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 |
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| Authors: | 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 |
| Source: | EMBO Molecular Medicine, Vol 9, Iss 8, Pp 1132-1149 (2017) |
| Publisher Information: | Springer Nature, 2017. |
| Publication Year: | 2017 |
| Collection: | LCC:Medicine (General) LCC:Genetics |
| Subject Terms: | azoospermia, exome sequencing, genetics, infertility, spermatogenesis, Medicine (General), R5-920, Genetics, QH426-470 |
| More Details: | 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. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 1757-4676 1757-4684 |
| Relation: | https://doaj.org/toc/1757-4676; https://doaj.org/toc/1757-4684 |
| DOI: | 10.15252/emmm.201607461 |
| Access URL: | https://doaj.org/article/acfdace776ce4e4b925803c814b43c54 |
| Accession Number: | edsdoj.fdace776ce4e4b925803c814b43c54 |
| Database: | Directory of Open Access Journals |
| ISSN: | 17574676 17574684 |
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| DOI: | 10.15252/emmm.201607461 |
| Published in: | EMBO Molecular Medicine |
| Language: | English |