Dosage effects of ZP2 and ZP3 heterozygous mutations cause human infertility
Dosage effects of ZP2 and ZP3 heterozygous mutations cause human infertility
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ZP2和ZP3杂合突变导致人类不育的剂量效应
DOI：
10.1007/s00439-017-1822-7
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发表时间：
2017-08-01
期刊：
影响因子：
5.3
通讯作者：
Gao, Shaorong
中科院分区：
文献类型：
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作者：
Liu, Wenqiang;Li, Kunming;Gao, Shaorong
透明带(ZP)是广泛存在于哺乳动物卵子周围的一种细胞外基质，对卵子发生、受精和着床前胚胎发育至关重要。在这里，我们发现了两个新的ZP和ZP3可遗传突变，都发生在一名ZP异常卵子不育的女性患者中。用CRISPR/Cas9基因编辑系统建立了相同突变的小鼠模型，其中任何一个杂合子突变的雌性小鼠卵母细胞的ZP厚度约为野生型卵母细胞的一半。重要的是，根据患者的家系，具有这两种杂合突变的卵母细胞显示出更薄的甚至缺失的ZP，这无法避免多精子受精。进一步分析证实，突变的ZP2或ZP3产生的前体蛋白不能锚定到卵母细胞膜上。由此，我们得出结论，ZP突变具有剂量效应，可导致人类女性不孕。最后，这位患者接受了卵胞浆内单精子注射(ICSI)和改进的培养系统的治疗，并成功地生下了一个健康的婴儿。
The zona pellucida (ZP) is an extracellular matrix universally surrounding mammalian eggs, which is essential for oogenesis, fertilization, and pre-implantation embryo development. Here, we identified two novel heritable mutations ofZP2andZP3, both occurring in an infertile female patient with ZP-abnormal eggs. Mouse models with the same mutations were generated by CRISPR/Cas9 gene editing system, and oocytes obtained from female mice with either single heterozygous mutation showed approximately half of the normal ZP thickness compared to wild-type oocytes. Importantly, oocytes with both heterozygous mutations showed a much thinner or even missing ZP that could not avoid polyspermy fertilization, following the patient’s pedigree. Further analysis confirmed that precursor proteins produced from either mutated ZP2 or ZP3 could not anchor to oocyte membranes. From these, we conclude thatZPmutations have dosage effects which can cause female infertility in humans. Finally, this patient was treated by intracytoplasmic sperm injection (ICSI) with an improved culture system and successfully delivered a healthy baby.