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<scp>SPINK</scp>2 deficiency causes infertility by inducing sperm defects in heterozygotes and azoospermia in homozygotes
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- Zine‐Eddine Kherraf
- Genetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble France
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- Marie Christou‐Kent
- Genetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble France
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- Thomas Karaouzene
- Genetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble France
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- Amir Amiri‐Yekta
- Genetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble France
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- Guillaume Martinez
- Genetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble France
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- Alexandra S Vargas
- Genetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble France
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- Emeline Lambert
- Genetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble France
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- Christelle Borel
- Department of Genetic Medicine and Development University of Geneva Medical School Geneva 4 Switzerland
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- Béatrice Dorphin
- Laboratoire d'Aide Médicale à la Procréation Centre AMP 74 Contamine‐sur‐Arve France
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- Isabelle Aknin‐Seifer
- Laboratoire de Biologie de la Reproduction Hôpital Nord Saint Etienne France
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- Michael J Mitchell
- Aix Marseille Univ INSERM GMGF Marseille France
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- Catherine Metzler‐Guillemain
- Aix Marseille Univ INSERM GMGF Marseille France
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- Jessica Escoffier
- Genetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble France
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- Serge Nef
- Department of Genetic Medicine and Development University of Geneva Medical School Geneva 4 Switzerland
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- Mariane Grepillat
- Genetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble France
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- Nicolas Thierry‐Mieg
- Univ. Grenoble Alpes / CNRS TIMC‐IMAG Grenoble France
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- Véronique Satre
- Genetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble France
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- Marc Bailly
- Department of Reproductive Biology and Gynaecology Poissy General Hospital Poissy France
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- Florence Boitrelle
- Department of Reproductive Biology and Gynaecology Poissy General Hospital Poissy France
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- Karin Pernet‐Gallay
- Grenoble Neuroscience Institute INSERM 1216 Grenoble France
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- Sylviane Hennebicq
- Genetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble France
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- Julien Fauré
- CHU de Grenoble UF de Biochimie Génétique et Moléculaire Grenoble France
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- Serge P Bottari
- Genetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble France
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- Charles Coutton
- Genetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble France
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- Pierre F Ray
- Genetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble France
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- 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
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- EMBO Molecular Medicine
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EMBO Molecular Medicine 9 (8), 1132-1149, 2017-05-29
Springer Science and Business Media LLC
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Details 詳細情報について
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- CRID
- 1363670320786538368
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- ISSN
- 17574684
- 17574676
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- Data Source
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- Crossref