A pannexin 1 channelopathy causes human oocyte death
A pannexin 1 channelopathy causes human oocyte death
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pannexin 1 通道病导致人类卵母细胞死亡
DOI：
10.1126/scitranslmed.aav8731
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发表时间：
2019-03-27
影响因子：
17.1
通讯作者：
Wang, Lei
中科院分区：
文献类型：
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作者：
Sang, Qing;Zhang, Zhihua;Wang, Lei
PANX1 的遗传性显性突变会导致女性不孕，其特征是卵母细胞死亡。卵母细胞的重要基因 不孕症在男性和女性中都很常见，但女性不孕症的生物学原因尚不清楚。桑等人。确定了四个患有遗传性女性不孕症的家庭，并且具有相似的表型，即在受精前或受精后不久在体外出现卵母细胞死亡。作者发现这种表型是由 pannexin 1 突变引起的，pannexin 1 是一种参与细胞通讯的通道蛋白。作者研究了与这些突变相关的发病机制，并表明患者衍生的突变在小鼠模型中引起相同的卵母细胞死亡模式，为治疗开发提供了可能的目标。连接蛋白和泛连接蛋白是在细胞通讯中发挥重要作用的两个蛋白质家族。 Pannexin 1 (PANX1) 是 Pannexin 家族的成员之一，是一种通道蛋白。它被糖基化并形成三个物种：GLY0、GLY1 和 GLY2。在这里，我们描述了四个独立的家族，其中 PANX1 突变通过我们称之为“卵母细胞死亡”的表型导致家族性或散发性女性不孕。这些与卵母细胞死亡相关的突变会改变 PANX1 糖基化模式，影响培养细胞中 PANX1 的亚细胞定位，并导致异常的 PANX1 通道活性、卵母细胞中的 ATP 释放和突变的 PANX1 GLY1。小鼠中患者来源的突变过度表达会导致不孕，重现人类卵母细胞死亡表型。我们的研究结果证明了 PANX1 在人类卵母细胞发育中的关键作用，为不孕不育亚型提供了遗传学解释，并提出了该疾病治疗干预的潜在目标。
Inherited dominant mutations in PANX1 cause female infertility characterized by oocyte death. A vital gene for oocytes Infertility is common in both males and females, but the biological causes of female infertility are not as well understood. Sang et al. identified four families with inherited female infertility and a similar phenotype that presents with oocyte death in vitro, either before or shortly after fertilization. The authors found that this phenotype was caused by mutations in pannexin 1, a channel protein involved in cellular communication. The authors examined the mechanism of pathogenesis associated with these mutations and showed that a patient-derived mutation causes the same pattern of oocyte death in a mouse model, providing a possible target for therapeutic development. Connexins and pannexins are two protein families that play an important role in cellular communication. Pannexin 1 (PANX1), one of the members of pannexin family, is a channel protein. It is glycosylated and forms three species, GLY0, GLY1, and GLY2. Here, we describe four independent families in which mutations in PANX1 cause familial or sporadic female infertility via a phenotype that we term “oocyte death.” The mutations, which are associated with oocyte death, alter the PANX1 glycosylation pattern, influence the subcellular localization of PANX1 in cultured cells, and result in aberrant PANX1 channel activity, ATP release in oocytes, and mutant PANX1 GLY1. Overexpression of a patient-derived mutation in mice causes infertility, recapitulating the human oocyte death phenotype. Our findings demonstrate the critical role of PANX1 in human oocyte development, provide a genetic explanation for a subtype of infertility, and suggest a potential target for therapeutic intervention for this disease.