Lack of CCDC146, a ubiquitous centriole and microtubule-associated protein, leads to non-syndromic male infertility in human and mouse
| Title: | Lack of CCDC146, a ubiquitous centriole and microtubule-associated protein, leads to non-syndromic male infertility in human and mouse |
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| Authors: | Jana Muroňová, Zine Eddine Kherraf, Elsa Giordani, Emeline Lambert, Simon Eckert, Caroline Cazin, Amir Amiri-Yekta, Magali Court, Geneviève Chevalier, Guillaume Martinez, Yasmine Neirijnck, Francoise Kühne, Lydia Wehrli, Nikolai Klena, Virginie Hamel, Lisa De Macedo, Jessica Escoffier, Paul Guichard, Charles Coutton, Selima Fourati Ben Mustapha, Mahmoud Kharouf, Anne-Pacale Bouin, Raoudha Zouari, Nicolas Thierry-Mieg, Serge Nef, Stefan Geimer, Corinne Loeuillet, Pierre F Ray, Christophe Arnoult |
| Source: | eLife, Vol 12 (2024) |
| Publisher Information: | eLife Sciences Publications Ltd, 2024. |
| Publication Year: | 2024 |
| Collection: | LCC:Medicine LCC:Science LCC:Biology (General) |
| Subject Terms: | infertility, sperm, flagellum, Medicine, Science, Biology (General), QH301-705.5 |
| More Details: | From a cohort of 167 infertile patients suffering from multiple morphological abnormalities of the flagellum (MMAF), pathogenic bi-allelic mutations were identified in the CCDC146 gene. In somatic cells, CCDC146 is located at the centrosome and at multiple microtubule-related organelles during mitotic division, suggesting that it is a microtubule-associated protein (MAP). To decipher the molecular pathogenesis of infertility associated with CCDC146 mutations, a Ccdc146 knock-out (KO) mouse line was created. KO male mice were infertile, and sperm exhibited a phenotype identical to CCDC146 mutated patients. CCDC146 expression starts during late spermiogenesis. In the spermatozoon, the protein is conserved but is not localized to centrioles, unlike in somatic cells, rather it is present in the axoneme at the level of microtubule doublets. Expansion microscopy associated with the use of the detergent sarkosyl to solubilize microtubule doublets suggests that the protein may be a microtubule inner protein (MIP). At the subcellular level, the absence of CCDC146 impacted all microtubule-based organelles such as the manchette, the head–tail coupling apparatus (HTCA), and the axoneme. Through this study, a new genetic cause of infertility and a new factor in the formation and/or structure of the sperm axoneme were characterized. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 2050-084X |
| Relation: | https://elifesciences.org/articles/86845; https://doaj.org/toc/2050-084X |
| DOI: | 10.7554/eLife.86845 |
| Access URL: | https://doaj.org/article/078af173188c4adb858332ae057a3a05 |
| Accession Number: | edsdoj.078af173188c4adb858332ae057a3a05 |
| Database: | Directory of Open Access Journals |
| ISSN: | 2050084X |
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| DOI: | 10.7554/eLife.86845 |
| Published in: | eLife |
| Language: | English |