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

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

  • J Med Genet. 2020 Oct;57(10):708-716. doi: 10.1136/jmedgenet-2019-106775.
Guillaume Martinez # 1 2,  Julie Beurois # 1,  Denis Dacheux 3 4,  Caroline Cazin 1,  Marie Bidart 1 5,  Zine-Eddine Kherraf 1 6,  Derrick R Robinson 4,  Véronique Satre 1 2,  Gerald Le Gac 7 8,  Chandran Ka 7,  Isabelle Gourlaouen 7,  Yann Fichou 7,  Graciane Petre 9,  Emmanuel Dulioust 10 11,  Raoudha Zouari 12,  Nicolas Thierry-Mieg 13,  Aminata Touré 11 14 15,  Christophe Arnoult 1,  Mélanie Bonhivers 3,  Pierre Ray # 1 6,  Charles Coutton # 16 2
Affiliations

Affiliations

  • 1 Univ. Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility, Grenoble, France.
  • 2 CHU Grenoble Alpes, UM de Génétique Chromosomique, Grenoble, France.
  • 3 Université de Bordeaux, Microbiologie Fondamentale et Pathogénicité, CNRS UMR 5234, Bordeaux, France.
  • 4 Institut Polytechnique de Bordeaux, Microbiologie Fondamentale et Pathogénicité, CNRS UMR 5234, Bordeaux, France.
  • 5 CHU Grenoble Alpes, Unité Médicale de Génétique Moléculaire : Maladies Héréditaires et Oncologie, Pôle Biologie, Institut de Biologie et de Pathologie, Grenoble, France.
  • 6 CHU Grenoble Alpes, UM GI-DPI, Grenoble, France.
  • 7 INSERM UMR1078, Université Bretagne Loire - Université de Brest, Etablissement Français du Sang - Bretagne, Institut Brestois Santé-Agro-Matière, Brest, France.
  • 8 Service de Génétique Médicale et Biologie de la Reproduction, Laboratoire de Génétique Moléculaire et Histocompatibilité, CHRU de Brest, Hôpital Morvan, Brest, France.
  • 9 INSERM U1205, UFR Chimie Biologie, Univ. Grenoble Alpes, Grenoble, France.
  • 10 Laboratoire d'Histologie Embryologie - Biologie de la Reproduction, GH Cochin Broca Hôtel Dieu, Assistance Publique-Hôpitaux de Paris, Paris, France.
  • 11 Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
  • 12 Polyclinique les Jasmins, Centre d'Aide Médicale à la Procréation, Centre Urbain Nord, Tunis, Tunisia.
  • 13 Univ. Grenoble Alpes, CNRS UMR 5525, TIMC-IMAG / BCM, Grenoble, France.
  • 14 INSERM U1016, Institut Cochin, Paris, France.
  • 15 Centre National de la Recherche Scientifique UMR8104, Paris, France.
  • 16 Univ. Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility, Grenoble, France [email protected].
  • # Contributed equally.
PMID: 32161152 DOI: 10.1136/jmedgenet-2019-106775
Abstract

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.

Keywords

genetics; molecular genetics; reproductive medicine.

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