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


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.

SUBMITTER: Coutton C 

PROVIDER: S-EPMC5814398 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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

Coutton Charles C   Vargas Alexandra S AS   Vargas Alexandra S AS   Amiri-Yekta Amir A   Kherraf Zine-Eddine ZE   Ben Mustapha Selima Fourati SF   Le Tanno Pauline P   Wambergue-Legrand Clémentine C   Karaouzène Thomas T   Martinez Guillaume G   Crouzy Serge S   Daneshipour Abbas A   Hosseini Seyedeh Hanieh SH   Mitchell Valérie V   Halouani Lazhar L   Marrakchi Ouafi O   Makni Mounir M   Latrous Habib H   Kharouf Mahmoud M   Deleuze Jean-François JF   Boland Anne A   Hennebicq Sylviane S   Satre Véronique V   Jouk Pierre-Simon PS   Thierry-Mieg Nicolas N   Conne Beatrice B   Dacheux Denis D   Landrein Nicolas N   Schmitt Alain A   Stouvenel Laurence L   Lorès Patrick P   El Khouri Elma E   Bottari Serge P SP   Fauré Julien J   Wolf Jean-Philippe JP   Pernet-Gallay Karin K   Escoffier Jessica J   Gourabi Hamid H   Robinson Derrick R DR   Nef Serge S   Dulioust Emmanuel E   Zouari Raoudha R   Bonhivers Mélanie M   Touré Aminata A   Arnoult Christophe C   Ray Pierre F PF  

Nature communications 20180215 1


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)  ...[more]

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