2. Academic Validation
  3. Mutations in DNAH17, Encoding a Sperm-Specific Axonemal Outer Dynein Arm Heavy Chain, Cause Isolated Male Infertility Due to Asthenozoospermia

Mutations in DNAH17, Encoding a Sperm-Specific Axonemal Outer Dynein Arm Heavy Chain, Cause Isolated Male Infertility Due to Asthenozoospermia

  • Am J Hum Genet. 2019 Jul 3;105(1):198-212. doi: 10.1016/j.ajhg.2019.04.015.
Marjorie Whitfield 1,  Lucie Thomas 2,  Emilie Bequignon 3,  Alain Schmitt 1,  Laurence Stouvenel 1,  Guy Montantin 4,  Sylvie Tissier 4,  Philippe Duquesnoy 2,  Bruno Copin 4,  Sandra Chantot 4,  Florence Dastot 4,  Catherine Faucon 5,  Anne Laure Barbotin 6,  Anne Loyens 7,  Jean-Pierre Siffroi 8,  Jean-François Papon 9,  Estelle Escudier 8,  Serge Amselem 8,  Valérie Mitchell 6,  Aminata Touré 10,  Marie Legendre 8
Affiliations

Affiliations

  • 1 Institut National de la Santé et de la Recherche Médicale U1016, Institut Cochin, Paris 75014, France; Centre National de la Recherche Scientifique UMR8104, Paris 75014, France; Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France.
  • 2 Sorbonne Université, Institut National de la Santé et de la Recherche Médicale U933, Hôpital Trousseau, Paris 75012, France.
  • 3 Assistance Publique-Hôpitaux de Paris, Hôpital Henri Mondor et Centre Hospitalier Intercommunal de Créteil, Service d'Oto-Rhino-Laryngologie et de Chirurgie Cervico-Faciale, Créteil 94000, France; Institut National de la Santé et de la Recherche Médicale U955, Centre National de la Recherche Scientifique, Equipe de Recherche Labellisée 7240, Université Paris-Est, Faculté de Médecine, Créteil 94010, France.
  • 4 Assistance Publique-Hôpitaux de Paris, Département de Génétique Médicale, Hôpital Trousseau, Paris 75012, France.
  • 5 Centre Hospitalier Intercommunal de Créteil, Laboratoire de Microscopie Électronique, Service d'Anatomopathologie, Créteil 94010, France.
  • 6 Centre Hospitalier Universitaire de Lille, Reproductive Biology - Spermiology - Centres d'Etudes et de Conservation des Oeufs et du Sperme Institute, Jeanne de Flandre Hospital, F-59000 Lille, France; EA4308: Gametogenesis and Gamete Quality, Lille University, F-59000 Lille, France.
  • 7 Jean-Pierre Aubert Research Center, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Institut National de la Santé et de la Recherche Médicale U1172, Lille University, F59000 Lille, France.
  • 8 Sorbonne Université, Institut National de la Santé et de la Recherche Médicale U933, Hôpital Trousseau, Paris 75012, France; Assistance Publique-Hôpitaux de Paris, Département de Génétique Médicale, Hôpital Trousseau, Paris 75012, France.
  • 9 Institut National de la Santé et de la Recherche Médicale U955, Centre National de la Recherche Scientifique, Equipe de Recherche Labellisée 7240, Université Paris-Sud, Faculté de Médecine, Créteil 94010, France; Assistance Publique-Hôpitaux de Paris, Service d'Oto-Rhino-Laryngologie et de Chirurgie Cervico-Faciale, Hôpital Bicêtre, Le Kremlin-Bicêtre F-94275, France.
  • 10 Institut National de la Santé et de la Recherche Médicale U1016, Institut Cochin, Paris 75014, France; Centre National de la Recherche Scientifique UMR8104, Paris 75014, France; Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France. Electronic address: [email protected].
PMID: 31178125 DOI: 10.1016/j.ajhg.2019.04.015
Abstract

Motile cilia and sperm flagella share an evolutionarily conserved axonemal structure. Their structural and/or functional defects are associated with primary ciliary dyskinesia (PCD), a genetic disease characterized by chronic respiratory-tract infections and in which most males are infertile due to asthenozoospermia. Among the well-characterized axonemal protein complexes, the outer dynein arms (ODAs), through ATPase activity of their heavy chains (HCs), play a major role for cilia and flagella beating. However, the contribution of the different HCs (γ-type: DNAH5 and DNAH8 and β-type: DNAH9, DNAH11, and DNAH17) in ODAs from both organelles is unknown. By analyzing five male individuals who consulted for isolated infertility and displayed a loss of ODAs in their sperm cells but not in their respiratory cells, we identified bi-allelic mutations in DNAH17. The isolated infertility phenotype prompted us to compare the protein composition of ODAs in the sperm and ciliary axonemes from control individuals. We show that DNAH17 and DNAH8, but not DNAH5, DNAH9, or DNAH11, colocalize with α-tubulin along the sperm axoneme, whereas the reverse picture is observed in respiratory cilia, thus explaining the phenotype restricted to sperm cells. We also demonstrate the loss of function associated with DNAH17 mutations in two unrelated individuals by performing immunoblot and immunofluorescence analyses on sperm cells; these analyses indicated the absence of DNAH17 and DNAH8, whereas DNAH2 and DNALI, two inner dynein arm components, were present. Overall, this study demonstrates that mutations in DNAH17 are responsible for isolated male infertility and provides information regarding ODA composition in human spermatozoa.

Keywords

DNAH17; ODA; PCD; axoneme; cilia; dynein; male infertility; sperm flagellum.

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