Bi-allelic truncating variants in CFAP206 cause male infertility in human and mouse

Autor: Yunxia Cao, Véronique Satre, Chunyu Liu, Charles Coutton, Qunshan Shen, Marjorie Whitfield, Kuokuo Li, Julie Beurois, Hongbin Liu, Xiaojin He, Dan Liang, Pierre F. Ray, Guillaume Martinez, Marie Bidart, Tristan Celse, Nicolas Thierry-Mieg, Huan Wu, Feng Zhang, Zine-Eddine Kherraf, Fangbiao Tao, Caroline Cazin, Christophe Arnoult, Mingrong Lv, Bing Song, Amir Amiri-Yekta, Aminata Touré
Přispěvatelé: Anhui Medical University, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), CHU Grenoble, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Royan Institute for Reproductive Biomedicine [Tehran, Iran], Centre Hospitalier Universitaire [Grenoble] (CHU), Biologie Computationnelle et Modélisation (TIMC-BCM ), Translational Innovation in Medicine and Complexity / Recherche Translationnelle et Innovation en Médecine et Complexité - UMR 5525 (TIMC ), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA), Fudan University [Shanghai], Anhui Medical University [Hefei, China], Thierry-Mieg, Nicolas
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: Human Genetics
Human Genetics, Springer Verlag, 2021, 140 (9), pp.1367-1377. ⟨10.1007/s00439-021-02313-z⟩
Human Genetics, 2021, 140 (9), pp.1367-1377. ⟨10.1007/s00439-021-02313-z⟩
ISSN: 0340-6717
1432-1203
DOI: 10.1007/s00439-021-02313-z⟩
Popis: International audience; Spermatozoa are polarized cells with a head and a flagellum joined together by the connecting piece. Flagellum integrity is critical for normal sperm function, and flagellum defects consistently lead to male infertility. Multiple morphological abnormalities of the flagella (MMAF) is a distinct sperm phenotype consistently leading to male infertility due to a reduced or absent sperm motility associated with severe morphological and ultrastructural flagellum defects. Despite numerous genes recently described to be recurrently associated with MMAF, more than half of the cases analyzed remain unresolved, suggesting that many yet uncharacterized gene defects account for this phenotype. By performing a retrospective exome analysis of the unsolved cases from our initial cohort of 167 infertile men with a MMAF phenotype, we identified one individual carrying a homozygous frameshift variant in CFAP206, a gene encoding a microtubule-docking adapter for radial spoke and inner dynein arm. Immunostaining experiments in the patient's sperm cells demonstrated the absence of WDR66 and RSPH1 proteins suggesting severe radial spokes and calmodulin and spoke-associated complex defects. Using the CRISPR-Cas9 technique, we generated homozygous Cfap206 knockout (KO) mice which presented with male infertility due to functional, structural and ultrastructural sperm flagellum defects associated with a very low rate of embryo development using ICSI. Overall, we showed that CFAP206 is essential for normal sperm flagellum structure and function in human and mouse and that bi-allelic mutations in CFAP206 cause male infertility in man and mouse by inducing morphological and functional defects of the sperm flagellum that may also cause ICSI failures.
Databáze: OpenAIRE
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