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

Coutton, Charles and Vargas, Alexandra S and Vargas, Alexandra S and Amiri-Yekta, Amir and Kherraf, Zine-Eddine and Ben Mustapha, Selima Fourati and Le Tanno, Pauline and Wambergue-Legrand, Clémentine and Karaouzène, Thomas and Martinez, Guillaume and Crouzy, Serge and Daneshipour, Abbas and Hosseini, Seyedeh Hanieh and Mitchell, Valérie and Halouani, Lazhar and Marrakchi, Ouafi and Makni, Mounir and Latrous, Habib and Kharouf, Mahmoud and Deleuze, Jean-François and Boland, Anne and Hennebicq, Sylviane and Satre, Véronique and Jouk, Pierre-Simon and Thierry-Mieg, Nicolas and Conne, Beatrice and Dacheux, Denis and Landrein, Nicolas and Schmitt, Alain and Stouvenel, Laurence and Lorès, Patrick and El Khouri, Elma and Bottari, Serge P and Fauré, Julien and Wolf, Jean-Philippe and Pernet-Gallay, Karin and Escoffier, Jessica and Gourabi, Hamid and Robinson, Derrick R and Nef, Serge and Dulioust, Emmanuel and Zouari, Raoudha and Bonhivers, Mélanie and Touré, Aminata and Arnoult, Christophe and Ray, Pierre F


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.