Genetic disruption of the oncogenic HMGA2–PLAG1–IGF2 pathway causes fetal growth restriction

• Published in: Genetics in medicine Vol. 20; no. 2; pp. 250 - 258
• Main Authors: Abi Habib, Walid, Brioude, Frédéric, Edouard, Thomas, Bennett, James T, Lienhardt-Roussie, Anne, Tixier, Frédérique, Salem, Jennifer, Yuen, Tony, Azzi, Salah, Le Bouc, Yves, Harbison, Madeleine D, Netchine, Irène
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2018; Elsevier Limited; Nature Publishing Group
• Subjects: 631/208/2489/1381; 631/208/2489/144; 692/700/1720/3186; Biomedical and Life Sciences; Biomedicine; Cell Line; Development Biology; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Embryology and Organogenesis; Epigenesis, Genetic; Facies; Female; Fetal Growth Retardation - diagnosis; Fetal Growth Retardation - genetics; Fetal Growth Retardation - metabolism; Gene Expression Regulation, Developmental; Genes; Genetic Association Studies; Genetic counseling; Genetic Predisposition to Disease; Genetic Variation; Genetics; Genotype; Growth Charts; HMGA2 Protein - genetics; HMGA2 Protein - metabolism; Human Genetics; Humans; Insulin-Like Growth Factor II - genetics; Insulin-Like Growth Factor II - metabolism; Laboratory Medicine; Life Sciences; Models, Biological; Mutation; Original; original-research-article; Pedigree; Physical growth; Prenatal development; Signal Transduction; Silver-Russell Syndrome - diagnosis; Silver-Russell Syndrome - genetics; Silver-Russell Syndrome - metabolism; Whole Genome Sequencing; IGF2; HMGA2; Silver–Russell syndrome; fetal growth restriction; PLAG1
• ISSN: 1098-3600; 1530-0366; 1530-0366
• DOI: 10.1038/gim.2017.105

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.