SPINK2 deficiency causes infertility by inducing sperm defects in heterozygotes and azoospermia in homozygotes

• DOI: 10.15252/emmm.201607461
• Publication Date: 2017-05-30T00:10:34Z
• 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‐Se...; Michael J Mitchell; Catherine Metzler...; 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
• Keywords: Male; 570; Medicine (General); Heterozygote; 610; Urogenital System; [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics; Gene Therapy & Genetic Disease; QH426-470; Mice; 03 medical and health sciences; R5-920; Genetics; Animals; ddc:576.5; genetics; spermatogenesis Subject Categories Genetics; Research Articles; Azoospermia; Glycoproteins; Mice, Knockout; 0303 health sciences; Serine Peptidase Inhibitors, Kazal Type; azoospermia; Homozygote; spermatogenesis; Disease Models, Animal; [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics; Asthenozoospermia; infertility; exome sequencing

AbstractAzoospermia, 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.