• PMID: 32161152
• Gene Name: CFAP91
• Condition: Astheno-teratozoospermia and male infertility
• Association: Associated
• Mutation: c.682+1G>A, 3 c.124G>C; p.(Asp42His)
• Population size: 167
• Population details: 167 infertile men with an MMAF phenotype
• Sex: Male
• Infertility type: Male infertility
• Associated genes: NGS

Biallelic variants in MAATS1 encoding CFAP91, a calmodulin-associated and spoke-associated complex protein, cause severe astheno-teratozoospermia and male infertility

Martinez G, Beurois J, Dacheux D, Cazin C, Bidart M, Kherraf ZE, Robinson DR, Satre V, Le Gac G, Ka C, Gourlaouen I, Fichou Y, Petre G, Dulioust E, Zouari R, Thierry-Mieg N, Touré A, Arnoult C, Bonhivers M, Ray P, Coutton C.

BACKGROUND: Multiple morphological abnormalities of the flagella (MMAF) consistently lead to male infertility due to a reduced or absent sperm motility defined as asthenozoospermia. Despite numerous genes recently described to be recurrently associated with MMAF, more than half of the cases analysed remain unresolved, suggesting that many yet uncharacterised gene defects account for this phenotype METHODS: Exome sequencing was performed on 167 infertile men with an MMAF phenotype. Immunostaining and transmission electron microscopy (TEM) in sperm cells from affected individuals were performed to characterise the ultrastructural sperm defects. Gene inactivation using RNA interference (RNAi) was subsequently performed in Trypanosoma. RESULTS: We identified six unrelated affected patients carrying a homozygous deleterious variants in MAATS1, a gene encoding CFAP91, a calmodulin-associated and spoke-associated complex (CSC) protein. TEM and immunostaining experiments in sperm cells showed severe central pair complex (CPC) and radial spokes defects. Moreover, we confirmed that the WDR66 protein is a physical and functional partner of CFAP91 into the CSC. Study of Trypanosoma MAATS1's orthologue (TbCFAP91) highlighted high sequence and structural analogies with the human protein and confirmed the axonemal localisation of the protein. Knockdown of TbCFAP91 using RNAi impaired flagellar movement led to CPC defects in Trypanosoma as observed in humans. CONCLUSIONS: We showed that CFAP91 is essential for normal sperm flagellum structure and function in human and Trypanosoma and that biallelic variants in this gene lead to severe flagellum malformations resulting in astheno-teratozoospermia and primary male infertility. CI - © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ. FAU - Martinez, Guillaume AU - Martinez G AD - Univ. Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility, Grenoble, France. AD - CHU Grenoble Alpes, UM de Génétique Chromosomique, Grenoble, France. FAU - Beurois, Julie AU - Beurois J AD - Univ. Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility, Grenoble, France. FAU - Dacheux, Denis AU - Dacheux D AD - Université de Bordeaux, Microbiologie Fondamentale et Pathogénicité, CNRS UMR 5234, Bordeaux, France. AD - Institut Polytechnique de Bordeaux, Microbiologie Fondamentale et Pathogénicité, CNRS UMR 5234, Bordeaux, France. FAU - Cazin, Caroline AU - Cazin C AD - Univ. Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility, Grenoble, France. FAU - Bidart, Marie AU - Bidart M AD - Univ. Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility, Grenoble, France. AD - CHU Grenoble Alpes, Unité Médicale de Génétique Moléculaire : Maladies Héréditaires et Oncologie, Pôle Biologie, Institut de Biologie et de Pathologie, Grenoble, France. FAU - Kherraf, Zine-Eddine AU - Kherraf ZE AD - Univ. Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility, Grenoble, France. AD - CHU Grenoble Alpes, UM GI-DPI, Grenoble, France. FAU - Robinson, Derrick R AU - Robinson DR AD - Institut Polytechnique de Bordeaux, Microbiologie Fondamentale et Pathogénicité, CNRS UMR 5234, Bordeaux, France. FAU - Satre, Véronique AU - Satre V AD - Univ. Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility, Grenoble, France. AD - CHU Grenoble Alpes, UM de Génétique Chromosomique, Grenoble, France. FAU - Le Gac, Gerald AU - Le Gac G AD - INSERM UMR1078, Université Bretagne Loire - Université de Brest, Etablissement Français du Sang - Bretagne, Institut Brestois Santé-Agro-Matière, Brest, France. AD - Service de Génétique Médicale et Biologie de la Reproduction, Laboratoire de Génétique Moléculaire et Histocompatibilité, CHRU de Brest, Hôpital Morvan, Brest, France. FAU - Ka, Chandran AU - Ka C AD - INSERM UMR1078, Université Bretagne Loire - Université de Brest, Etablissement Français du Sang - Bretagne, Institut Brestois Santé-Agro-Matière, Brest, France. FAU - Gourlaouen, Isabelle AU - Gourlaouen I AD - INSERM UMR1078, Université Bretagne Loire - Université de Brest, Etablissement Français du Sang - Bretagne, Institut Brestois Santé-Agro-Matière, Brest, France. FAU - Fichou, Yann AU - Fichou Y AD - INSERM UMR1078, Université Bretagne Loire - Université de Brest, Etablissement Français du Sang - Bretagne, Institut Brestois Santé-Agro-Matière, Brest, France. FAU - Petre, Graciane AU - Petre G AD - INSERM U1205, UFR Chimie Biologie, Univ. Grenoble Alpes, Grenoble, France. FAU - Dulioust, Emmanuel AU - Dulioust E AD - Laboratoire d'Histologie Embryologie - Biologie de la Reproduction, GH Cochin Broca Hôtel Dieu, Assistance Publique-Hôpitaux de Paris, Paris, France. AD - Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France. FAU - Zouari, Raoudha AU - Zouari R AD - Polyclinique les Jasmins, Centre d'Aide Médicale à la Procréation, Centre Urbain Nord, Tunis, Tunisia. FAU - Thierry-Mieg, Nicolas AU - Thierry-Mieg N AD - Univ. Grenoble Alpes, CNRS UMR 5525, TIMC-IMAG / BCM, Grenoble, France. FAU - Touré, Aminata AU - Touré A AD - Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France. AD - INSERM U1016, Institut Cochin, Paris, France. AD - Centre National de la Recherche Scientifique UMR8104, Paris, France. FAU - Arnoult, Christophe AU - Arnoult C AD - Univ. Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility, Grenoble, France. FAU - Bonhivers, Mélanie AU - Bonhivers M AD - Université de Bordeaux, Microbiologie Fondamentale et Pathogénicité, CNRS UMR 5234, Bordeaux, France. FAU - Ray, Pierre AU - Ray P AD - Univ. Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility, Grenoble, France. AD - CHU Grenoble Alpes, UM GI-DPI, Grenoble, France.