• PMID: 28554943
• Gene Name: SPINK2
• Condition: Azoospermia
• Association: Associated
• Mutation: c.56?3C>G
• Population size: 2
• Population details: 2
• Sex: Male
• Infertility type: Male infertility
• Associated genes: NGS

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

Kherraf ZE, Christou-Kent M, Karaouzene T, Amiri-Yekta A, Martinez G, Vargas AS, Lambert E, Borel C, Dorphin B, Aknin-Seifer I, Mitchell MJ, Metzler-Guillemain C, Escoffier J, Nef S, Grepillat M, Thierry-Mieg N, Satre V, Bailly M, Boitrelle F, Pernet-Gallay K, Hennebicq S, Fauré J, Bottari SP, Coutton C, Ray PF, Arnoult C.

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. CI - © 2017 The Authors. Published under the terms of the CC BY 4.0 license. FAU - Kherraf, Zine-Eddine AU - Kherraf ZE AD - Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, Inserm U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France. FAU - Christou-Kent, Marie AU - Christou-Kent M AD - Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, Inserm U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France. FAU - Karaouzene, Thomas AU - Karaouzene T AD - Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, Inserm U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France. FAU - Amiri-Yekta, Amir AU - Amiri-Yekta A AD - Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, Inserm U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France. AD - CHU de Grenoble, UF de Biochimie Génétique et Moléculaire, Grenoble, France. AD - Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran. FAU - Martinez, Guillaume AU - Martinez G AD - Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, Inserm U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France. FAU - Vargas, Alexandra S AU - Vargas AS AD - Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, Inserm U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France. FAU - Lambert, Emeline AU - Lambert E AD - Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, Inserm U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France. FAU - Borel, Christelle AU - Borel C AD - Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva 4, Switzerland. FAU - Dorphin, Béatrice AU - Dorphin B AD - Laboratoire d'Aide Médicale à la Procréation, Centre AMP 74, Contamine-sur-Arve, France. FAU - Aknin-Seifer, Isabelle AU - Aknin-Seifer I AD - Laboratoire de Biologie de la Reproduction, Hôpital Nord, Saint Etienne, France. FAU - Mitchell, Michael J AU - Mitchell MJ AD - Aix Marseille Univ INSERM GMGF, Marseille, France. FAU - Metzler-Guillemain, Catherine AU - Metzler-Guillemain C AD - Aix Marseille Univ INSERM GMGF, Marseille, France. FAU - Escoffier, Jessica AU - Escoffier J AD - Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, Inserm U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France. FAU - Nef, Serge AU - Nef S AD - Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva 4, Switzerland. FAU - Grepillat, Mariane AU - Grepillat M AD - Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, Inserm U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France. FAU - Thierry-Mieg, Nicolas AU - Thierry-Mieg N AD - Univ. Grenoble Alpes / CNRS, TIMC-IMAG, Grenoble, France. FAU - Satre, Véronique AU - Satre V AD - Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, Inserm U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France. AD - CHU de Grenoble, UF de Génétique Chromosomique, Grenoble, France. FAU - Bailly, Marc AU - Bailly M AD - Department of Reproductive Biology and Gynaecology, Poissy General Hospital, Poissy, France. AD - EA 7404 GIG, Université de Versailles Saint Quentin Montigny le Bretonneux, France. FAU - Boitrelle, Florence AU - Boitrelle F AD - Department of Reproductive Biology and Gynaecology, Poissy General Hospital, Poissy, France. AD - EA 7404 GIG, Université de Versailles Saint Quentin Montigny le Bretonneux, France. FAU - Pernet-Gallay, Karin AU - Pernet-Gallay K AD - Grenoble Neuroscience Institute, INSERM 1216, Grenoble, France. FAU - Hennebicq, Sylviane AU - Hennebicq S AD - Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, Inserm U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France. AD - CHU de Grenoble, UF de Biologie de la procréation, Grenoble, France. FAU - Fauré, Julien AU - Fauré J AD - CHU de Grenoble, UF de Biochimie Génétique et Moléculaire, Grenoble, France. AD - Grenoble Neuroscience Institute, INSERM 1216, Grenoble, France. FAU - Bottari, Serge P AU - Bottari SP AD - Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, Inserm U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France. AD - CHU de Grenoble, UF de Radioanalyses, Grenoble, France. FAU - Coutton, Charles AU - Coutton C AD - Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, Inserm U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France. AD - CHU de Grenoble, UF de Génétique Chromosomique, Grenoble, France. FAU - Ray, Pierre F AU - Ray PF AUID- ORCID: 0000-0003-1544-7449 AD - Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, Inserm U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France pray@chu-grenoble.fr. AD - CHU de Grenoble, UF de Biochimie Génétique et Moléculaire, Grenoble, France.