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

• Published in: Nature communications 2018-02, Vol.9 (1), p.686-18, Article 686
• Main Authors: Coutton, Charles, Vargas, Alexandra S., Amiri-Yekta, Amir, Kherraf, Zine-Eddine, Ben Mustapha, Selima Fourati, Le Tanno, Pauline, Wambergue-Legrand, Clémentine, Karaouzène, Thomas, Martinez, Guillaume, Crouzy, Serge, Daneshipour, Abbas, Hosseini, Seyedeh Hanieh, Mitchell, Valérie, Halouani, Lazhar, Marrakchi, Ouafi, Makni, Mounir, Latrous, Habib, Kharouf, Mahmoud, Deleuze, Jean-François, Boland, Anne, Hennebicq, Sylviane, Satre, Véronique, Jouk, Pierre-Simon, Thierry-Mieg, Nicolas, Conne, Beatrice, Dacheux, Denis, Landrein, Nicolas, Schmitt, Alain, Stouvenel, Laurence, Lorès, Patrick, El Khouri, Elma, Bottari, Serge P., Fauré, Julien, Wolf, Jean-Philippe, Pernet-Gallay, Karin, Escoffier, Jessica, Gourabi, Hamid, Robinson, Derrick R., Nef, Serge, Dulioust, Emmanuel, Zouari, Raoudha, Bonhivers, Mélanie, Touré, Aminata, Arnoult, Christophe, Ray, Pierre F.
• Format: Article
• Language: English
• Subjects: 14/1; 14/19; 14/28; 45/23; 49/88; 631/208; 631/80/128/1383; 64/60; 692/699/2732/1577; 692/699/2768/294; Abnormalities; Adult; Animals; Axoneme; Clustered Regularly Interspaced Short Palindromic Repeats; Cohort Studies; CRISPR; Defects; Fertility; Flagella; Flagella - metabolism; Flagella - physiology; Genetics; Homozygote; Human genetics; Humanities and Social Sciences; Humans; Infertility; Infertility, Male - genetics; Life Sciences; Localization; Male; Men; Mice; Mice, Knockout; Microscopy; Microscopy, Immunoelectron; Microtubule Proteins - genetics; Microtubules; Middle Aged; multidisciplinary; Mutation; Nuclear Proteins - genetics; Peptide Hydrolases - genetics; Proteins; Reproductive Biology; Science; Science (multidisciplinary); Sperm; Sperm Motility; Spermatogenesis; Spermatozoa - metabolism; Spermatozoa - physiology; Trypanosoma; Trypanosoma - physiology; Whole Exome Sequencing
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-02792-7

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. Asthenozoospermia is a major cause of male infertility, and multiple morphological abnormalities of the flagella (MMAF) is a particularly severe form. Here, using whole-exome sequencing of 78 MMAF patients, the authors identify mutations in two WDR proteins, CFAP43 and CFAP44, and confirm that these proteins are required for flagellogenesis in mouse and Trypanosoma brucei .