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

Charles Coutton, Alexandra S. Vargas, Amir Amiri-Yekta, Zine-Eddine Kherraf, Selima Fourati Mustapha, Pauline Tanno, Clémentine Wambergue-Legrand, Thomas Karaouzène, Guillaume Martinez, Serge Crouzy, Abbas Daneshipour, Seyedeh Hanieh Hosseini, Valérie Mitchell, Lazhar Halouani, Ouafi Marrakchi, Mounir Makni, Habib Latrous, Mahmoud Kharouf, Jean-François Deleuze, Anne Boland, Sylviane Hennebicq, Véronique Satre, Pierre-Simon Jouk, Nicolas Thierry-Mieg, Beatrice Conne, Denis Dacheux, Nicolas Landrein, Alain Schmitt, Laurence Stouvenel, Patrick Lorès, Elma El Khouri, Serge P. Bottari, Julien Fauré, Jean-Philippe Wolf, Karin Pernet-Gallay, Jessica Escoffier, Hamid Gourabi, Derrick R. Robinson, Serge Nef, Emmanuel Dulioust, Raoudha Zouari, Mélanie Bonhivers, Aminata Touré, Christophe Arnoult and Pierre F. Ray ()
Additional contact information
Charles Coutton: Université Grenoble Alpes
Alexandra S. Vargas: Université Grenoble Alpes
Amir Amiri-Yekta: Université Grenoble Alpes
Zine-Eddine Kherraf: Université Grenoble Alpes
Selima Fourati Mustapha: Centre Urbain Nord
Pauline Tanno: Université Grenoble Alpes
Clémentine Wambergue-Legrand: Université Grenoble Alpes
Thomas Karaouzène: Université Grenoble Alpes
Guillaume Martinez: Université Grenoble Alpes
Serge Crouzy: Université Grenoble Alpes
Abbas Daneshipour: ACER
Seyedeh Hanieh Hosseini: ACECR
Valérie Mitchell: University Medical Center
Lazhar Halouani: Centre Urbain Nord
Ouafi Marrakchi: Centre Urbain Nord
Mounir Makni: Centre Urbain Nord
Habib Latrous: Centre Urbain Nord
Mahmoud Kharouf: Centre Urbain Nord
Jean-François Deleuze: CEA
Anne Boland: CEA
Sylviane Hennebicq: Université Grenoble Alpes
Véronique Satre: Université Grenoble Alpes
Pierre-Simon Jouk: UF de Génétique Médicale
Nicolas Thierry-Mieg: Univ. Grenoble Alpes/CNRS TIMC-IMAG
Beatrice Conne: University of Geneva Medical School
Denis Dacheux: University Bordeaux
Nicolas Landrein: University Bordeaux
Alain Schmitt: Institut Cochin
Laurence Stouvenel: Institut Cochin
Patrick Lorès: Institut Cochin
Elma El Khouri: Institut Cochin
Serge P. Bottari: Université Grenoble Alpes
Julien Fauré: CHU de Grenoble UF de Biochimie Génétique et Moléculaire
Jean-Philippe Wolf: Université Paris Descartes
Karin Pernet-Gallay: INSERM 1216
Jessica Escoffier: Université Grenoble Alpes
Hamid Gourabi: ACER
Derrick R. Robinson: University Bordeaux
Serge Nef: University of Geneva Medical School
Emmanuel Dulioust: Université Paris Descartes
Raoudha Zouari: Centre Urbain Nord
Mélanie Bonhivers: University Bordeaux
Aminata Touré: Institut Cochin
Christophe Arnoult: Université Grenoble Alpes
Pierre F. Ray: Université Grenoble Alpes

Nature Communications, 2018, vol. 9, issue 1, 1-18

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-017-02792-7

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