eLife (Nov 2023)
Novel axonemal protein ZMYND12 interacts with TTC29 and DNAH1, and is required for male fertility and flagellum function
- Denis Dacheux,
- Guillaume Martinez,
- Christine E Broster Reix,
- Julie Beurois,
- Patrick Lores,
- Magamba Tounkara,
- Jean-William Dupuy,
- Derrick Roy Robinson,
- Corinne Loeuillet,
- Emeline Lambert,
- Zeina Wehbe,
- Jessica Escoffier,
- Amir Amiri-Yekta,
- Abbas Daneshipour,
- Seyedeh-Hanieh Hosseini,
- Raoudha Zouari,
- Selima Fourati Ben Mustapha,
- Lazhar Halouani,
- Xiaohui Jiang,
- Ying Shen,
- Chunyu Liu,
- Nicolas Thierry-Mieg,
- Amandine Septier,
- Marie Bidart,
- Véronique Satre,
- Caroline Cazin,
- Zine Eddine Kherraf,
- Christophe Arnoult,
- Pierre F Ray,
- Aminata Toure,
- Mélanie Bonhivers,
- Charles Coutton
Affiliations
- Denis Dacheux
- University of Bordeaux, CNRS, Bordeaux, France; Bordeaux INP, Microbiologie Fondamentale et Pathogénicité, Bordeaux, France
- Guillaume Martinez
- ORCiD
- CHU Grenoble-Alpes, UM de Génétique Chromosomique, Grenoble, France
- Christine E Broster Reix
- University of Bordeaux, CNRS, Bordeaux, France
- Julie Beurois
- Institute for Advanced Biosciences, INSERM U1209, CNRS UMR 5309, Université Grenoble Alpes, Team Genetics Epigenetics and Therapies of Infertility, Grenoble, France
- Patrick Lores
- Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris Cite, Paris, France
- Magamba Tounkara
- University of Bordeaux, CNRS, Bordeaux, France
- Jean-William Dupuy
- Université Bordeaux, Plateforme Protéome, Bordeaux, France
- Derrick Roy Robinson
- ORCiD
- University of Bordeaux, CNRS, Bordeaux, France
- Corinne Loeuillet
- Institute for Advanced Biosciences, INSERM U1209, CNRS UMR 5309, Université Grenoble Alpes, Team Genetics Epigenetics and Therapies of Infertility, Grenoble, France
- Emeline Lambert
- Institute for Advanced Biosciences, INSERM U1209, CNRS UMR 5309, Université Grenoble Alpes, Team Genetics Epigenetics and Therapies of Infertility, Grenoble, France
- Zeina Wehbe
- Institute for Advanced Biosciences, INSERM U1209, CNRS UMR 5309, Université Grenoble Alpes, Team Genetics Epigenetics and Therapies of Infertility, Grenoble, France
- Jessica Escoffier
- ORCiD
- Institute for Advanced Biosciences, INSERM U1209, CNRS UMR 5309, Université Grenoble Alpes, Team Genetics Epigenetics and Therapies of Infertility, Grenoble, France
- Amir Amiri-Yekta
- Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Islamic Republic of Iran
- Abbas Daneshipour
- Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Islamic Republic of Iran
- Seyedeh-Hanieh Hosseini
- Department of Andrology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Islamic Republic of Iran
- Raoudha Zouari
- Polyclinique les Jasmins, Centre d'Aide Médicale à la Procréation, Centre Urbain Nord, Tunis, Tunisia
- Selima Fourati Ben Mustapha
- Polyclinique les Jasmins, Centre d'Aide Médicale à la Procréation, Centre Urbain Nord, Tunis, Tunisia
- Lazhar Halouani
- Polyclinique les Jasmins, Centre d'Aide Médicale à la Procréation, Centre Urbain Nord, Tunis, Tunisia
- Xiaohui Jiang
- Human Sperm Bank, West China Second University Hospital of Sichuan University, Sichuan, China; NHC Key Laboratory of Chronobiology, Sichuan University, Sichuan, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Sichuan, China
- Ying Shen
- NHC Key Laboratory of Chronobiology, Sichuan University, Sichuan, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Sichuan, China
- Chunyu Liu
- Obstetrics and Gynecology Hospital, Fudan University, Fudan, China
- Nicolas Thierry-Mieg
- Université Grenoble Alpes, CNRS, Grenoble, France
- Amandine Septier
- Université Grenoble Alpes, CNRS, Grenoble, France
- Marie Bidart
- Institute for Advanced Biosciences, INSERM U1209, CNRS UMR 5309, Université Grenoble Alpes, Team Genetics Epigenetics and Therapies of Infertility, Grenoble, France; CHU Grenoble Alpes, Laboratoire de Génétique Moléculaire: Maladies Héréditaires et Oncologie, Grenoble, France
- Véronique Satre
- CHU Grenoble-Alpes, UM de Génétique Chromosomique, Grenoble, France; Institute for Advanced Biosciences, INSERM U1209, CNRS UMR 5309, Université Grenoble Alpes, Team Genetics Epigenetics and Therapies of Infertility, Grenoble, France
- Caroline Cazin
- CHU Grenoble-Alpes, UM de Génétique Chromosomique, Grenoble, France; Institute for Advanced Biosciences, INSERM U1209, CNRS UMR 5309, Université Grenoble Alpes, Team Genetics Epigenetics and Therapies of Infertility, Grenoble, France; CHU de Grenoble, UM GI-DPI, Grenoble, France
- Zine Eddine Kherraf
- Institute for Advanced Biosciences, INSERM U1209, CNRS UMR 5309, Université Grenoble Alpes, Team Genetics Epigenetics and Therapies of Infertility, Grenoble, France; CHU de Grenoble, UM GI-DPI, Grenoble, France
- Christophe Arnoult
- ORCiD
- Institute for Advanced Biosciences, INSERM U1209, CNRS UMR 5309, Université Grenoble Alpes, Team Genetics Epigenetics and Therapies of Infertility, Grenoble, France
- Pierre F Ray
- Institute for Advanced Biosciences, INSERM U1209, CNRS UMR 5309, Université Grenoble Alpes, Team Genetics Epigenetics and Therapies of Infertility, Grenoble, France; CHU de Grenoble, UM GI-DPI, Grenoble, France
- Aminata Toure
- ORCiD
- Institute for Advanced Biosciences, INSERM U 1209, CNRS UMR 5309, Université Grenoble Alpes, Team Physiology and Pathophysiology of Sperm cells, Grenoble, France
- Mélanie Bonhivers
- ORCiD
- University of Bordeaux, CNRS, Bordeaux, France
- Charles Coutton
- ORCiD
- Institute for Advanced Biosciences, INSERM U1209, CNRS UMR 5309, Université Grenoble Alpes, Team Genetics Epigenetics and Therapies of Infertility, Grenoble, France
- DOI
- https://doi.org/10.7554/eLife.87698
- Journal volume & issue
-
Vol. 12
Abstract
Male infertility is common and complex, presenting a wide range of heterogeneous phenotypes. Although about 50% of cases are estimated to have a genetic component, the underlying cause often remains undetermined. Here, from whole-exome sequencing on samples from 168 infertile men with asthenoteratozoospermia due to severe sperm flagellum, we identified homozygous ZMYND12 variants in four unrelated patients. In sperm cells from these individuals, immunofluorescence revealed altered localization of DNAH1, DNALI1, WDR66, and TTC29. Axonemal localization of ZMYND12 ortholog TbTAX-1 was confirmed using the Trypanosoma brucei model. RNAi knock-down of TbTAX-1 dramatically affected flagellar motility, with a phenotype similar to the sperm from men bearing homozygous ZMYND12 variants. Co-immunoprecipitation and ultrastructure expansion microscopy in T. brucei revealed TbTAX-1 to form a complex with TTC29. Comparative proteomics with samples from Trypanosoma and Ttc29 KO mice identified a third member of this complex: DNAH1. The data presented revealed that ZMYND12 is part of the same axonemal complex as TTC29 and DNAH1, which is critical for flagellum function and assembly in humans, and Trypanosoma. ZMYND12 is thus a new asthenoteratozoospermia-associated gene, bi-allelic variants of which cause severe flagellum malformations and primary male infertility.
Keywords