Lack of CCDC146, a ubiquitous centriole and microtubule-associated protein, leads to non-syndromic male infertility in human and mouse - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue eLife Année : 2024

Lack of CCDC146, a ubiquitous centriole and microtubule-associated protein, leads to non-syndromic male infertility in human and mouse

Jana Muroňová
  • Fonction : Auteur
Zine-Eddine Kherraf
  • Fonction : Auteur
Elsa Giordani
  • Fonction : Auteur
Simon Eckert
  • Fonction : Auteur
Caroline Cazin
  • Fonction : Auteur
Amir Amiri-Yekta
  • Fonction : Auteur
Emeline Lambert
  • Fonction : Auteur
Geneviève Chevalier
  • Fonction : Auteur
Guillaume Martinez
Yasmine Neirijnck
  • Fonction : Auteur
Francoise Kühne
  • Fonction : Auteur
Lydia Wehrli
  • Fonction : Auteur
Nikolai Klena
  • Fonction : Auteur
Virginie Hamel
Jessica Escoffier
Paul Guichard
Charles Coutton
  • Fonction : Auteur
Selima Fourati Ben Mustapha
  • Fonction : Auteur
Mahmoud Kharouf
  • Fonction : Auteur
Raoudha Zouari
  • Fonction : Auteur
Nicolas Thierry-Mieg
Serge Nef
Stefan Geimer
  • Fonction : Auteur
Pierre Ray

Résumé

Genetic mutations are a recurrent cause of male infertility. Multiple morphological abnormalities of the flagellum (MMAF) syndrome is a heterogeneous genetic disease, with which more than 50 genes have been linked. Nevertheless, for 50% of patients with this condition, no genetic cause is identified. From a study of a cohort of 167 MMAF patients, pathogenic bi-allelic mutations were identified in the CCDC146 gene in two patients. This gene encodes a poorly characterized centrosomal protein which we studied in detail here. First, protein localization was studied in two cell lines. We confirmed the centrosomal localization in somatic cells and showed that the protein also presents multiple microtubule-related localizations during mitotic division, suggesting that it is a microtubule-associated protein (MAP). To better understand the function of the protein at the sperm level, and the molecular pathogenesis of infertility associated with CCDC146 mutations, two genetically modified mouse models were created: a Ccdc146 knockout (KO) and a knock-in (KI) expressing a HA-tagged CCDC146 protein. KO male mice were completely infertile, and sperm exhibited a phenotype identical to our two MMAF patient's phenotype with CCDC146 mutations. No other pathology was observed, and the animals were viable. CCDC146 expression starts during late spermiogenesis, at the time of flagellum biogenesis. 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, provided evidence that the protein could be a microtubule inner protein (MIP). At the subcellular level, the absence of CCDC146 affected the formation, localization and morphology of all microtubule-based organelles such as the manchette, the head-tail coupling apparatus (HTCA), and the axoneme. Through this study, we have characterized a new genetic cause of infertility, identified a new factor in the formation and/or structure of the sperm axoneme, and demonstrated that the CCDC146 protein plays several cellular roles, depending on the cell type and the stages in the cell cycle.
Fichier principal
Vignette du fichier
2023.02.27.530236v1.full.pdf (7.4 Mo) Télécharger le fichier
Origine : Fichiers produits par l'(les) auteur(s)

Dates et versions

hal-04236524 , version 1 (11-10-2023)

Identifiants

Citer

Jana Muroňová, Zine-Eddine Kherraf, Elsa Giordani, Simon Eckert, Caroline Cazin, et al.. Lack of CCDC146, a ubiquitous centriole and microtubule-associated protein, leads to non-syndromic male infertility in human and mouse. eLife, 2024, ⟨10.7554/eLife.86845.2⟩. ⟨hal-04236524⟩

Collections

UGA CNRS TIMC-MAGE
13 Consultations
14 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More