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Bi-allelic Mutations in ARMC2 Lead to Severe Astheno-Teratozoospermia Due to Sperm Flagellum Malformations in Humans and Mice

Charles Coutton 1 Guillaume Martinez 1 Zine-Eddine Kherraf 1 Amir Amiri-Yekta 1 Magalie Boguenet 1 Antoine Saut 1 Xiaojin He Feng Zhang 2 Marie Cristou-Kent 1 Jessica Escoffier 1 Marie Bidart 3, 4 Veronique Satre 1, 3 Béatrice Conne 5 Selima Fourati Ben Mustapha 6 Lazhar Halouani 6 Ouafi Marrakchi 6 Mounir Makni 6 Habib Latrous 6 Mahmoud Kharouf 6 Karin Pernet-Gallay 7 Melanie Bonhivers 8 Sylviane Hennebicq 1 Nathalie Rives 9 Emmanuel Dulioust 10, 11 Aminata Touré 10, 12 Hamid Gourabi 13 Yunxia Cao Raoudha Zouari 6 Seyedeh Hanieh Hosseini 13 Serge Nef Nicolas Thierry-Mieg 14 Christophe Arnoult 1 Pierre Ray 1
Abstract : Male infertility is a major health concern. Among its different causes, multiple morphological abnormalities of the flagella (MMAF) induces asthenozoospermia and is one of the most severe forms of qualitative sperm defects. Sperm of affected men display short, coiled, absent, and/or irregular flagella. To date, six genes (DNAH1, CFAP43, CFAP44, CFAP69, FSIP2, and WDR66) have been found to be recurrently associated with MMAF, but more than half of the cases analyzed remain unresolved, suggesting that many yet-uncharacterized gene defects account for this phenotype. Here, whole-exome sequencing (WES) was performed on 168 infertile men who had a typical MMAF phenotype. Five unrelated affected individuals carried a homozygous deleterious mutation in ARMC2, a gene not previously linked to the MMAF phenotype. Using the CRISPR-Cas9 technique, we generated homozygous Armc2 mutant mice, which also presented an MMAF phenotype, thus confirming the involvement of ARMC2 in human MMAF. Immunostaining experiments in AMRC2-mutated individuals and mutant mice evidenced the absence of the axonemal central pair complex (CPC) proteins SPAG6 and SPEF2, whereas the other tested axonemal and peri-axonemal components were present, suggesting that ARMC2 is involved in CPC assembly and/or stability. Overall, we showed that bi-allelic mutations in ARMC2 cause male infertility in humans and mice by inducing a typical MMAF phenotype, indicating that this gene is necessary for sperm flagellum structure and assembly.
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https://hal.archives-ouvertes.fr/hal-02003335
Contributeur : Nicolas Thierry-Mieg <>
Soumis le : mercredi 17 avril 2019 - 15:12:10
Dernière modification le : lundi 24 juin 2019 - 16:24:40

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Charles Coutton, Guillaume Martinez, Zine-Eddine Kherraf, Amir Amiri-Yekta, Magalie Boguenet, et al.. Bi-allelic Mutations in ARMC2 Lead to Severe Astheno-Teratozoospermia Due to Sperm Flagellum Malformations in Humans and Mice. American Journal of Human Genetics, Elsevier (Cell Press), 2019, 104 (2), pp.331-340. ⟨10.1016/j.ajhg.2018.12.013⟩. ⟨hal-02003335⟩

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