAP4, one of the main proteins interacting with FSIP2, would induce a MMAF phenotype. Finally, this work reinforces the demonstration that WES sequencing is a good strategy to reach a genetic diagnosis for patients with severe male infertility phenotypes., Study Funding/competing Interest(s): This work was supported by the following grants: the 'MAS-Flagella' project financed by the French ANR and the DGOS for the program PRTS 2014 (14-CE15) and the 'Whole genome sequencing of patients with Flagellar Growth Defects (FGD)' project financed by the Fondation Maladies Rares for the program Séquençage à haut débit 2012. The authors have no conflict of interest.

Published
2018
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13. A Homozygous Ancestral SVA-Insertion-Mediated Deletion in WDR66 Induces Multiple Morphological Abnormalities of the Sperm Flagellum and Male Infertility.

Author

Kherraf ZE, Amiri-Yekta A, Dacheux D, Karaouzène T, Coutton C, Christou-Kent M, Martinez G, Landrein N, Le Tanno P, Fourati Ben Mustapha S, Halouani L, Marrakchi O, Makni M, Latrous H, Kharouf M, Pernet-Gallay K, Gourabi H, Robinson DR, Crouzy S, Blum M, Thierry-Mieg N, Touré A, Zouari R, Arnoult C, Bonhivers M, and Ray PF

Subjects
Axoneme genetics, Cohort Studies, Dyneins genetics, Homozygote, Humans, Male, Testis pathology, Exome Sequencing methods, Abnormalities, Multiple genetics, Calcium-Binding Proteins genetics, Flagella genetics, Infertility, Male genetics, Mutation genetics, Sperm Tail pathology, Spermatozoa abnormalities
Abstract

Multiple morphological abnormalities of the sperm flagellum (MMAF) is a severe form of male infertility defined by the presence of a mosaic of anomalies, including short, bent, curled, thick, or absent flagella, resulting from a severe disorganization of the axoneme and of the peri-axonemal structures. Mutations in DNAH1, CFAP43, and CFAP44, three genes encoding axoneme-related proteins, have been described to account for approximately 30% of the MMAF cases reported so far. Here, we searched for pathological copy-number variants in whole-exome sequencing data from a cohort of 78 MMAF-affected subjects to identify additional genes associated with MMAF. In 7 of 78 affected individuals, we identified a homozygous deletion that removes the two penultimate exons of WDR66 (also named CFAP251), a gene coding for an axonemal protein preferentially localized in the testis and described to localize to the calmodulin- and spoke-associated complex at the base of radial spoke 3. Sequence analysis of the breakpoint region revealed in all deleted subjects the presence of a single chimeric SVA (SINE-VNTR-Alu) at the breakpoint site, suggesting that the initial deletion event was potentially mediated by an SVA insertion-recombination mechanism. Study of Trypanosoma WDR66's ortholog (TbWDR66) highlighted high sequence and structural analogy with the human protein and confirmed axonemal localization of the protein. Reproduction of the human deletion in TbWDR66 impaired flagellar movement, thus confirming WDR66 as a gene associated with the MMAF phenotype and highlighting the importance of the WDR66 C-terminal region., (Copyright © 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Published
2018
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14. PATL2 is a key actor of oocyte maturation whose invalidation causes infertility in women and mice.

Author

Christou-Kent M, Kherraf ZE, Amiri-Yekta A, Le Blévec E, Karaouzène T, Conne B, Escoffier J, Assou S, Guttin A, Lambert E, Martinez G, Boguenet M, Fourati Ben Mustapha S, Cedrin Durnerin I, Halouani L, Marrakchi O, Makni M, Latrous H, Kharouf M, Coutton C, Thierry-Mieg N, Nef S, Bottari SP, Zouari R, Issartel JP, Ray PF, and Arnoult C

Subjects
Adult, Animals, Cohort Studies, Female, Humans, Meiosis genetics, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Nuclear Proteins genetics, Oocytes cytology, RNA-Binding Proteins genetics, Young Adult, Codon, Nonsense, Gene Expression Profiling methods, Infertility genetics, Nuclear Proteins physiology, Oocytes metabolism, RNA-Binding Proteins physiology, Exome Sequencing methods
Abstract

The genetic causes of oocyte meiotic deficiency (OMD), a form of primary infertility characterised by the production of immature oocytes, remain largely unexplored. Using whole exome sequencing, we found that 26% of a cohort of 23 subjects with OMD harboured the same homozygous nonsense pathogenic mutation in PATL2 , a gene encoding a putative RNA-binding protein. Using Patl2 knockout mice, we confirmed that PATL2 deficiency disturbs oocyte maturation, since oocytes and zygotes exhibit morphological and developmental defects, respectively. PATL2's amphibian orthologue is involved in the regulation of oocyte mRNA as a partner of CPEB However, Patl2's expression profile throughout oocyte development in mice, alongside colocalisation experiments with Cpeb1, Msy2 and Ddx6 (three oocyte RNA regulators) suggest an original role for Patl2 in mammals. Accordingly, transcriptomic analysis of oocytes from WT and Patl2 -/- animals demonstrated that in the absence of Patl2, expression levels of a select number of highly relevant genes involved in oocyte maturation and early embryonic development are deregulated. In conclusion, PATL2 is a novel actor of mammalian oocyte maturation whose invalidation causes OMD in humans., (© 2018 The Authors. Published under the terms of the CC BY 4.0 license.)

Published
2018
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15. Patients with multiple morphological abnormalities of the sperm flagella due to DNAH1 mutations have a good prognosis following intracytoplasmic sperm injection.

Author

Wambergue C, Zouari R, Fourati Ben Mustapha S, Martinez G, Devillard F, Hennebicq S, Satre V, Brouillet S, Halouani L, Marrakchi O, Makni M, Latrous H, Kharouf M, Amblard F, Arnoult C, Ray PF, and Coutton C

Subjects
Adult, Axoneme ultrastructure, DNA Fragmentation, Female, Flagella ultrastructure, Humans, In Situ Hybridization, Fluorescence, In Situ Nick-End Labeling, Infertility, Male therapy, Male, Oocyte Retrieval, Ovulation Induction, Pregnancy, Pregnancy Rate, Prognosis, Retrospective Studies, Treatment Outcome, Axoneme genetics, Dyneins genetics, Infertility, Male genetics, Mutation, Sperm Injections, Intracytoplasmic, Spermatozoa abnormalities
Abstract

Study Question: Does DNAH1 status influence intracytoplasmic sperm injection (ICSI) outcomes for patients with multiple morphological abnormalities of the sperm flagella (MMAF)?, Summary Answer: Despite a highly abnormal morphology, sperm from MMAF patients with DNAH1 mutations have a low aneuploidy rate and good nuclear quality, leading to good embryonic development following ICSI and a high pregnancy rate., What Is Known Already: Teratozoospermia represents a heterogeneous group including a wide range of phenotypes. Among all these qualitative defects, a flagellar phenotype called MMAF is characterized by a mosaic of morphological abnormalities of the flagellum, including coiled, bent, irregular, short or/and absent flagella, mainly due to the absence of the axonemal central pair microtubules. We previously demonstrated that homozygous mutations in the DNAH1 gene, encoding an inner arm heavy chain dynein, are frequently found in patients with MMAF (28% of the patients from the initial cohort). Numerous studies have reported an increased rate of aneuploidy and a poor sperm nuclear quality related to sperm flagellar abnormalities, which could impede ICSI outcome. Moreover, success rates after ICSI may be influenced by the type of ultrastructural flagellar defects and/or by the gene defects carried by the patients., Study Design, Size, Duration: This retrospective cohort study included 6 infertile males with MMAF due to deleterious homozygous DNAH1 mutations and their respective spouses, who underwent 9 ISCI cycles, with 16 embryos being transferred. ICSI results were compared with two control populations of 13 MMAF men without DNAH1 mutations and an aged-matched control group of 1431 non-MMAF couples. All ICSI attempts took place between 2000 and 2012., Participants/materials, Setting, Methods: Clinical and biological data were collected from patients treated for infertility at the CPSR les Jasmins in Tunis (Tunisia). We compared the ICSI outcomes obtained with couples including DNAH1 mutated and nonmutated patients and non-MMAF couples. For the analysis of the chromosomal status, fluorescence in situ hybridization (FISH) analyses were performed on sperm cells from 3 DNAH1-mutated patients and from 29 fertile control subjects. Sperm chromatin condensation and DNA fragmentation were evaluated using aniline blue staining and TUNEL assays, respectively, on sperm cells from 3 DNAH1-mutated men and 6 fertile controls., Main Results and the Role of Chance: There was a significantly increased proportion of disomy XY and 18 in sperm from DNAH1 mutated patients compared with fertile controls (1.52 versus 0.28%, P = 0.0001 and 0.64 versus 0.09%, P = 0.0001). However, there were no statistically significant differences among sperm from the two groups in their frequencies of either 13, 21, XX or YY disomy or diploidy. Measures of DNA compaction and fragmentation demonstrated a good nuclear sperm quality among DNAH1 mutated men. The overall fertilization, pregnancy and delivery rates of couples including DNAH1 mutated men were of 70.8, 50.0 and 37.5%, respectively. There were no statistically significant differences in any of these parameters compared with the two control groups (P > 0.05)., Limitations, Reasons for Caution: A limitation of this study is the small number of DNAH1-mutated patients available and the low number of genes identified in MMAF. Further genetic studies are warranted to identify other MMAF-inducing genes to better characterize the genetic etiology of the MMAF phenotype and to improve the management of patients diagnosed with flagellar defects., Wider Implications of the Findings: MMAF patients with DNAH1 mutations have low aneuploidy rates and good nuclear sperm quality, explaining the high pregnancy rate obtained with these patients. Good ICSI results were obtained for both MMAF groups (DNAH1 mutated and nonmutated), suggesting that patients presenting with asthenozoospermia due to flagellar defects have a good ICSI prognosis irrespective of their genotype. The majority of MMAF cases currently remain idiopathic with no genetic cause yet identified. In depth genetic analysis of these patients using next generation sequencing should reveal new causal genes. Subsequent genotype phenotype analyses could improve advice and care provided to MMAF patients., Study Funding/competing Interests: None of the authors have any competing interest. This work is part of the project 'Identification and Characterization of Genes Involved in Infertility (ICG2I)', funded by the program GENOPAT 2009 from the French Research Agency (ANR) and the MAS-Flagella project, financed by the French ANR and the Direction Générale de l'Offre de Soins (DGOS)., (© The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Published
2016
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16. In Vitro fertilization failure of normozoospermic men: search for a lack of testicular isozyme of angiotensin-converting enzyme.

Author

Fourati Ben Mustapha S, Coulet F, Eyries M, De Larouziere V, Ravel C, Berthaut I, Antoine JM, Soubrier F, and Mandelbaum J

Abstract

Background: Angiotensin converting enzyme (ACE) is a metalloprotease with two isoforms. The somatic isoform is a key component of the renin-angiotensin system; its main function is to hydrolyse angiotensin I into angiotensin II. The germinal or testicular isoform (tACE) located at the plasma membrane of the spermatozoa, plays a crucial role in the spermatozoa-oocyte interaction during in vivo fertilization, in rodents. Disruption of the tACE in mice has revealed that homozygous male tACE-/- sire few pups despite mating normally. Few spermatozoa from these tACE-/- mice are bound to the zona pellucida (ZP) despite normal semen parameters. Based on these findings in mice models, we hypothesized that some infertile men that have the same phenotype as the tACE-/- mice, ie normal semen parameters and a lack of sperm bind to the ZP in vitro, may have a tACE defect., Methods: Twenty four men participated to this study. The case subjects (n = 10) had normal semen parameters according to the WHO guidelines (WHO 1999) but a total in vitro fertilization failure with absence of sperm fixation to the ZP. The control subjects (n = 14) also had normal semen parameters and a normal fertilization rate ≥65%. We investigated the tACE expression in spermatozoa by Western-Blot and performed a DNA sequencing of the tACE gene., Results: Three case-subjects and one control-subject had no tACE expression. There were no statistic differences between the two groups. No mutation was detected in the tACE DNA sequence., Conclusions: Our results didn't show any involvement of tACE in human fertilization especially in ZP binding.

Published
2013
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