Association of FOXD1 variants with adverse pregnancy outcomes in mice and humans.
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.
Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France.|Inserm, U1016 Paris, France.|Centro de Investigación en Genética y Genómica-CIGGUR, Grupo GENIUROS, Escuela de Medicina y Ciencias de la Salud, Universidad del Rosario, Bogotá, Colombia.
Paul
P
Laissue
Department of Cytogenetics and Reproductive Biology, Farhat Hached University Teaching Hospital, Sousse, Tunisia.
Besma
B
Lakhal
Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France.|Inserm, U1016 Paris, France.
Magalie
M
Vatin
Department of Cell Biology, Albert Einstein College of Medicine, New York, NY 10461, USA.
Frank
F
Batista
Institut Pasteur, Unité de Génétique des Mammifères, Paris, France.|Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, the Australian National University, 131 Garran Road, Canberra 2601, Australian Capital Territory, Australia.
Gaëtan
G
Burgio
Department of Haematology, University Hospital, Nîmes. Faculty of Pharmacy and Research Team EA 2992, University of Montpellier, Montpellier, France.
Eric
E
Mercier
GIG-EA 7404, Université de Versailles-Saint Quentin en Yvelines, Unité de Formation et de Recherche des Sciences de la Santé Simone Veil, 78180 Montigny-le-Bretonneux, France.|Service de Biologie Médicale, Centre Hospitalier de Poissy-Saint-Germain, 78300 Poissy, France.
Esther Dos
ED
Santos
Centre National de la Recherche Scientifique UMR 7278, IRD198, INSERM U1095, Aix-Marseille Université, Marseille, France.
Christophe
C
Buffat
Centro de Investigación en Genética y Genómica-CIGGUR, Grupo GENIUROS, Escuela de Medicina y Ciencias de la Salud, Universidad del Rosario, Bogotá, Colombia.
Diana Carolina
DC
Sierra-Diaz
Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France.|Inserm, U1016 Paris, France.
Gilles
G
Renault
Institut Pasteur, Unité de Génétique des Mammifères, Paris, France.
Xavier
X
Montagutelli
Department of Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA.
Jane
J
Salmon
INRA-CNRS, Université de Tours-Haras Nationaux, IFR 135, 37380 Nouzilly, France.
Philippe
P
Monget
Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France.|Inserm, U1016 Paris, France.
Reiner A
RA
Veitia
Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France.|Inserm, U1016 Paris, France.
Céline
C
Méhats
Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France.|Inserm, U1016 Paris, France.
Marc
M
Fellous
Department of Haematology, University Hospital, Nîmes. Faculty of Pharmacy and Research Team EA 2992, University of Montpellier, Montpellier, France.
Jean-Christophe
JC
Gris
Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France.|Inserm, U1016 Paris, France.
Julie
J
Cocquet
Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France daniel.vaiman@inserm.fr.|Inserm, U1016 Paris, France.
Daniel
0000-0002-1915-0717
D
Vaiman
D000022:Abortion, Spontaneous / Q000235:genetics*; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D020964:Embryo Loss / Q000235:genetics* / Q000662:veterinary; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics*; D020869:Gene Expression Profiling / Q000379:methods; D056726:Genetic Association Studies; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010920:Placenta / Q000737:chemistry; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D014599:Uterus / Q000737:chemistry
C500800:FOXD1 protein, human; D051858:Forkhead Transcription Factors; C489562:Foxd1 protein, mouse
implantation; interspecific recombinant congenic mice; recurrent spontaneous abortion