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Nat Commun. 2018 Feb 15;9(1):686. doi: 10.1038/s41467-017-02792-7.

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

Author information

1
Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, Inserm U1209, CNRS UMR 5309, Université Grenoble Alpes, 38000, Grenoble, France.
2
CHU de Grenoble, UM de Génétique Chromosomique, 38000, Grenoble, France.
3
CHU de Grenoble, UM GI-DPI, 38000, Grenoble, France.
4
Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACER, Tehran, 16635-148, Iran.
5
Polyclinique les Jasmins, Centre d'Aide Médicale à la Procréation, Centre Urbain Nord, 1003, Tunis, Tunisia.
6
Laboratoire de Chimie et Biologie des Métaux, Institut de Recherche en Technologie et Sciences pour le Vivant, CEA iRTSV/LCBM/GMCT, CNRS UMR 5249, Université Grenoble Alpes, 38054, Grenoble, France.
7
Department of Andrology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, 16635-148, Iran.
8
EA 4308, Department of Reproductive Biology and Spermiology-CECOS Lille, University Medical Center, Lille, 59037, France.
9
Centre National de Génotypage, Institut de Génomique, CEA, 91000, Evry, France.
10
CHU de Grenoble, UF de Biologie de la procréation, 38000, Grenoble, France.
11
CHU de Grenoble, UF de Génétique Médicale, 38000, Grenoble, France.
12
Univ. Grenoble Alpes/CNRS TIMC-IMAG, 38000, Grenoble, France.
13
Department of Genetic Medicine and Development, University of Geneva Medical School, 1211, Geneva, Switzerland.
14
Microbiologie Fondamentale et Pathogénicité CNRS UMR 5234, University Bordeaux, 33000, Bordeaux, France.
15
Bordeaux-INP, Microbiologie Fondamentale et Pathogénicité, UMR-CNRS 5234, 33000, Bordeaux, France.
16
Institut National de la Santé et de la Recherche Médicale, INSERM U1016, Institut Cochin, 75014, Paris, France.
17
Centre National de la Recherche Scientifique, CNRS UMR8104, 75014, Paris, France.
18
Sorbonne Paris Cité, Faculté de Médecine, Université Paris Descartes, 75014, Paris, France.
19
CHU de Grenoble UF de Biochimie Génétique et Moléculaire, 38000, Grenoble, France.
20
Grenoble Neuroscience Institute, INSERM 1216, 38000, Grenoble, France.
21
Laboratoire d'Histologie Embryologie - Biologie de la Reproduction, GH Cochin Broca Hôtel Dieu, Assistance Publique-Hôpitaux de Paris, 75014, Paris, France.
22
Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, Inserm U1209, CNRS UMR 5309, Université Grenoble Alpes, 38000, Grenoble, France. pray@chu-grenoble.fr.
23
CHU de Grenoble, UM GI-DPI, 38000, Grenoble, France. pray@chu-grenoble.fr.

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.

PMID:
29449551
PMCID:
PMC5814398
DOI:
10.1038/s41467-017-02792-7
[Indexed for MEDLINE]
Free PMC Article

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