Abstract
BackgroundInsulin 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.MethodsWe 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.ResultsWe 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).ConclusionsOur 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.
Highlights
Insulin like growth factor 2 (IGF2) is an imprinted gene, which has an important role in fetal growth as established in mice models
Aberrant imprinting of the IGF2/H19 locus on chromosome 11p15.5 has a crucial role in Beckwith-Wiedemann syndrome (BWS, OMIM #130650) [1], Silver-Russell syndrome (SRS, OMIM#180860) [2,3] and several human cancers [4,5]
The H19 differentially methylated region (DMR) locus is known as the imprinting control region (ICR) of the IGF2-H19 locus because it is the centre from where methylation on the paternal allele is propagated, including the IGF2 DMR0, H19 promoter DMR, in addition to containing the recognition sites for CCCTC binding factor (CTCF)
Summary
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 caused by downregulation of IGF2 through hypomethylation, gene mutation or structural chromosomal abnormalities. Paternal IGF2 and maternal H19 expression in humans, correlates with the close regulation in mice, by two differentially methylated regions (DMRs).
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