FOXD1 mutations are related to repeated implantation failure, intra-uterine growth restriction and preeclampsia

Abstract

Background Human 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. Methods FOXD1 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. Results Nine 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. Conclusions Our 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. Keywords Recurrent pregnancy loss, Preeclampsia, Intra-uterine growth restriction, FOXD1 Electronic supplementary material The online version of this article (10.1186/s10020-019-0104-3) contains supplementary material, which is available to authorized users.

Smoking and Smoking Cessation in the Risk for Fetal Growth Restriction and Low Birth Weight and Additive Effect of Maternal Obesity

“…The mechanisms of the relationships found (between smoking in the first trimester and the risk of birth weight <10th percentile, LBW, and FGR) are not fully understood. The main factors affecting fetal growth include the placenta, which guarantees the flow of nutrients to the fetus [14][15][16]. Factors causing hypoxia and reductions of blood flow in the placenta may increase the risk of FGR, SGA, and LBW [2,7].…”

“…Fetal growth restriction (FGR) was diagnosed based on ultrasound in pregnancy (all cases were recorded, regardless of phenotype) [14][15][16]. FGR was defined as the fetus' inability to reach its full growth potential and was diagnosed based on ultrasound in pregnancy.…”

“…The effect of multi-direction impacts of different components of cigarette smoke on complex multi-factor processes associated with the fetal growth are difficult to assess [12,13]. In addition to genetic factors, the main factors affecting fetal growth include the placenta, which guarantees the flow of nutrients to the fetus [14][15][16], as well as the mother's nutritional status [13] and environmental factors [14]. Blood flow reductions in placenta, placental ischemia, hypoxia, and intensified oxidative stress and inflammation have been identified as key elements of pathogenesis of adverse fetal outcomes.…”

Whole-Exome Sequencing in Patients Affected by Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Reveals New Variants Potentially Contributing to the Phenotype

“…It has been established that creating gene subsets from WES for studying unrelated patients on a large genomic scale is a powerful strategy for identifying new genes and mutations related to complex polygenic phenotypes. [19][20][21][22] Three subsets (AE, PH and TF) were created in this study, forming the starting point for filtering candidate sequence variants regarding different genomic and pathophysiology hypotheses. We consider that the PH category contains a comprehensive collection of genes that have been well-documented concerning drug metabolism, some of which are available for commercial/diagnostic purposes (eg, ABCB1, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2D6, CYP3A4, UGT1A1, SLC47A2, D2 and HTR2A).…”

“…A previous study using this methodology identified FOXD1 as a major gene involved in the regulation of embryo implantation in mice and various reproductive disorders in humans. 20,25 Variant filtering assumed that rare (MAF <1%) nonsynonymous variants in AE, PH and/or TF subsets (underlining potential moderate/drastic functional effects) might contribute towards the origin of SJS-TEN. Indeed, it has been demonstrated that using NGS for studying extreme phenotypes facilitates mapping rare sequence variants contributing to complex traits' origins.…”