BackgroundHuman reproductive disorders consist of frequently occurring dysfunctions including a broad range of phenotypes affecting fertility and women’s health during pregnancy. Several female-related diseases have been associated with hypofertility/infertility phenotypes, such as recurrent pregnancy loss (RPL). Other occurring diseases may be life-threatening for the mother and foetus, such as preeclampsia (PE) and intra-uterine growth restriction (IUGR). FOXD1 was defined as a major molecule involved in embryo implantation in mice and humans by regulating endometrial/placental genes. FOXD1 mutations in human species have been functionally linked to RPL’s origin.MethodsFOXD1 gene mutation screening, in 158 patients affected by PE, IUGR, RPL and repeated implantation failure (RIF), by direct sequencing and bioinformatics analysis. Plasmid constructs including FOXD1 mutations were used to perform in vitro gene reporter assays.ResultsNine non-synonymous sequence variants were identified. Functional experiments revealed that p.His267Tyr and p.Arg57del led to disturbances of promoter transcriptional activity (C3 and PlGF genes). The FOXD1 p.Ala356Gly and p.Ile364Met deleterious mutations (previously found in RPL patients) have been identified in the present work in women suffering PE and IUGR.ConclusionsOur results argue in favour of FOXD1 mutations’ central role in RPL, RIF, IUGR and PE pathogenesis via C3 and PlGF regulation and they describe, for the first time, a functional link between FOXD1 and implantation/placental diseases. FOXD1 could therefore be used in clinical environments as a molecular biomarker for these diseases in the near future.KeywordsRecurrent pregnancy loss, Preeclampsia, Intra-uterine growth restriction, FOXD1

中文翻译：

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FOXD1突变与反复着床失败、宫内生长受限和先兆子痫有关

背景人类生殖障碍包括频繁发生的功能障碍，包括影响生育能力和怀孕期间妇女健康的广泛表型。一些女性相关疾病与低生育力/不孕症表型有关，例如复发性流产 (RPL)。其他发生的疾病可能危及母亲和胎儿的生命，例如先兆子痫 (PE) 和宫内生长受限 (IUGR)。FOXD1 被定义为通过调节子宫内膜/胎盘基因参与小鼠和人类胚胎植入的主要分子。人类物种中的FOXD1突变与RPL的起源在功能上相关。方法通过直接测序和生物信息学分析，对158例PE、IUGR、RPL和重复植入失败(RIF)患者进行FOXD1基因突变筛查。使用包含 FOXD1 突变的质粒构建体进行体外基因报告基因检测。结果鉴定了九个非同义序列变体。功能实验表明 p.His267Tyr 和 p.Arg57del 导致启动子转录活性（C3 和 PlGF 基因）的干扰。FOXD1 p.Ala356Gly 和 p.Ile364Met 有害突变（以前在 RPL 患者中发现）已在目前患有 PE 和 IUGR 的女性中发现。结论我们的结果支持 FOXD1 突变在 RPL、RIF、IUGR 和通过 C3 和 PlGF 调节的 PE 发病机制，他们首次描述了 FOXD1 与植入/胎盘疾病之间的功能联系。因此，在不久的将来，FOXD1 可以在临床环境中用作这些疾病的分子生物标志物。