Association of FOXD1 variants with adverse pregnancy outcomes in mice and humans

Abstract

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.

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

“…The control group for Colombian patients consisted of 203 women (from the same ethnical origin) over 50 years-old having had at least one live birth child without antecedents of medical complications during pregnancy and lacking hypertensive disorders. Regarding the French controls, we used data previously reported by our group (Laissue et al, 2016). In that study, FOXD1 was sequenced in 271 French controls lacking antecedents of obstetrical disorders.…”

“…A series of studies using a genetic mouse model of interspecific congenic strains allowed us to map quantitative trait loci (QTL) related to embryo resorption (a phenotype analogous to RPL in humans) to short chromosome regions (Laissue et al, 2016, 2009; Vatin et al, 2012). One of these regions was found to contain FOXD1 , encoding a forkhead transcription factor, shown to be involved in the regulation of embryo implantation in mice (Laissue et al, 2016, 2009; Quintero-Ronderos and Laissue, 2018). The mouse Foxd1-Thr152Ala variant (carried naturally by the Musspretus species), when expressed in the C57BL/6 J genetic background, was associated to embryo resorption and massive deregulation of the expression of placental and endometrial genes (Laissue et al, 2016).…”

“…One of these regions was found to contain FOXD1 , encoding a forkhead transcription factor, shown to be involved in the regulation of embryo implantation in mice (Laissue et al, 2016, 2009; Quintero-Ronderos and Laissue, 2018). The mouse Foxd1-Thr152Ala variant (carried naturally by the Musspretus species), when expressed in the C57BL/6 J genetic background, was associated to embryo resorption and massive deregulation of the expression of placental and endometrial genes (Laissue et al, 2016). FOXD1 mutations in humans have now been functionally linked to RPL’s origin, thereby constituting a diagnostically useful molecular biomarker (Laissue et al, 2016; Quintero-Ronderos and Laissue, 2018).…”

Novel genes and mutations in patients affected by recurrent pregnancy loss

“…Some studies using a particular congenic mouse model (the interspecific recombinant congenic strains-IRCS model), leading to QTL identification, have reported small chromosomal loci containing a limited number of candidate genes related to embryonic resorption, a phenotype analogous to human RPL [ 15 – 18 ]. More recently, a functional association between FOXD1 mutations and RPL has been described [ 19 ].…”

Analysis of C3 gene variants in patients with idiopathic, recurrent, spontaneous pregnancy loss

“…In humans, C3 levels was shown to be higher in patients suffering three consecutive miscarriages, compared with women who went on having a live birth after two miscarriages (16). In vitro data also suggest that mutations in FOXD1, a transcription factor that directly seems to target C3, leading to both decreased and increased C3 expression, were deleterious (17). Genetic variants in the C3 gene have also been reported to be associated with severe preeclampsia (18).…”