IGF2/H19 hypomethylation in a patient with very low birthweight, preocious pubarche and insulin resistance

Abstract

Background: 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.

Methods: 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.

Results: 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).

Conclusions: 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.

Figure 1

A Structural characteristics of the humanIGF2/ H19 locus with nine exons and five exons for IGF2 and H19 genes respectively. Transcription start site and promoters used are indicated by arrows. Regions of differentially methylated regions (DMRs) are shown with black bars. For each DMR, the number of CpGs analysed is indicated and their relative positions are represented by filled stars corresponding to the methylation site horizontal axis of Figure 1B. B Graph of methylation patterns of the IGF2/H19 locus (expressed as percentage for each CpG) for each case and mean with 95% confidence interval for the 95 control samples.