<scp>SPINK</scp>2 deficiency causes infertility by inducing sperm defects in heterozygotes and azoospermia in homozygotes

  • Zine‐Eddine Kherraf
    Genetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble France
  • Marie Christou‐Kent
    Genetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble France
  • Thomas Karaouzene
    Genetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble France
  • Amir Amiri‐Yekta
    Genetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble France
  • Guillaume Martinez
    Genetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble France
  • Alexandra S Vargas
    Genetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble France
  • Emeline Lambert
    Genetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble France
  • Christelle Borel
    Department of Genetic Medicine and Development University of Geneva Medical School Geneva 4 Switzerland
  • Béatrice Dorphin
    Laboratoire d'Aide Médicale à la Procréation Centre AMP 74 Contamine‐sur‐Arve France
  • Isabelle Aknin‐Seifer
    Laboratoire de Biologie de la Reproduction Hôpital Nord Saint Etienne France
  • Michael J Mitchell
    Aix Marseille Univ INSERM GMGF Marseille France
  • Catherine Metzler‐Guillemain
    Aix Marseille Univ INSERM GMGF Marseille France
  • Jessica Escoffier
    Genetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble France
  • Serge Nef
    Department of Genetic Medicine and Development University of Geneva Medical School Geneva 4 Switzerland
  • Mariane Grepillat
    Genetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble France
  • Nicolas Thierry‐Mieg
    Univ. Grenoble Alpes / CNRS TIMC‐IMAG Grenoble France
  • Véronique Satre
    Genetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble France
  • Marc Bailly
    Department of Reproductive Biology and Gynaecology Poissy General Hospital Poissy France
  • Florence Boitrelle
    Department of Reproductive Biology and Gynaecology Poissy General Hospital Poissy France
  • Karin Pernet‐Gallay
    Grenoble Neuroscience Institute INSERM 1216 Grenoble France
  • Sylviane Hennebicq
    Genetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble France
  • Julien Fauré
    CHU de Grenoble UF de Biochimie Génétique et Moléculaire Grenoble France
  • Serge P Bottari
    Genetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble France
  • Charles Coutton
    Genetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble France
  • Pierre F Ray
    Genetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble France
  • Christophe Arnoult
    Genetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble France

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Description

<jats:title>Abstract</jats:title><jats:p>Azoospermia, characterized by the absence of spermatozoa in the ejaculate, is a common cause of male infertility with a poorly characterized etiology. Exome sequencing analysis of two azoospermic brothers allowed the identification of a homozygous splice mutation in <jats:italic><jats:styled-content style="fixed-case">SPINK</jats:styled-content>2,</jats:italic> encoding a serine protease inhibitor believed to target acrosin, the main sperm acrosomal protease. In accord with these findings, we observed that homozygous <jats:italic>Spink2 </jats:italic><jats:styled-content style="fixed-case">KO</jats:styled-content> male mice had azoospermia. Moreover, despite normal fertility, heterozygous male mice had a high rate of morphologically abnormal spermatozoa and a reduced sperm motility. Further analysis demonstrated that in the absence of Spink2, protease‐induced stress initiates Golgi fragmentation and prevents acrosome biogenesis leading to spermatid differentiation arrest. We also observed a deleterious effect of acrosin overexpression in <jats:styled-content style="fixed-case">HEK</jats:styled-content> cells, effect that was alleviated by <jats:styled-content style="fixed-case">SPINK</jats:styled-content>2 coexpression confirming its role as acrosin inhibitor. These results demonstrate that <jats:styled-content style="fixed-case">SPINK</jats:styled-content>2 is necessary to neutralize proteases during their cellular transit toward the acrosome and that its deficiency induces a pathological continuum ranging from oligoasthenoteratozoospermia in heterozygotes to azoospermia in homozygotes.</jats:p>

Journal

  • EMBO Molecular Medicine

    EMBO Molecular Medicine 9 (8), 1132-1149, 2017-05-29

    Springer Science and Business Media LLC

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