Association of FOXD1 variants with adverse pregnancy outcomes in mice and humans
Association of FOXD1 variants with adverse pregnancy outcomes in mice and humans
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DOI：
10.1098/rsob.160109
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发表时间：
2016-10-01
期刊：
影响因子：
5.8
通讯作者：
Vaiman, Daniel
中科院分区：
文献类型：
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作者：
Laissue, Paul;Lakhal, Besma;Vaiman, Daniel
复发性自然流产（RSA）是不孕症的常见原因，但以前试图确定RSA致病基因相对不成功。这种未能描述RSA病因基因的原因可能是，生殖表型应被视为数量性状，由众多的遗传，表观遗传和环境因素的复杂相互作用。在这里，我们研究了来自C57 BL 6/J小鼠品系的小家鼠种间重组同类系（IRCS），该品系携带来自小家鼠小鼠（66 H-MMU 13品系）13号染色体的约5 Mb DNA片段，具有高胚胎吸收率（ER）。对这些小鼠子宫内膜和胎盘组织的转录组分析显示，与凝血和炎症反应途径相关的许多基因失调。生物信息学方法使我们选择Foxd 1作为可能与ER和RSA相关的候选基因。对66 H-MMU 13株、556例RSA患者和271例对照组的Foxd 1基因进行测序分析，发现存在非同义序列变异。体外试验表明，一些导致扰动FOXD 1的反式激活特性的基因启动子具有关键作用，在植入/胎盘，这表明该基因在哺乳动物植入过程中的作用。
Recurrent spontaneous abortion (RSA) is a common cause of infertility, but previous attempts at identifying RSA causative genes have been relatively unsuccessful. Such failure to describe RSAaetiological genes might be explained by the fact that reproductive phenotypes should be considered as quantitative traits resulting from the intricate interaction of numerous genetic, epigenetic and environmental factors. Here, we studied an interspecific recombinant congenic strain (IRCS) of Mus musculus from the C57BL6/J strain of mice harbouring an approximate 5 Mb DNA fragment from chromosome 13 from Mus spretus mice (66H-MMU13 strain), with a high rate of embryonic resorption (ER). Transcriptome analyses of endometrial and placental tissues from these mice showed a deregulation of many genes associated with the coagulation and inflammatory response pathways. Bioinformatics approaches led us to select Foxd1 as a candidate gene potentially related to ER and RSA. Sequencing analysis of Foxd1 in the 66H-MMU13 strain, and in 556women affected by RSA and 271 controls revealed non-synonymous sequence variants. In vitro assays revealed that some led to perturbations in FOXD1 transactivation properties on promoters of genes having key roles during implantation/placentation, suggesting a role of this gene in mammalian implantation processes.