The University of Southampton
University of Southampton Institutional Repository

Deletions and rearrangements of the H19/IGF2 enhancer region in patients with Silver-Russell syndrome and growth retardation

Deletions and rearrangements of the H19/IGF2 enhancer region in patients with Silver-Russell syndrome and growth retardation
Deletions and rearrangements of the H19/IGF2 enhancer region in patients with Silver-Russell syndrome and growth retardation
Silver–Russell syndrome (SRS) is characterised by prenatal and postnatal growth retardation, dysmorphic facial features, and body asymmetry. In 35–60% of SRS cases the paternally methylated imprinting control region (ICR) upstream of the H19 gene (H19-ICR) is hypomethylated, leading to downregulation of IGF2 and bi-allelic expression of H19. H19 and IGF2 are reciprocally imprinted genes on chromosome 11p15. The expression is regulated by the imprinted methylation of the ICR, which modulates the transcription of H19 and IGF2 facilitated by enhancers downstream of H19. A promoter element of IGF2, IGF2P0, is differentially methylated equivalently to the H19-ICR, though in a small number of SRS cases this association is disrupted—that is, hypomethylation affects either H19-ICR or IGF2P0.

Three pedigrees associated with hypomethylation of IGF2P0 in the probands are presented here, two with paternally derived deletions, and one with a balanced translocation of inferred paternal origin. They all have a breakpoint within the H19/IGF2 enhancer region. One proband has severe growth retardation, the others have SRS.

This is the first report of paternally derived structural chromosomal mutations in 11p15 causing SRS. These cases define a novel aetiology of the growth retardation in SRS, namely, dissociation of IGF2 from its enhancers.

0022-2593
308-311
Gronskov, Karen
14d6ffce-f137-4373-ab26-c466a712ecd8
Poole, Rebecca L.
d8fe00fa-9deb-4a34-a7d8-4b7f57ce82fa
Hahnemann, Johanne M.D.
62ac6788-908f-410b-a825-96cc9c91abc1
Thomson, Jennifer
3209adc8-4863-4f55-993d-494a92435549
Tumer, Zeynup
a21d902e-447e-48d9-a949-215713c0df44
Brondum-Nielsen, Karen
3104e138-0058-45dd-b26d-916d92b69e82
Murphy, Rinki
9b647919-6b97-48d3-b24d-d09c9be1afc1
Ravn, Kirstine
bff32894-253b-416c-a030-7ba2f0832a6c
Melchior, Linea
e8aafb77-3389-4807-ba13-a5e7dad15bd3
Dedic, Alma
d72a8b20-8b38-4909-a335-effeb1ffbfa7
Dolmer, Birgitte
23ea550f-4f9a-4a9c-920b-149fdc0e6974
Temple, I. Karen
d63e7c66-9fb0-46c8-855d-ee2607e6c226
Boonen, Susanne E.
635ea5a0-76e3-4b60-bd4e-b9dd8998022c
Mackay, Deborah J.G.
588a653e-9785-4a00-be71-4e547850ee4a
Gronskov, Karen
14d6ffce-f137-4373-ab26-c466a712ecd8
Poole, Rebecca L.
d8fe00fa-9deb-4a34-a7d8-4b7f57ce82fa
Hahnemann, Johanne M.D.
62ac6788-908f-410b-a825-96cc9c91abc1
Thomson, Jennifer
3209adc8-4863-4f55-993d-494a92435549
Tumer, Zeynup
a21d902e-447e-48d9-a949-215713c0df44
Brondum-Nielsen, Karen
3104e138-0058-45dd-b26d-916d92b69e82
Murphy, Rinki
9b647919-6b97-48d3-b24d-d09c9be1afc1
Ravn, Kirstine
bff32894-253b-416c-a030-7ba2f0832a6c
Melchior, Linea
e8aafb77-3389-4807-ba13-a5e7dad15bd3
Dedic, Alma
d72a8b20-8b38-4909-a335-effeb1ffbfa7
Dolmer, Birgitte
23ea550f-4f9a-4a9c-920b-149fdc0e6974
Temple, I. Karen
d63e7c66-9fb0-46c8-855d-ee2607e6c226
Boonen, Susanne E.
635ea5a0-76e3-4b60-bd4e-b9dd8998022c
Mackay, Deborah J.G.
588a653e-9785-4a00-be71-4e547850ee4a

Gronskov, Karen, Poole, Rebecca L., Hahnemann, Johanne M.D., Thomson, Jennifer, Tumer, Zeynup, Brondum-Nielsen, Karen, Murphy, Rinki, Ravn, Kirstine, Melchior, Linea, Dedic, Alma, Dolmer, Birgitte, Temple, I. Karen, Boonen, Susanne E. and Mackay, Deborah J.G. (2011) Deletions and rearrangements of the H19/IGF2 enhancer region in patients with Silver-Russell syndrome and growth retardation. Journal of Medical Genetics, 48 (5), 308-311. (doi:10.1136/jmg.2010.086504). (PMID:21278389)

Record type: Article

Abstract

Silver–Russell syndrome (SRS) is characterised by prenatal and postnatal growth retardation, dysmorphic facial features, and body asymmetry. In 35–60% of SRS cases the paternally methylated imprinting control region (ICR) upstream of the H19 gene (H19-ICR) is hypomethylated, leading to downregulation of IGF2 and bi-allelic expression of H19. H19 and IGF2 are reciprocally imprinted genes on chromosome 11p15. The expression is regulated by the imprinted methylation of the ICR, which modulates the transcription of H19 and IGF2 facilitated by enhancers downstream of H19. A promoter element of IGF2, IGF2P0, is differentially methylated equivalently to the H19-ICR, though in a small number of SRS cases this association is disrupted—that is, hypomethylation affects either H19-ICR or IGF2P0.

Three pedigrees associated with hypomethylation of IGF2P0 in the probands are presented here, two with paternally derived deletions, and one with a balanced translocation of inferred paternal origin. They all have a breakpoint within the H19/IGF2 enhancer region. One proband has severe growth retardation, the others have SRS.

This is the first report of paternally derived structural chromosomal mutations in 11p15 causing SRS. These cases define a novel aetiology of the growth retardation in SRS, namely, dissociation of IGF2 from its enhancers.

Full text not available from this repository.

More information

Accepted/In Press date: 28 January 2011
Published date: May 2011
Organisations: Human Genetics

Identifiers

Local EPrints ID: 175297
URI: http://eprints.soton.ac.uk/id/eprint/175297
ISSN: 0022-2593
PURE UUID: afacf032-af64-438a-9cbe-2ca2f4c12869
ORCID for I. Karen Temple: ORCID iD orcid.org/0000-0002-6045-1781
ORCID for Deborah J.G. Mackay: ORCID iD orcid.org/0000-0003-3088-4401

Catalogue record

Date deposited: 22 Feb 2011 13:22
Last modified: 19 Nov 2019 01:53

Export record

Altmetrics

Contributors

Author: Karen Gronskov
Author: Rebecca L. Poole
Author: Johanne M.D. Hahnemann
Author: Jennifer Thomson
Author: Zeynup Tumer
Author: Karen Brondum-Nielsen
Author: Rinki Murphy
Author: Kirstine Ravn
Author: Linea Melchior
Author: Alma Dedic
Author: Birgitte Dolmer
Author: I. Karen Temple ORCID iD
Author: Susanne E. Boonen

University divisions

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×