Laissue Paul, Lakhal Besma, Vatin Magalie, Batista Frank, Burgio Gaëtan, Mercier Eric, Santos Esther Dos, Buffat Christophe, Sierra-Diaz Diana Carolina, Renault Gilles, Montagutelli Xavier, Salmon Jane, Monget Philippe, Veitia Reiner A, Méhats Céline, Fellous Marc, Gris Jean-Christophe, Cocquet Julie, Vaiman Daniel
Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France.
Inserm, U1016 Paris, France.
Open Biol. 2016 Oct;6(10). doi: 10.1098/rsob.160109.
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 RSA aetiological 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 556 women 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.
复发性自然流产（RSA）是导致不孕的常见原因，但以往在鉴定RSA致病基因方面的尝试相对不太成功。未能描述RSA病因基因可能是因为生殖表型应被视为由众多遗传、表观遗传和环境因素复杂相互作用产生的数量性状。在此，我们研究了一种小家鼠的种间重组近交系（IRCS），它来自C57BL6/J品系小鼠，携带来自西班牙小鼠（66H-MMU13品系）13号染色体上约5 Mb的DNA片段，具有较高的胚胎吸收（ER）率。对这些小鼠的子宫内膜和胎盘组织进行转录组分析，结果显示许多与凝血和炎症反应途径相关的基因表达失调。生物信息学方法使我们选择Foxd1作为可能与ER和RSA相关的候选基因。对66H-MMU13品系以及556名受RSA影响的女性和271名对照者的Foxd1进行测序分析，发现了非同义序列变异。体外试验表明，其中一些变异导致FOXD1对在着床/胎盘形成过程中起关键作用的基因启动子的反式激活特性受到干扰，这表明该基因在哺乳动物着床过程中发挥作用。
