• PMID: 29449551
• Gene Name: CFAP43
• Condition: Male Infertility
• Association: Associated
• Mutation: c.3541?2A>C (p.Ser1181Lysfs*4), c.1240_1241delGT (p.Val414LeufsTer46), c.2658G>A (p.Trp886Ter), c.2680C>T (p.Arg894Ter), c.3882delA (p.Glu1294AspfsTer47 ), c.3352C>T (p.Arg1118Ter), c.1302dupT (p.Leu435SerfsTer26 ), c.1040T>C (p.Val347Ala), c.2141+5G>A (p
• Population size: 78
• Population details: 78 MMAF
• Sex: Male
• Infertility type: Male infertility

Mutations in CFAP43 and CFAP44 cause male infertility and flagellum defects in Trypanosoma and human

Coutton C, Vargas AS, Amiri-Yekta A, Kherraf ZE, Ben Mustapha SF, Le Tanno P, Wambergue-Legrand C, Karaouzène T, Martinez G, Crouzy S, Daneshipour A, Hosseini SH, Mitchell V, Halouani L, Marrakchi O, Makni M, Latrous H, Kharouf M, Deleuze JF, Boland A, Hennebicq S, Satre V, Jouk PS, Thierry-Mieg N, Conne B, Dacheux D, Landrein N, Schmitt A, Stouvenel L, Lorès P, El Khouri E, Bottari SP, Fauré J, Wolf JP, Pernet-Gallay K, Escoffier J, Gourabi H, Robinson DR, Nef S, Dulioust E, Zouari R, Bonhivers M, Touré A, Arnoult C, Ray PF.

Spermatogenesis defects concern millions of men worldwide, yet the vast majority remains undiagnosed. Here we report men with primary infertility due to multiple morphological abnormalities of the sperm flagella with severe disorganization of the sperm axoneme, a microtubule-based structure highly conserved throughout evolution. Whole-exome sequencing was performed on 78 patients allowing the identification of 22 men with bi-allelic mutations in DNAH1 (n = 6), CFAP43 (n = 10), and CFAP44 (n = 6). CRISPR/Cas9 created homozygous CFAP43/44 male mice that were infertile and presented severe flagellar defects confirming the human genetic results. Immunoelectron and stimulated-emission-depletion microscopy performed on CFAP43 and CFAP44 orthologs in Trypanosoma brucei evidenced that both proteins are located between the doublet microtubules 5 and 6 and the paraflagellar rod. Overall, we demonstrate that CFAP43 and CFAP44 have a similar structure with a unique axonemal localization and are necessary to produce functional flagella in species ranging from Trypanosoma to human. FAU - Coutton, Charles AU - Coutton C AD - Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, Inserm U1209, CNRS UMR 5309, Université Grenoble Alpes, 38000, Grenoble, France. AD - CHU de Grenoble, UM de Génétique Chromosomique, 38000, Grenoble, France. FAU - Vargas, Alexandra S AU - Vargas AS AUID- ORCID: 0000-0002-9826-0526 AD - Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, Inserm U1209, CNRS UMR 5309, Université Grenoble Alpes, 38000, Grenoble, France. FAU - Amiri-Yekta, Amir AU - Amiri-Yekta A AUID- ORCID: 0000-0002-8099-7984 AD - Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, Inserm U1209, CNRS UMR 5309, Université Grenoble Alpes, 38000, Grenoble, France. AD - CHU de Grenoble, UM GI-DPI, 38000, Grenoble, France. AD - Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACER, Tehran, 16635-148, Iran. FAU - Kherraf, Zine-Eddine AU - Kherraf ZE AD - Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, Inserm U1209, CNRS UMR 5309, Université Grenoble Alpes, 38000, Grenoble, France. AD - CHU de Grenoble, UM GI-DPI, 38000, Grenoble, France. FAU - Ben Mustapha, Selima Fourati AU - Ben Mustapha SF AD - Polyclinique les Jasmins, Centre d'Aide Médicale à la Procréation, Centre Urbain Nord, 1003, Tunis, Tunisia. FAU - Le Tanno, Pauline AU - Le Tanno P AD - Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, Inserm U1209, CNRS UMR 5309, Université Grenoble Alpes, 38000, Grenoble, France. AD - CHU de Grenoble, UM de Génétique Chromosomique, 38000, Grenoble, France. FAU - Wambergue-Legrand, Clémentine AU - Wambergue-Legrand C AD - Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, Inserm U1209, CNRS UMR 5309, Université Grenoble Alpes, 38000, Grenoble, France. AD - CHU de Grenoble, UM GI-DPI, 38000, Grenoble, France. FAU - Karaouzène, Thomas AU - Karaouzène T AD - Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, Inserm U1209, CNRS UMR 5309, Université Grenoble Alpes, 38000, Grenoble, France. AD - CHU de Grenoble, UM GI-DPI, 38000, Grenoble, France. FAU - Martinez, Guillaume AU - Martinez G AD - Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, Inserm U1209, CNRS UMR 5309, Université Grenoble Alpes, 38000, Grenoble, France. AD - CHU de Grenoble, UM de Génétique Chromosomique, 38000, Grenoble, France. FAU - Crouzy, Serge AU - Crouzy S AD - Laboratoire de Chimie et Biologie des Métaux, Institut de Recherche en Technologie et Sciences pour le Vivant, CEA iRTSV/LCBM/GMCT, CNRS UMR 5249, Université Grenoble Alpes, 38054, Grenoble, France. FAU - Daneshipour, Abbas AU - Daneshipour A AD - Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACER, Tehran, 16635-148, Iran. FAU - Hosseini, Seyedeh Hanieh AU - Hosseini SH AD - Department of Andrology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, 16635-148, Iran. FAU - Mitchell, Valérie AU - Mitchell V AD - EA 4308, Department of Reproductive Biology and Spermiology-CECOS Lille, University Medical Center, Lille, 59037, France. FAU - Halouani, Lazhar AU - Halouani L AD - Polyclinique les Jasmins, Centre d'Aide Médicale à la Procréation, Centre Urbain Nord, 1003, Tunis, Tunisia. FAU - Marrakchi, Ouafi AU - Marrakchi O AD - Polyclinique les Jasmins, Centre d'Aide Médicale à la Procréation, Centre Urbain Nord, 1003, Tunis, Tunisia. FAU - Makni, Mounir AU - Makni M AD - Polyclinique les Jasmins, Centre d'Aide Médicale à la Procréation, Centre Urbain Nord, 1003, Tunis, Tunisia. FAU - Latrous, Habib AU - Latrous H AD - Polyclinique les Jasmins, Centre d'Aide Médicale à la Procréation, Centre Urbain Nord, 1003, Tunis, Tunisia. FAU - Kharouf, Mahmoud AU - Kharouf M AD - Polyclinique les Jasmins, Centre d'Aide Médicale à la Procréation, Centre Urbain Nord, 1003, Tunis, Tunisia. FAU - Deleuze, Jean-François AU - Deleuze JF AD - Centre National de Génotypage, Institut de Génomique, CEA, 91000, Evry, France. FAU - Boland, Anne AU - Boland A AD - Centre National de Génotypage, Institut de Génomique, CEA, 91000, Evry, France. FAU - Hennebicq, Sylviane AU - Hennebicq S AD - Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, Inserm U1209, CNRS UMR 5309, Université Grenoble Alpes, 38000, Grenoble, France. AD - CHU de Grenoble, UF de Biologie de la procréation, 38000, Grenoble, France. FAU - Satre, Véronique AU - Satre V AD - Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, Inserm U1209, CNRS UMR 5309, Université Grenoble Alpes, 38000, Grenoble, France. AD - CHU de Grenoble, UM de Génétique Chromosomique, 38000, Grenoble, France. FAU - Jouk, Pierre-Simon AU - Jouk PS AD - CHU de Grenoble, UF de Génétique Médicale, 38000, Grenoble, France. FAU - Thierry-Mieg, Nicolas AU - Thierry-Mieg N AD - Univ. Grenoble Alpes/CNRS TIMC-IMAG, 38000, Grenoble, France. FAU - Conne, Beatrice AU - Conne B AD - Department of Genetic Medicine and Development, University of Geneva Medical School, 1211, Geneva, Switzerland. FAU - Dacheux, Denis AU - Dacheux D AD - Microbiologie Fondamentale et Pathogénicité CNRS UMR 5234, University Bordeaux, 33000, Bordeaux, France. AD - Bordeaux-INP, Microbiologie Fondamentale et Pathogénicité, UMR-CNRS 5234, 33000, Bordeaux, France. FAU - Landrein, Nicolas AU - Landrein N AD - Microbiologie Fondamentale et Pathogénicité CNRS UMR 5234, University Bordeaux, 33000, Bordeaux, France. FAU - Schmitt, Alain AU - Schmitt A AD - Institut National de la Santé et de la Recherche Médicale, INSERM U1016, Institut Cochin, 75014, Paris, France. AD - Centre National de la Recherche Scientifique, CNRS UMR8104, 75014, Paris, France. AD - Sorbonne Paris Cité, Faculté de Médecine, Université Paris Descartes, 75014, Paris, France. FAU - Stouvenel, Laurence AU - Stouvenel L AD - Institut National de la Santé et de la Recherche Médicale, INSERM U1016, Institut Cochin, 75014, Paris, France. AD - Centre National de la Recherche Scientifique, CNRS UMR8104, 75014, Paris, France. AD - Sorbonne Paris Cité, Faculté de Médecine, Université Paris Descartes, 75014, Paris, France. FAU - Lorès, Patrick AU - Lorès P AD - Institut National de la Santé et de la Recherche Médicale, INSERM U1016, Institut Cochin, 75014, Paris, France. AD - Centre National de la Recherche Scientifique, CNRS UMR8104, 75014, Paris, France. AD - Sorbonne Paris Cité, Faculté de Médecine, Université Paris Descartes, 75014, Paris, France. FAU - El Khouri, Elma AU - El Khouri E AD - Institut National de la Santé et de la Recherche Médicale, INSERM U1016, Institut Cochin, 75014, Paris, France. AD - Centre National de la Recherche Scientifique, CNRS UMR8104, 75014, Paris, France. AD - Sorbonne Paris Cité, Faculté de Médecine, Université Paris Descartes, 75014, Paris, France. FAU - Bottari, Serge P AU - Bottari SP AD - Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, Inserm U1209, CNRS UMR 5309, Université Grenoble Alpes, 38000, Grenoble, France. FAU - Fauré, Julien AU - Fauré J AD - CHU de Grenoble UF de Biochimie Génétique et Moléculaire, 38000, Grenoble, France. AD - Grenoble Neuroscience Institute, INSERM 1216, 38000, Grenoble, France. FAU - Wolf, Jean-Philippe AU - Wolf JP AD - Sorbonne Paris Cité, Faculté de Médecine, Université Paris Descartes, 75014, Paris, France. AD - Laboratoire d'Histologie Embryologie - Biologie de la Reproduction, GH Cochin Broca Hôtel Dieu, Assistance Publique-Hôpitaux de Paris, 75014, Paris, France. FAU - Pernet-Gallay, Karin AU - Pernet-Gallay K AD - Grenoble Neuroscience Institute, INSERM 1216, 38000, Grenoble, France. FAU - Escoffier, Jessica AU - Escoffier J AD - Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, Inserm U1209, CNRS UMR 5309, Université Grenoble Alpes, 38000, Grenoble, France. FAU - Gourabi, Hamid AU - Gourabi H AD - Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACER, Tehran, 16635-148, Iran. FAU - Robinson, Derrick R AU - Robinson DR AD - Microbiologie Fondamentale et Pathogénicité CNRS UMR 5234, University Bordeaux, 33000, Bordeaux, France. FAU - Nef, Serge AU - Nef S AD - Department of Genetic Medicine and Development, University of Geneva Medical School, 1211, Geneva, Switzerland. FAU - Dulioust, Emmanuel AU - Dulioust E AD - Sorbonne Paris Cité, Faculté de Médecine, Université Paris Descartes, 75014, Paris, France. AD - Laboratoire d'Histologie Embryologie - Biologie de la Reproduction, GH Cochin Broca Hôtel Dieu, Assistance Publique-Hôpitaux de Paris, 75014, Paris, France. FAU - Zouari, Raoudha AU - Zouari R AD - Polyclinique les Jasmins, Centre d'Aide Médicale à la Procréation, Centre Urbain Nord, 1003, Tunis, Tunisia. FAU - Bonhivers, Mélanie AU - Bonhivers M AUID- ORCID: 0000-0001-9179-8473 AD - Microbiologie Fondamentale et Pathogénicité CNRS UMR 5234, University Bordeaux, 33000, Bordeaux, France. FAU - Touré, Aminata AU - Touré A AD - Institut National de la Santé et de la Recherche Médicale, INSERM U1016, Institut Cochin, 75014, Paris, France. AD - Centre National de la Recherche Scientifique, CNRS UMR8104, 75014, Paris, France. AD - Sorbonne Paris Cité, Faculté de Médecine, Université Paris Descartes, 75014, Paris, France. FAU - Arnoult, Christophe AU - Arnoult C AD - Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, Inserm U1209, CNRS UMR 5309, Université Grenoble Alpes, 38000, Grenoble, France.