Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, Paris, France.
Service d'Explorations Fonctionnelles Endocriniennes, AP-HP, Hôpital Trousseau, Paris, France.
Genet Med. 2018 Feb;20(2):250-258. doi: 10.1038/gim.2017.105. Epub 2017 Aug 10.
PurposeFetal 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.MethodsWhole-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.ResultsWe 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.ConclusionGenetic 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.
目的
胎儿生长是一个涉及母体、胎盘和胎儿因素的复杂过程。在许多情况下，胎儿生长迟缓的病因仍不清楚。本研究的目的是鉴定与 Silver-Russell 综合征（SRS）相关的新人类突变和基因，SRS 是一种胎儿生长迟缓的综合征形式，通常是由强效胎儿生长因子 IGF2 的表观遗传下调引起的。
方法
对一个 SRS 家族病例的成员进行全外显子组测序。在一个疑似 SRS 患者的大队列中，通过靶向高通量测序筛选来自家族病例和另外两个基因的候选基因。然后进行功能实验将这些基因关联到一个调控途径中。
结果
我们报告了人类 PLAG1 基因的第一个突变，以及六个散发的和/或家族性 SRS 病例中 HMGA2 和 IGF2 的新突变。我们证明 HMGA2 通过 PLAG1 并以 PLAG1 独立的方式调节 IGF2 的表达。
结论
HMGA2-PLAG1-IGF2 途径的遗传缺陷可导致胎儿和出生后生长受限，突出了该致癌途径在生理胎儿/出生后生长精细调节中的作用。这项工作定义了 SRS 的新遗传原因，对遗传咨询很重要。
