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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
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Published in EMBO Molecular Medicine. 2017, vol. 9, no. 8, p. 1132-1149
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.
PMID: 28554943
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Article (Published version) (3.1 MB) - document accessible for UNIGE members only Limited access to UNIGE
Research groups Abus de substances (834)
Mécanismes moléculaires et génétiques du développement sexuel (778)
FNS: 31003a-173070/1
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KHERRAF, Zine-Eddine et al. SPINK2 deficiency causes infertility by inducing sperm defects in heterozygotes and azoospermia in homozygotes. In: EMBO Molecular Medicine, 2017, vol. 9, n° 8, p. 1132-1149. doi: 10.15252/emmm.201607461 https://archive-ouverte.unige.ch/unige:99219

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Deposited on : 2017-11-17

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