SPINK2 deficiency causes infertility by inducing sperm defects in heterozygotes and azoospermia in homozygotes.
SPINK2 deficiency causes infertility by inducing sperm defects in heterozygotes and azoospermia in homozygotes.
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DOI：
10.15252/emmm.201607461
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发表时间：
2017-08
影响因子：
11.1
通讯作者：
Arnoult C
中科院分区：
文献类型：
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作者：
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
无精子症是男性不育的常见原因，其特征在于射精中没有精子。两个无精子症兄弟的外显子组测序分析允许鉴定SPINK2中的纯合剪接突变，编码丝氨酸蛋白酶抑制剂，据信靶向顶体蛋白酶，主要的精子顶体蛋白酶。与这些发现雅阁，我们观察到纯合子Spink 2 KO雄性小鼠具有无精子症。此外，尽管生育能力正常，杂合子雄性小鼠的精子形态异常率高，精子活力降低。进一步的分析表明，在Spink2不存在的情况下，蛋白酶诱导的应激启动高尔基体片段化并阻止顶体生物发生，导致精子细胞分化停滞。我们还观察到顶体酶过表达在HEK细胞中的有害作用，SPINK2共表达可减轻这种作用，证实其作为顶体酶抑制剂的作用。这些结果表明，SPINK 2是必要的，以中和蛋白酶在其细胞转运向顶体和它的缺陷引起的病理连续性，从寡弱畸形精子症的杂合子无精子症的纯合子。
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.