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SPINK2 deficiency causes infertility by inducing sperm defects in heterozygotes and azoospermia in homozygotes
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 proteas...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538632/ https://www.ncbi.nlm.nih.gov/pubmed/28554943 http://dx.doi.org/10.15252/emmm.201607461 |
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author | Kherraf, Zine‐Eddine Christou‐Kent, Marie Karaouzene, Thomas Amiri‐Yekta, Amir Martinez, Guillaume Vargas, Alexandra S Lambert, Emeline Borel, Christelle Dorphin, Béatrice Aknin‐Seifer, Isabelle Mitchell, Michael J Metzler‐Guillemain, Catherine Escoffier, Jessica Nef, Serge Grepillat, Mariane Thierry‐Mieg, Nicolas Satre, Véronique Bailly, Marc Boitrelle, Florence Pernet‐Gallay, Karin Hennebicq, Sylviane Fauré, Julien Bottari, Serge P Coutton, Charles Ray, Pierre F Arnoult, Christophe |
author_facet | Kherraf, Zine‐Eddine Christou‐Kent, Marie Karaouzene, Thomas Amiri‐Yekta, Amir Martinez, Guillaume Vargas, Alexandra S Lambert, Emeline Borel, Christelle Dorphin, Béatrice Aknin‐Seifer, Isabelle Mitchell, Michael J Metzler‐Guillemain, Catherine Escoffier, Jessica Nef, Serge Grepillat, Mariane Thierry‐Mieg, Nicolas Satre, Véronique Bailly, Marc Boitrelle, Florence Pernet‐Gallay, Karin Hennebicq, Sylviane Fauré, Julien Bottari, Serge P Coutton, Charles Ray, Pierre F Arnoult, Christophe |
author_sort | Kherraf, Zine‐Eddine |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5538632 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-55386322017-08-04 SPINK2 deficiency causes infertility by inducing sperm defects in heterozygotes and azoospermia in homozygotes Kherraf, Zine‐Eddine Christou‐Kent, Marie Karaouzene, Thomas Amiri‐Yekta, Amir Martinez, Guillaume Vargas, Alexandra S Lambert, Emeline Borel, Christelle Dorphin, Béatrice Aknin‐Seifer, Isabelle Mitchell, Michael J Metzler‐Guillemain, Catherine Escoffier, Jessica Nef, Serge Grepillat, Mariane Thierry‐Mieg, Nicolas Satre, Véronique Bailly, Marc Boitrelle, Florence Pernet‐Gallay, Karin Hennebicq, Sylviane Fauré, Julien Bottari, Serge P Coutton, Charles Ray, Pierre F Arnoult, Christophe EMBO Mol Med Research Articles 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. John Wiley and Sons Inc. 2017-05-29 2017-08 /pmc/articles/PMC5538632/ /pubmed/28554943 http://dx.doi.org/10.15252/emmm.201607461 Text en © 2017 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the Creative Commons Attribution 4.0 (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Articles Kherraf, Zine‐Eddine Christou‐Kent, Marie Karaouzene, Thomas Amiri‐Yekta, Amir Martinez, Guillaume Vargas, Alexandra S Lambert, Emeline Borel, Christelle Dorphin, Béatrice Aknin‐Seifer, Isabelle Mitchell, Michael J Metzler‐Guillemain, Catherine Escoffier, Jessica Nef, Serge Grepillat, Mariane Thierry‐Mieg, Nicolas Satre, Véronique Bailly, Marc Boitrelle, Florence Pernet‐Gallay, Karin Hennebicq, Sylviane Fauré, Julien Bottari, Serge P Coutton, Charles Ray, Pierre F Arnoult, Christophe SPINK2 deficiency causes infertility by inducing sperm defects in heterozygotes and azoospermia in homozygotes |
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 | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538632/ https://www.ncbi.nlm.nih.gov/pubmed/28554943 http://dx.doi.org/10.15252/emmm.201607461 |
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