Epigenetic Analysis of the IGF2/H19 locus in the NESTEGGG Small for Gestational Age Population

Lead Research Organisation: Queen Mary, University of London
Department Name: Unlisted

Abstract

Amongst low birth weight babies there is a subgroup with certain clinical features that are defined as Silver-Russell syndrome. Recent work elsewhere has shown there to be abnormalities in specific modifications to the DNA in the IGF-2 gene in a proportion of SRS patients. This so-called ‘epigenetic‘ modification results in reduced production of the IGF-2 growth factor which thus provides an explanation for the syndrome. Independently of this work the Endocrine Centre has led the collection of ~1500 families with one or more children born with low birth weight and/or failure of childhood growth (the NESTEGG study). The Fellow will investigate the frequency of epigenetic abnormalities of the IGF-2 gene in SRS and non-SRS patients in NESTEGG, and will further examine whether other causes of reduced production or action of IGF-2 contribute to this syndrome, or to low birth weight in general.

Technical Summary

Small for gestational age (SGA) infants are known to be at increased risk of developing a number of metabolic alterations. Silver-Russell Syndrome (SRS) is a distinct subtype of the SGA population with poor fetal and postnatal growth. A proportion of these patients have duplication in the chromosome 11p15 locus which contains the IGF2 gene. This is known to be important in fetal growth with complex control mechanisms for expression including maternal imprinting and multiple promoters. It has recently been demonstrated that up to 30% of all SRS patients have undermethylation in the IGF2/H19 locus with associated reduced IGF2 expression. The hypothesis is that SRS is a result of IGF2 deficiency which is not necessarily secondary to the methylation abnormalities. The aim of the project is look at the methylation status of various differentially methylated regions in the IGF2-H19 locus using EBV transformed lymphocytes taken from patients enrolled in the NESTEGG study and to compare this with IGF2 expression. Methylation status will be examined using bisulphite treatment of DNA in conjunction with either product subcloning and sequencing or with pyrosequencing. IGF2 expression will be quantified using real-time TaqMan assay. An IGF2 ELISA assay will be used to compare protein expression to investigate translation of message. If IGF2 deficiency is more widespread compared to methylation abnormalities, alternative pathogenic mechanisms such as defective promoter function or abnormal histone acetylation and methylation will be investigated. If IGF2 deficiency is shown to be exclusive to those patients with methylation abnormalities, the IGF2 receptor epigenetics and function will be investigated further. Although poor fetal growth is known to have significant effects on cardiovascular risk in adulthood it remains a poorly understood and clinically heterogeneous phenomenon. This project aims to further understand the role that IGF2 and epigenetics may play in poor fetal and postnatal growth.
 
Description Additional Funding (MRC)
Amount £5,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 06/2009 
End 09/2009
 
Description Clinical Research Training Felllowship
Amount £100,000 (GBP)
Organisation Barts Charity 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2006 
End 09/2009
 
Description Clinical Research Training Felllowship (MRC)
Amount £12,100 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 09/2007 
End 09/2009
 
Description Small Grant Programme
Amount £7,000 (GBP)
Organisation Child Growth Foundation 
Sector Charity/Non Profit
Country United Kingdom
Start  
End 09/2009
 
Description Epigenetics of Silver-Russell Syndrome 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Participants in your research and patient groups
Results and Impact talk on genetics of Silver-Russell Syndrome aimed at lay audience

Patient recruitment
Year(s) Of Engagement Activity 2009
 
Description Patient Support Group Annual conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Participants in your research and patient groups
Results and Impact Description of current research and results at annual conference of child growth foundation in oral presentation as well as contribution to the foundation's newsletter

NA
Year(s) Of Engagement Activity 2008