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.
Highlights
Human infertility represents a public health concern affecting 10–15% of all couples [1]
We showed that the 66H-MMU13 interspecific recombinant congenic strain (IRCS) strain is affected by a high embryonic resorption (ER) rate (14.7% versus 4.6% observed in C57BL/6 J females, p, 0.01)
5 Mb DNA fragment located on chromosome 13 that is of Mus spretus origin in the 66HMMU13)
Summary
Human infertility represents a public health concern affecting 10–15% of all couples [1]. Some genetic markers indicative of an elevated risk of being affected by RSA have been proposed, functional evidence is rare This has restricted their efficient use in clinical studies. Genome-wide scan-based studies have been reported, they have not reached the classical accepted statistical threshold for significance and have apparently failed to identify specific genes [12,13]. Such failure to identify RSA aetiological genes might be explained by the fact that reproduction’s inherent complexity theoretically implies that mutations in hundreds of candidate genes may be responsible for the phenotype [10,14]. Compared with genetic analysis of ovarian infertility, which allowed discovery of interesting genes [15,16], pertinent candidates genes were seldom found when the infertility was linked to placental/endometrial defects, such as RSA [14]
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