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Hypomethylation at multiple maternally methylated imprinted regions including PLAGL1 and GNAS loci in Beckwith-Wiedemann syndrome

Hypomethylation at multiple maternally methylated imprinted regions including PLAGL1 and GNAS loci in Beckwith-Wiedemann syndrome
Hypomethylation at multiple maternally methylated imprinted regions including PLAGL1 and GNAS loci in Beckwith-Wiedemann syndrome
Genomic imprinting is an epigenetic phenomenon restricting gene expression in a manner dependent on parent of origin. Imprinted gene products are critical regulators of growth and development, and imprinting disorders are associated with both genetic and epigenetic mutations, including disruption of DNA methylation within the imprinting control regions (ICRs) of these genes. It was recently reported that some patients with imprinting disorders have a more generalised imprinting defect, with hypomethylation at a range of maternally methylated ICRs. We report a cohort of 149 patients with a clinical diagnosis of Beckwith–Wiedemann syndrome (BWS), including 81 with maternal hypomethylation of the KCNQ1OT1 ICR. Methylation analysis of 11 ICRs in these patients showed that hypomethylation affecting multiple imprinted loci was restricted to 17 patients with hypomethylation of the KCNQ1OT1 ICR, and involved only maternally methylated loci. Both partial and complete hypomethylation was demonstrated in these cases, suggesting a possible postzygotic origin of a mosaic imprinting error. Some ICRs, including the PLAGL1 and GNAS/NESPAS ICRs implicated in the aetiology of transient neonatal diabetes and pseudohypoparathyroidism type 1b, respectively, were more frequently affected than others. Although we did not find any evidence for mutation of the candidate gene DNMT3L, these results support the hypotheses that trans-acting factors affect the somatic maintenance of imprinting at multiple maternally methylated loci and that the clinical presentation of these complex cases may reflect the loci and tissues affected with the epigenetic abnormalities
beckwith-wiedemann syndrome (BWS), KCNQ1OT1, methylation, imprinting, imprinting disorder, hypomethylation of imprinted loci (HIL)
1018-4813
611-619
Bliek, Jet
71a7b9b1-a591-491d-832a-9b670ef05195
Verde, Gaetano
9887436f-11b4-47ad-8705-5cc19f28d673
Callaway, Jonathan
6ed89cc7-2dfe-4e63-82cb-90564bf85baa
Maas, Saskia M.
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De Crescenzo, Agostina
d5c12a55-5c14-47bd-9edf-f7725abb5b7a
Sparago, Angela
1ee5fe1e-3bbb-4544-9c20-08f035ed7fe0
Cerrato, Flavia
706b4aba-5ac6-48dd-800b-e9f13b685702
Russo, Silvia
c58120ef-376c-49f9-be98-0b72bd45d525
Ferraiuolo, Serena
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Rinaldi, Maria Michela
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Fischetto, Rita
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Lalatta, Faustina
cc4c4756-db64-468f-99f8-22e4e808e9a7
Giordano, Lucio
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Ferrari, Paolo
39b440e1-4f6a-4968-bd82-ecee14c271bf
Cubellis, Mara Vittoria
e8369d4d-a08e-49bb-a852-a5d863858969
Larizza, Lidia
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Temple, I. Karen
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Mannens, Marcel M.A.M.
bb288561-4e69-4243-956b-894269170cd1
Mackay, Deborah J.G.
588a653e-9785-4a00-be71-4e547850ee4a
Riccio, Andrea
0ac5879d-b47d-4c9f-beaf-ba15c0794954
Bliek, Jet
71a7b9b1-a591-491d-832a-9b670ef05195
Verde, Gaetano
9887436f-11b4-47ad-8705-5cc19f28d673
Callaway, Jonathan
6ed89cc7-2dfe-4e63-82cb-90564bf85baa
Maas, Saskia M.
5c29928c-22b8-4d42-8a5a-831ba536d809
De Crescenzo, Agostina
d5c12a55-5c14-47bd-9edf-f7725abb5b7a
Sparago, Angela
1ee5fe1e-3bbb-4544-9c20-08f035ed7fe0
Cerrato, Flavia
706b4aba-5ac6-48dd-800b-e9f13b685702
Russo, Silvia
c58120ef-376c-49f9-be98-0b72bd45d525
Ferraiuolo, Serena
3fb25871-8061-47cc-8cac-e0debbd36676
Rinaldi, Maria Michela
4f146524-3e70-4320-beba-da31ad123a3a
Fischetto, Rita
0a146d0c-9e4e-4ba8-858c-38f8490fc6d1
Lalatta, Faustina
cc4c4756-db64-468f-99f8-22e4e808e9a7
Giordano, Lucio
57f06c8f-d42c-40ae-b394-8eff80fb1c8f
Ferrari, Paolo
39b440e1-4f6a-4968-bd82-ecee14c271bf
Cubellis, Mara Vittoria
e8369d4d-a08e-49bb-a852-a5d863858969
Larizza, Lidia
6517e194-bf5b-470f-bfc6-6efbac4e8cca
Temple, I. Karen
d63e7c66-9fb0-46c8-855d-ee2607e6c226
Mannens, Marcel M.A.M.
bb288561-4e69-4243-956b-894269170cd1
Mackay, Deborah J.G.
588a653e-9785-4a00-be71-4e547850ee4a
Riccio, Andrea
0ac5879d-b47d-4c9f-beaf-ba15c0794954

Bliek, Jet, Verde, Gaetano, Callaway, Jonathan, Maas, Saskia M., De Crescenzo, Agostina, Sparago, Angela, Cerrato, Flavia, Russo, Silvia, Ferraiuolo, Serena, Rinaldi, Maria Michela, Fischetto, Rita, Lalatta, Faustina, Giordano, Lucio, Ferrari, Paolo, Cubellis, Mara Vittoria, Larizza, Lidia, Temple, I. Karen, Mannens, Marcel M.A.M., Mackay, Deborah J.G. and Riccio, Andrea (2009) Hypomethylation at multiple maternally methylated imprinted regions including PLAGL1 and GNAS loci in Beckwith-Wiedemann syndrome. European Journal of Human Genetics, 17 (5), 611-619. (doi:10.1038/ejhg.2008.233).

Record type: Article

Abstract

Genomic imprinting is an epigenetic phenomenon restricting gene expression in a manner dependent on parent of origin. Imprinted gene products are critical regulators of growth and development, and imprinting disorders are associated with both genetic and epigenetic mutations, including disruption of DNA methylation within the imprinting control regions (ICRs) of these genes. It was recently reported that some patients with imprinting disorders have a more generalised imprinting defect, with hypomethylation at a range of maternally methylated ICRs. We report a cohort of 149 patients with a clinical diagnosis of Beckwith–Wiedemann syndrome (BWS), including 81 with maternal hypomethylation of the KCNQ1OT1 ICR. Methylation analysis of 11 ICRs in these patients showed that hypomethylation affecting multiple imprinted loci was restricted to 17 patients with hypomethylation of the KCNQ1OT1 ICR, and involved only maternally methylated loci. Both partial and complete hypomethylation was demonstrated in these cases, suggesting a possible postzygotic origin of a mosaic imprinting error. Some ICRs, including the PLAGL1 and GNAS/NESPAS ICRs implicated in the aetiology of transient neonatal diabetes and pseudohypoparathyroidism type 1b, respectively, were more frequently affected than others. Although we did not find any evidence for mutation of the candidate gene DNMT3L, these results support the hypotheses that trans-acting factors affect the somatic maintenance of imprinting at multiple maternally methylated loci and that the clinical presentation of these complex cases may reflect the loci and tissues affected with the epigenetic abnormalities

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More information

Published date: 2009
Keywords: beckwith-wiedemann syndrome (BWS), KCNQ1OT1, methylation, imprinting, imprinting disorder, hypomethylation of imprinted loci (HIL)

Identifiers

Local EPrints ID: 69517
URI: https://eprints.soton.ac.uk/id/eprint/69517
ISSN: 1018-4813
PURE UUID: b433dd92-651f-4a5a-9ee6-027e8ae49af4
ORCID for Deborah J.G. Mackay: ORCID iD orcid.org/0000-0003-3088-4401

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Date deposited: 18 Nov 2009
Last modified: 06 Jun 2018 12:54

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Contributors

Author: Jet Bliek
Author: Gaetano Verde
Author: Jonathan Callaway
Author: Saskia M. Maas
Author: Agostina De Crescenzo
Author: Angela Sparago
Author: Flavia Cerrato
Author: Silvia Russo
Author: Serena Ferraiuolo
Author: Maria Michela Rinaldi
Author: Rita Fischetto
Author: Faustina Lalatta
Author: Lucio Giordano
Author: Paolo Ferrari
Author: Mara Vittoria Cubellis
Author: Lidia Larizza
Author: I. Karen Temple
Author: Marcel M.A.M. Mannens
Author: Andrea Riccio

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