SPINK2 deficiency causes infertility by inducing sperm defects in heterozygotes and azoospermia in homozygotes
Abstract 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 SPINK2, encoding a serin...
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| Format: | Article |
| Language: | English |
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Springer Nature
2017-08-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201607461 |
| _version_ | 1797279842876522496 |
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| author | Zine‐Eddine Kherraf Marie Christou‐Kent Thomas Karaouzene Amir Amiri‐Yekta Guillaume Martinez Alexandra S Vargas Emeline Lambert Christelle Borel Béatrice Dorphin Isabelle Aknin‐Seifer Michael J Mitchell Catherine Metzler‐Guillemain Jessica Escoffier Serge Nef Mariane Grepillat Nicolas Thierry‐Mieg Véronique Satre Marc Bailly Florence Boitrelle Karin Pernet‐Gallay Sylviane Hennebicq Julien Fauré Serge P Bottari Charles Coutton Pierre F Ray Christophe Arnoult |
| author_facet | Zine‐Eddine Kherraf Marie Christou‐Kent Thomas Karaouzene Amir Amiri‐Yekta Guillaume Martinez Alexandra S Vargas Emeline Lambert Christelle Borel Béatrice Dorphin Isabelle Aknin‐Seifer Michael J Mitchell Catherine Metzler‐Guillemain Jessica Escoffier Serge Nef Mariane Grepillat Nicolas Thierry‐Mieg Véronique Satre Marc Bailly Florence Boitrelle Karin Pernet‐Gallay Sylviane Hennebicq Julien Fauré Serge P Bottari Charles Coutton Pierre F Ray Christophe Arnoult |
| author_sort | Zine‐Eddine Kherraf |
| collection | DOAJ |
| description | Abstract 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 SPINK2, encoding a serine protease inhibitor believed to target acrosin, the main sperm acrosomal protease. In accord with these findings, we observed that homozygous Spink2 KO 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 HEK cells, effect that was alleviated by SPINK2 coexpression confirming its role as acrosin inhibitor. These results demonstrate that SPINK2 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. |
| first_indexed | 2024-03-07T16:31:49Z |
| format | Article |
| id | doaj.art-acfdace776ce4e4b925803c814b43c54 |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T16:31:49Z |
| publishDate | 2017-08-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-acfdace776ce4e4b925803c814b43c542024-03-03T10:18:27ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842017-08-01981132114910.15252/emmm.201607461SPINK2 deficiency causes infertility by inducing sperm defects in heterozygotes and azoospermia in homozygotesZine‐Eddine Kherraf0Marie Christou‐Kent1Thomas Karaouzene2Amir Amiri‐Yekta3Guillaume Martinez4Alexandra S Vargas5Emeline Lambert6Christelle Borel7Béatrice Dorphin8Isabelle Aknin‐Seifer9Michael J Mitchell10Catherine Metzler‐Guillemain11Jessica Escoffier12Serge Nef13Mariane Grepillat14Nicolas Thierry‐Mieg15Véronique Satre16Marc Bailly17Florence Boitrelle18Karin Pernet‐Gallay19Sylviane Hennebicq20Julien Fauré21Serge P Bottari22Charles Coutton23Pierre F Ray24Christophe Arnoult25Genetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble FranceGenetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble FranceGenetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble FranceGenetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble FranceGenetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble FranceGenetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble FranceGenetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble FranceDepartment of Genetic Medicine and Development University of Geneva Medical School Geneva 4 SwitzerlandLaboratoire d'Aide Médicale à la Procréation Centre AMP 74 Contamine‐sur‐Arve FranceLaboratoire de Biologie de la Reproduction Hôpital Nord Saint Etienne FranceAix Marseille Univ INSERM GMGF Marseille FranceAix Marseille Univ INSERM GMGF Marseille FranceGenetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble FranceDepartment of Genetic Medicine and Development University of Geneva Medical School Geneva 4 SwitzerlandGenetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble FranceUniv. Grenoble Alpes / CNRS TIMC‐IMAG Grenoble FranceGenetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble FranceDepartment of Reproductive Biology and Gynaecology Poissy General Hospital Poissy FranceDepartment of Reproductive Biology and Gynaecology Poissy General Hospital Poissy FranceGrenoble Neuroscience Institute INSERM 1216 Grenoble FranceGenetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble FranceCHU de Grenoble UF de Biochimie Génétique et Moléculaire Grenoble FranceGenetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble FranceGenetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble FranceGenetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble FranceGenetic Epigenetic and Therapies of Infertility Institute for Advanced Biosciences Inserm U1209, CNRS UMR 5309 Université Grenoble Alpes Grenoble FranceAbstract 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 SPINK2, encoding a serine protease inhibitor believed to target acrosin, the main sperm acrosomal protease. In accord with these findings, we observed that homozygous Spink2 KO 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 HEK cells, effect that was alleviated by SPINK2 coexpression confirming its role as acrosin inhibitor. These results demonstrate that SPINK2 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.https://doi.org/10.15252/emmm.201607461azoospermiaexome sequencinggeneticsinfertilityspermatogenesis |
| spellingShingle | Zine‐Eddine Kherraf Marie Christou‐Kent Thomas Karaouzene Amir Amiri‐Yekta Guillaume Martinez Alexandra S Vargas Emeline Lambert Christelle Borel Béatrice Dorphin Isabelle Aknin‐Seifer Michael J Mitchell Catherine Metzler‐Guillemain Jessica Escoffier Serge Nef Mariane Grepillat Nicolas Thierry‐Mieg Véronique Satre Marc Bailly Florence Boitrelle Karin Pernet‐Gallay Sylviane Hennebicq Julien Fauré Serge P Bottari Charles Coutton Pierre F Ray Christophe Arnoult SPINK2 deficiency causes infertility by inducing sperm defects in heterozygotes and azoospermia in homozygotes EMBO Molecular Medicine azoospermia exome sequencing genetics infertility spermatogenesis |
| title | SPINK2 deficiency causes infertility by inducing sperm defects in heterozygotes and azoospermia in homozygotes |
| title_full | SPINK2 deficiency causes infertility by inducing sperm defects in heterozygotes and azoospermia in homozygotes |
| title_fullStr | SPINK2 deficiency causes infertility by inducing sperm defects in heterozygotes and azoospermia in homozygotes |
| title_full_unstemmed | SPINK2 deficiency causes infertility by inducing sperm defects in heterozygotes and azoospermia in homozygotes |
| title_short | SPINK2 deficiency causes infertility by inducing sperm defects in heterozygotes and azoospermia in homozygotes |
| title_sort | spink2 deficiency causes infertility by inducing sperm defects in heterozygotes and azoospermia in homozygotes |
| topic | azoospermia exome sequencing genetics infertility spermatogenesis |
| url | https://doi.org/10.15252/emmm.201607461 |
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