2. Academic Validation
  3. A Homozygous Ancestral SVA-Insertion-Mediated Deletion in WDR66 Induces Multiple Morphological Abnormalities of the Sperm Flagellum and Male Infertility

A Homozygous Ancestral SVA-Insertion-Mediated Deletion in WDR66 Induces Multiple Morphological Abnormalities of the Sperm Flagellum and Male Infertility

  • Am J Hum Genet. 2018 Sep 6;103(3):400-412. doi: 10.1016/j.ajhg.2018.07.014.
Zine-Eddine Kherraf 1,  Amir Amiri-Yekta 2,  Denis Dacheux 3,  Thomas Karaouzène 4,  Charles Coutton 5,  Marie Christou-Kent 4,  Guillaume Martinez 5,  Nicolas Landrein 6,  Pauline Le Tanno 4,  Selima Fourati Ben Mustapha 7,  Lazhar Halouani 7,  Ouafi Marrakchi 7,  Mounir Makni 7,  Habib Latrous 7,  Mahmoud Kharouf 7,  Karin Pernet-Gallay 8,  Hamid Gourabi 9,  Derrick R Robinson 6,  Serge Crouzy 10,  Michael Blum 11,  Nicolas Thierry-Mieg 11,  Aminata Touré 12,  Raoudha Zouari 7,  Christophe Arnoult 4,  Mélanie Bonhivers 6,  Pierre F Ray 13
Affiliations

Affiliations

  • 1 Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, INSERM U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble 38000, France; Centre Hospitalier Universitaire de Grenoble, UM GI-DPI, Grenoble 38000, France.
  • 2 Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, INSERM U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble 38000, France; Centre Hospitalier Universitaire de Grenoble, UM GI-DPI, Grenoble 38000, France; Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, Academic Center for Education, Culture, and Research, PO Box 16635-148, Tehran, Iran.
  • 3 University Bordeaux, Microbiologie Fondamentale et Pathogénicité, CNRS UMR 5234, Bordeaux, France; Institut Polytechnique de Bordeaux, Microbiologie Fondamentale et Pathogénicité, CNRS UMR 5234, Bordeaux, France.
  • 4 Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, INSERM U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble 38000, France.
  • 5 Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, INSERM U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble 38000, France; Centre Hospitalier Universitaire de Grenoble, UM de Génétique Chromosomique, Grenoble 38000, France.
  • 6 University Bordeaux, Microbiologie Fondamentale et Pathogénicité, CNRS UMR 5234, Bordeaux, France.
  • 7 Polyclinique les Jasmins, Centre d'Aide Médicale à la Procréation, Centre Urbain Nord, 1003 Tunis, Tunisia.
  • 8 Grenoble Neuroscience Institute, INSERM 1216, Grenoble 38000, France.
  • 9 Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, Academic Center for Education, Culture, and Research, PO Box 16635-148, Tehran, Iran.
  • 10 Laboratoire de Chimie et Biologie des Métaux, Institut de Recherche en Technologie et Sciences pour le Vivant, CEA iRTSV/LCBM/GMCT, CNRS UMR 5249, Université Grenoble Alpes, Grenoble 38054, Cedex 9, France.
  • 11 Université Grenoble Alpes, CNRS, TIMC-IMAG, Grenoble 38000, France.
  • 12 INSERM U1016, Institut Cochin, Paris 75014, France; CNRS UMR 8104, Paris 75014, France; Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris 75014, France.
  • 13 Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, INSERM U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble 38000, France; Centre Hospitalier Universitaire de Grenoble, UM GI-DPI, Grenoble 38000, France. Electronic address: [email protected].
PMID: 30122540 DOI: 10.1016/j.ajhg.2018.07.014
Abstract

Multiple morphological abnormalities of the sperm flagellum (MMAF) is a severe form of male infertility defined by the presence of a mosaic of anomalies, including short, bent, curled, thick, or absent flagella, resulting from a severe disorganization of the axoneme and of the peri-axonemal structures. Mutations in DNAH1, CFAP43, and CFAP44, three genes encoding axoneme-related proteins, have been described to account for approximately 30% of the MMAF cases reported so far. Here, we searched for pathological copy-number variants in whole-exome sequencing data from a cohort of 78 MMAF-affected subjects to identify additional genes associated with MMAF. In 7 of 78 affected individuals, we identified a homozygous deletion that removes the two penultimate exons of WDR66 (also named CFAP251), a gene coding for an axonemal protein preferentially localized in the testis and described to localize to the calmodulin- and spoke-associated complex at the base of radial spoke 3. Sequence analysis of the breakpoint region revealed in all deleted subjects the presence of a single chimeric SVA (SINE-VNTR-Alu) at the breakpoint site, suggesting that the initial deletion event was potentially mediated by an SVA insertion-recombination mechanism. Study of Trypanosoma WDR66's ortholog (TbWDR66) highlighted high sequence and structural analogy with the human protein and confirmed axonemal localization of the protein. Reproduction of the human deletion in TbWDR66 impaired flagellar movement, thus confirming WDR66 as a gene associated with the MMAF phenotype and highlighting the importance of the WDR66 C-terminal region.

Keywords

MMAF; axoneme; male infertility; multiple morphological anomalies of the sperm flagella; sperm flagella; spermatogenesis.

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