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人类新遗传疾

2019-03-28 13:58:34     来源:中新网     责任编辑:刘欣

人类新的孟德尔遗传病、糖基化疾病及离子通道疾病——“卵子死亡”被中国科学家发现并命名。

上海交通大学医学院附属第九人民医院匡延平团队与复旦大学桑庆、王磊团队合作研究揭示了PANX1突变致病机制,同时提供了首个深入研究PANX1病理学功能的鼠模型。

3月28日,这一重要研究成果发表于《科学》(Science)杂志子刊《科学-转化医学》(Science Translational Medicine)。

据介绍,研究人员历时15年,在4个独立家系中,发现了细胞连接蛋白家族成员PANX1存在不同的突变,并通过细胞水平、爪蟾卵子、鼠模型等多个角度深入揭示了致病机制:突变通过影响蛋白糖基化、激活通道、加速ATP释放,致表型出现,从而证明了卵子死亡是一种全新的孟德尔遗传病及糖基化疾病,也是PANX家族成员异常的首个离子通道疾病。

细胞之间的连接与交流是生物有机体维持正常生理功能的必要环节。联接蛋白(Connexin)与通道蛋白(Pannexin)家族是形成细胞之间连接的重要离子通道,它们控制的信号通路在细胞正常生理作用中发挥关键的作用。Connexin (Cx)家族包括21个成员,其中一些成员发生突变已被发现引起诸多疾病。

Pannnexin(PANX)家族由三个成员PANX1, 2, 3组成。迄今尚未发现任何疾病由此三个成员突变导致。PANX1在2003年被克隆, 随后的10余年间,大量研究报道其与炎症、感染、局部缺血等生理病理学过程有关,但是,PANX1敲除鼠没有明显异常:敲除鼠可育,也不存在其他器官的异常。这些证据似乎又表明PANX1并不重要。

2003年,匡延平教授在临床试管婴儿术中发现了一个奇特的病例:患者取卵数、卵子形态及体外受精均正常,但受精第二天后,所有胚胎均出现发黑、萎缩、退化的现象。随后又陆续发现了一个具有相似表型的家族性患者(家系2)及一例具有更严重表型的散发患者:卵子取出后,未受精即表现为发黑、萎缩、退化(家系3)。当时,无医学文献报道过此疾病,也无人描述过,此疾病的致病原因及机制不得而知。

2015年,匡延平团队与桑庆、王磊团队着手开展研究。期间,西北妇女儿童医院生殖中心的师娟子教授也发现了一例类似的家族性患者(家系1)。当时,研究团队将此疾病命名为“卵子死亡”。

通过3年多的联合攻关,研究人员在四个独立家系中发现了PANX1存在不同的突变,此疾病符合孟德尔显性遗传特点,明确“卵子死亡”是一种新的孟德尔遗传病。

PANX1为糖基化蛋白,随后的细胞及卵子的系列功能实验证明:突变会改变PANX1的糖基化模式,被改变的糖基化模式与疾病密切相关,表明卵子死亡亦属于一种新的糖基化疾病。

通过对体外鼠卵子、爪蟾卵子研究显示:突变引起PANX1通道异常激活,加速了卵子内部ATP释放,导致疾病出现。试验中,四个PANX1点突变鼠的生育力均正常且无明显表型,而PANX1在人卵中的表达却显著高于鼠卵,研究人员推测这可能是突变鼠无表型的原因。于是进一步制作了在卵子特异表达的野生型及突变型PANX1过表达鼠模型。突变鼠模型表现为不孕,且准确模拟出了卵子死亡的表型。

专家认为,这项研究扩展了对人类孟德尔疾病的认知;揭示了人类卵子及早期胚胎发育中隐藏着大量前所未知的新基因;同时,也为相关患者的遗传咨询及实现辅助生殖中的精准医学实践奠定了基础。

据悉,桑庆副研究员、匡延平教授、王磊教授为本论文通讯作者。复旦生物医学研究院博士研究生张治华、西北妇女儿童医院师娟子教授,复旦大学附属妇产科医院孙晓溪教授、上海九院辅助生殖科李斌、闫铮博士为共同第一作者。中科院神经所竺淑佳团队,孙强研究员亦参与了此项研究。

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