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

BMC Medical Genetics

Jörg Tost³  Andrew Hattersley⁴  Lourdes Ibáñez¹  Rinki Murphy² 

[1] Endocrinology Unit, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Madrid, Spain;Faculty of Medical and Health Sciences, University of Auckland, Auckland, Private Bag 92019, New Zealand;Laboratory for Epigenetics, Centre National de Génotypage, CEA-Institut de Génomique, Evry, France;Institute of Biomedical and Clinical Sciences, Peninsula Medical School, Exeter, UK

关键词: Insulin resistance;    Short stature;    Intrauterine growth restriction;    Insulin like growth factor 2;   

Others  :  1177853
DOI  :  10.1186/1471-2350-13-42

 received in 2011-12-15, accepted in 2012-05-08,  发布年份 2012

【 摘 要 】

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.

【 授权许可】

   
2012 Murphy et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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