Faculty of Medical and Health Sciences, University of Auckland, Auckland, Private Bag 92019, New Zealand.
BMC Med Genet. 2012 May 30;13:42. doi: 10.1186/1471-2350-13-42.
Insulin like growth factor 2 (IGF2) is an imprinted gene, which has an important role in fetal growth as established in mice models. IGF2 is downregulated through hypomethylation of a differentially methylated region (DMR) in Silver Russell syndrome (SRS), characterised by growth restriction. We have previously reported that severe pre- and post-natal growth restriction associated with insulin resistance and precocious pubarche in a woman without body asymmetry or other SRS features resulted from a balanced translocation affecting the regulation of her IGF2 gene expression. We hypothesised that severe pre- and post-natal growth restriction associated with insulin resistance and precocious pubarche in the absence of SRS are also caused by downregulation of IGF2 through hypomethylation, gene mutation or structural chromosomal abnormalities.
We performed routine karyotyping, IGF2 gene sequencing and investigated DNA methylation of the IGF2 differentially methylated region (DMR)0 and H19 DMR using pyrosequencing, in four women selected for very low birth weight (<-3 SDS for gestational age), precocious pubarche, short adult stature (<-2 SDS), and insulin resistance (defined as HOMA-IS < 80%); and compared their methylation results to those of 95 control subjects.
We identified a 20 year old woman with severe hypomethylation at both DMRs. She was the smallest at birth (birthweight SDS,-3.9), and had the shortest adult height (143 cm). The patient was diagnosed with polycystic ovarian syndrome at the age of 15 years, and had impaired fasting glucose in the presence of a low BMI (19.2 kg/m2).
Our case of growth restriction, premature pubarche and insulin resistance in the absence of body asymmetry or other features of SRS adds to the expanding phenotype of IGF2/H19 methylation abnormalities. Further studies are needed to confirm whether growth restriction in association with premature pubarche and insulin resistance is a specific manifestation of reduced IGF2 expression.
胰岛素样生长因子 2（IGF2）是一种印迹基因，在小鼠模型中已被证实对胎儿生长具有重要作用。Silver Russell 综合征（SRS）中 IGF2 的下调是通过差异甲基化区域（DMR）的低甲基化实现的，其特征是生长受限。我们之前曾报道过，一名女性表现为胰岛素抵抗和性早熟，同时伴有严重的产前和产后生长受限，无身体不对称或其他 SRS 特征，这是由影响 IGF2 基因表达调控的平衡易位引起的。我们假设，在没有 SRS 的情况下，与胰岛素抵抗和性早熟相关的严重产前和产后生长受限也是由于 IGF2 的下调引起的，其原因可能是低甲基化、基因突变或结构性染色体异常。
我们选择了 4 名出生体重极低（< 胎龄 -3 SDS）、性早熟、成年身高矮小（<-2 SDS）和胰岛素抵抗（定义为 HOMA-IS < 80%）的女性进行常规核型分析、IGF2 基因测序，并使用焦磷酸测序法研究 IGF2 差异甲基化区域（DMR）0 和 H19 DMR 的 DNA 甲基化情况。我们将这些患者的甲基化结果与 95 名对照组进行了比较。
我们发现一名 20 岁的女性在两个 DMR 均出现严重的低甲基化。她出生时体重最小（体重 SDS，-3.9），成年身高最矮（143cm）。该患者在 15 岁时被诊断为多囊卵巢综合征，存在空腹血糖受损，同时 BMI 较低（19.2kg/m2）。
我们报道的这名患者存在生长受限、性早熟和胰岛素抵抗，但无身体不对称或其他 SRS 特征，这增加了 IGF2/H19 甲基化异常的扩展表型。需要进一步的研究来证实与性早熟和胰岛素抵抗相关的生长受限是否是 IGF2 表达减少的特定表现。
Zotero 插件