@article{f59ee85217264d24b5adf3087d9268b6,
title = "Genetic disruption of the oncogenic HMGA2-PLAG1-IGF2 pathway causes fetal growth restriction",
abstract = "Purpose: Fetal growth is a complex process involving maternal, placental and fetal factors. The etiology of fetal growth retardation remains unknown in many cases. The aim of this study is to identify novel human mutations and genes related to Silver-Russell syndrome (SRS), a syndromic form of fetal growth retardation, usually caused by epigenetic downregulation of the potent fetal growth factor IGF2. Methods: Whole-exome sequencing was carried out on members of an SRS familial case. The candidate gene from the familial case and two other genes were screened by targeted high-Throughput sequencing in a large cohort of suspected SRS patients. Functional experiments were then used to link these genes into a regulatory pathway. Results: We report the first mutations of the PLAG1 gene in humans, as well as new mutations in HMGA2 and IGF2 in six sporadic and/or familial cases of SRS. We demonstrate that HMGA2 regulates IGF2 expression through PLAG1 and in a PLAG1-independent manner. Conclusion: Genetic defects of the HMGA2-PLAG1-IGF2 pathway can lead to fetal and postnatal growth restriction, highlighting the role of this oncogenic pathway in the fine regulation of physiological fetal/postnatal growth. This work defines new genetic causes of SRS, important for genetic counseling.",
keywords = "Fetal growth restriction, HMGA2, IGF2, PLAG1, Silver-russell syndrome",
author = "Habib, {Walid Abi} and Fr{\'e}d{\'e}ric Brioude and Thomas Edouard and Bennett, {James T.} and Anne Lienhardt-Roussie and Fr{\'e}d{\'e}rique Tixier and Jennifer Salem and Tony Yuen and Salah Azzi and {Le Bouc}, Yves and Harbison, {Madeleine D.} and Ir{\`e}ne Netchine",
note = "Funding Information: This work was supported by the Institut National de la Sant{\'e} et de la Recherche M{\'e}dicale, funding from the Universit{\'e} Pierre et Marie Curie (UPMC-Paris6), the Agence Nationale de la Recherche (ANR EPIFEGRO 2010) and from the “Association Fran{\c c}aises des Familles ayant un enfant atteint du Syndrome Silver Russell ou n{\'e} Petit pour l'Age Gestationnel (AFIF/PAG)”. W.A.H. was supported by the People Programme Marie Curie Actions (MCA) of the European Union{\textquoteright}s Seventh Framework Programme FP7/ITN Ingenium 2007– 2013/ under REA grant agreement no. 290123 and by the Soci{\'e}t{\'e} Fran{\c c}aise d{\textquoteright}Endocrinologie et Diab{\'e}tologie P{\'e}diatrique. F.B. was supported by a Novonordisk “Growth Hormone, Growth and Metabolism” grant. J.T.B. is supported by a Pediatric Early Research Career Award from Seattle Children{\textquoteright}s Research Institute. We received funding from the Fondation des Maladies Rares (France) for exome sequencing in the familial case. We thank the patients, their families, and their physicians (Jeanne Languepin, Marie-Pierre Cordier, and Noel Peretti), and the MAGIC Foundation, for their support. We also thank Fran{\c c}oise Praz from the Saint Antoine Research Centre (INSERM_U938) for kindly providing the Hep3B cell line for the silencing assays and Sandra Chantot-Bastaraud for performing the SNP arrays for the familial case. In addition, we are grateful to Laurence Perin for performing IGF2 determinations on patients{\textquoteright} serum, and Nathalie Thibaut, Cristina Das Neves, Marilyne le Jule and Evelyne Tagodoe, the diagnostic technicians of the Pediatric Endocrinology Department, Trousseau Pediatric Hospital. W.A.H., I.N., and Y.L.B. are members of the European Union{\textquoteright}s Seventh Framework Programme FP7/ITN Ingenium 2007–2013. F.B. and I.N. are members of the EUCID.net network COST (BM1208).",
year = "2018",
month = feb,
day = "1",
doi = "10.1038/gim.2017.105",
language = "English",
volume = "20",
pages = "250--258",
journal = "Genetics in Medicine",
issn = "1098-3600",
publisher = "Elsevier B.V.",
number = "2",
}