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

Open Biol. 2016 Oct;6(10):160109. doi: 10.1098/rsob.160109.

Paul Laissue ¹ ² ³, Besma Lakhal ⁴, Magalie Vatin ¹ ², Frank Batista ⁵, Gaëtan Burgio ⁶ ⁷, Eric Mercier ⁸, Esther Dos Santos ⁹ ¹⁰, Christophe Buffat ¹¹, Diana Carolina Sierra-Diaz ³, Gilles Renault ¹ ², Xavier Montagutelli ⁶, Jane Salmon ¹², Philippe Monget ¹³, Reiner A Veitia ¹ ², Céline Méhats ¹ ², Marc Fellous ¹ ², Jean-Christophe Gris ⁸, Julie Cocquet ¹ ², Daniel Vaiman ¹⁴ ²

Affiliations

1 Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France.
2 Inserm, U1016 Paris, France.
3 Centro de Investigación en Genética y Genómica-CIGGUR, Grupo GENIUROS, Escuela de Medicina y Ciencias de la Salud, Universidad del Rosario, Bogotá, Colombia.
4 Department of Cytogenetics and Reproductive Biology, Farhat Hached University Teaching Hospital, Sousse, Tunisia.
5 Department of Cell Biology, Albert Einstein College of Medicine, New York, NY 10461, USA.
6 Institut Pasteur, Unité de Génétique des Mammifères, Paris, France.
7 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.
8 Department of Haematology, University Hospital, Nîmes. Faculty of Pharmacy and Research Team EA 2992, University of Montpellier, Montpellier, France.
9 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.
10 Service de Biologie Médicale, Centre Hospitalier de Poissy-Saint-Germain, 78300 Poissy, France.
11 Centre National de la Recherche Scientifique UMR 7278, IRD198, INSERM U1095, Aix-Marseille Université, Marseille, France.
12 Department of Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA.
13 INRA-CNRS, Université de Tours-Haras Nationaux, IFR 135, 37380 Nouzilly, France.
14 Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France [email protected].

PMID: 27805902 DOI: 10.1098/rsob.160109

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.

Keywords

implantation; interspecific recombinant congenic mice; recurrent spontaneous abortion.

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