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Beckwith–Wiedemann syndrome caused by maternally inherited mutation of an OCT-binding motif in the IGF2/H19-imprinting control region, ICR1

Beckwith–Wiedemann syndrome caused by maternally inherited mutation of an OCT-binding motif in the IGF2/H19-imprinting control region, ICR1
Beckwith–Wiedemann syndrome caused by maternally inherited mutation of an OCT-binding motif in the IGF2/H19-imprinting control region, ICR1
The imprinted expression of the IGF2 and H19 genes is controlled by the imprinting control region 1 (ICR1) located at chromosome 11p15.5. DNA methylation defects involving ICR1 result in two growth disorders with opposite phenotypes: an overgrowth disorder, the Beckwith–Wiedemann syndrome (maternal ICR1 hypermethylation in 10% of BWS cases) and a growth retardation disorder, the Silver–Russell syndrome (paternal ICR1 loss of methylation in 60% of SRS cases). In familial BWS, hypermethylation of ICR1 has been found in association with microdeletion of repetitive DNA motifs within ICR1 that bind the zinc finger protein CTCF; but more recently, ICR1 point mutations were described in BWS pedigrees. We present a case report of two brothers with BWS and prolonged post-pubertal growth resulting in very large stature. A maternally inherited point mutation was identified in ICR1 in both brothers, which altered binding of OCT transcription factors. The same mutation was present on the paternally inherited allele of their unaffected mother. This is a second report of a point mutation causing ICR1 hypermethylation by altering an OCT-binding motif. The atypical growth phenotype of the brothers may be connected to the unusual underlying cause of their BWS.

1018-4813
240-243
Poole, Rebecca L.
d8fe00fa-9deb-4a34-a7d8-4b7f57ce82fa
Leith, Donald J.
1b53a304-6a50-4b0c-b3db-d79ee3683ace
Docherty, Louise E.
4accb565-e53b-400f-8d62-83935e2ae410
Shmela, Mansur E.
6cbe65f3-0bc4-4c36-8a06-cadebd83381a
Gicquel, Christine
08c848d3-7813-4c89-9cdb-15d46a3ea6a4
Splitt, Miranda
6075f764-5f19-4a5e-8567-aa65781226f6
Temple, I. Karen
d63e7c66-9fb0-46c8-855d-ee2607e6c226
Mackay, Deborah J.G.
588a653e-9785-4a00-be71-4e547850ee4a
Poole, Rebecca L.
d8fe00fa-9deb-4a34-a7d8-4b7f57ce82fa
Leith, Donald J.
1b53a304-6a50-4b0c-b3db-d79ee3683ace
Docherty, Louise E.
4accb565-e53b-400f-8d62-83935e2ae410
Shmela, Mansur E.
6cbe65f3-0bc4-4c36-8a06-cadebd83381a
Gicquel, Christine
08c848d3-7813-4c89-9cdb-15d46a3ea6a4
Splitt, Miranda
6075f764-5f19-4a5e-8567-aa65781226f6
Temple, I. Karen
d63e7c66-9fb0-46c8-855d-ee2607e6c226
Mackay, Deborah J.G.
588a653e-9785-4a00-be71-4e547850ee4a

Poole, Rebecca L., Leith, Donald J., Docherty, Louise E., Shmela, Mansur E., Gicquel, Christine, Splitt, Miranda, Temple, I. Karen and Mackay, Deborah J.G. (2012) Beckwith–Wiedemann syndrome caused by maternally inherited mutation of an OCT-binding motif in the IGF2/H19-imprinting control region, ICR1. European Journal of Human Genetics, 20 (2), 240-243. (doi:10.1038/ejhg.2011.166). (PMID:21863054)

Record type: Article

Abstract

The imprinted expression of the IGF2 and H19 genes is controlled by the imprinting control region 1 (ICR1) located at chromosome 11p15.5. DNA methylation defects involving ICR1 result in two growth disorders with opposite phenotypes: an overgrowth disorder, the Beckwith–Wiedemann syndrome (maternal ICR1 hypermethylation in 10% of BWS cases) and a growth retardation disorder, the Silver–Russell syndrome (paternal ICR1 loss of methylation in 60% of SRS cases). In familial BWS, hypermethylation of ICR1 has been found in association with microdeletion of repetitive DNA motifs within ICR1 that bind the zinc finger protein CTCF; but more recently, ICR1 point mutations were described in BWS pedigrees. We present a case report of two brothers with BWS and prolonged post-pubertal growth resulting in very large stature. A maternally inherited point mutation was identified in ICR1 in both brothers, which altered binding of OCT transcription factors. The same mutation was present on the paternally inherited allele of their unaffected mother. This is a second report of a point mutation causing ICR1 hypermethylation by altering an OCT-binding motif. The atypical growth phenotype of the brothers may be connected to the unusual underlying cause of their BWS.

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More information

Accepted/In Press date: 24 August 2011
Published date: February 2012
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 196107
URI: http://eprints.soton.ac.uk/id/eprint/196107
ISSN: 1018-4813
PURE UUID: 59cd7a85-1b3f-4684-bb63-5a2dd40ea4ab
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

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Date deposited: 05 Sep 2011 07:58
Last modified: 10 Dec 2019 01:51

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Contributors

Author: Rebecca L. Poole
Author: Donald J. Leith
Author: Louise E. Docherty
Author: Mansur E. Shmela
Author: Christine Gicquel
Author: Miranda Splitt
Author: I. Karen Temple ORCID iD

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