YEARS

2007-2009

AUTHORS

Renuka Dias

TITLE

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

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.

FUNDED PUBLICATIONS

  • Diagnosis and treatment of Cushing's disease in children.
  • Familial isolated primary pigmented nodular adrenocortical disease associated with a novel low penetrance PRKAR1A gene splice site mutation.
  • Multiple segmental uniparental disomy associated with abnormal DNA methylation of imprinted Loci in silver-russell syndrome.
  • Diagnosis, management and therapeutic outcome in prepubertal Cushing's disease.
  • Isolated Addison's disease is unlikely to be caused by mutations in MC2R, MRAP or STAR, three genes responsible for familial glucocorticoid deficiency.
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    25 TRIPLES      17 PREDICATES      26 URIs      10 LITERALS

    Subject Predicate Object
    1 grants:c741f014f7e20fdd3bd510aac2c16693 sg: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.
    2 sg:endYear 2009
    3 sg:fundingAmount 131628.0
    4 sg:fundingCurrency GBP
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    17 sg:language English
    18 sg:license http://scigraph.springernature.com/explorer/license/
    19 Contains UK public sector information licensed under the Open Government Licence v2.0 (http://www.nationalarchives.gov.uk/doc/open-government-licence/version/2/).
    20 sg:scigraphId c741f014f7e20fdd3bd510aac2c16693
    21 sg:startYear 2007
    22 sg:title Epigenetic Analysis of the IGF2/H19 locus in the NESTEGGG Small for Gestational Age Population
    23 sg:webpage http://gtr.rcuk.ac.uk/project/B5782126-92A1-44B7-A62E-7A21BFF1C015
    24 rdf:type sg:Grant
    25 rdfs:label Grant: Epigenetic Analysis of the IGF2/H19 locus in the NESTEGGG Small for Gestational Age Population
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